%PDF-1.3 1 0 obj << /Type /Catalog /Outlines 2 0 R /Pages 3 0 R >> endobj 2 0 obj << /Type /Outlines /Count 0 >> endobj 3 0 obj << /Type /Pages /Kids [6 0 R 201 0 R 215 0 R 230 0 R 247 0 R 316 0 R 468 0 R 470 0 R ] /Count 8 /Resources << /ProcSet 4 0 R /Font << /F1 8 0 R /F2 9 0 R /F3 10 0 R /F4 11 0 R /F5 12 0 R /F6 232 0 R >> /XObject << /I1 13 0 R /I2 14 0 R /I3 221 0 R /I4 235 0 R /I5 238 0 R /I6 251 0 R >> >> /MediaBox [0.000 0.000 612.000 792.000] >> endobj 4 0 obj [/PDF /Text /ImageC ] endobj 5 0 obj << /Creator (DOMPDF) /CreationDate (D:20180721143953+00'00') /ModDate (D:20180721143953+00'00') /Title (Baroreceptor reflex dysfunction in the BACHD mouse model of Huntingtons disease. 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Schroeder)] TJ ET 0.271 0.267 0.267 rg BT 122.707 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 128.128 663.247 Td /F1 9.8 Tf [(Dawn H Loh)] TJ ET 0.271 0.267 0.267 rg BT 181.772 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 187.193 663.247 Td /F1 9.8 Tf [(Maria C. Jordan)] TJ ET 0.271 0.267 0.267 rg BT 256.545 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 261.966 663.247 Td /F1 9.8 Tf [(Kenneth P. Roos)] TJ ET 0.271 0.267 0.267 rg BT 335.676 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 341.097 663.247 Td /F1 9.8 Tf [(Christopher S. Colwell)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Schroeder AM, Loh DH, Jordan MC, Roos KP, Colwell CS. Baroreceptor reflex dysfunction in the BACHD mouse model of )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Huntingtons disease.. PLOS Currents Huntington Disease. 2011 Sep 28 . Edition 1. doi: 10.1371/currents.RRN1266.)] TJ ET q 15.000 19.411 577.500 617.646 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Huntingtons disease is a progressive, neurodegenerative disorder that presents with a triad of clinical symptoms, which include )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(movement abnormalities, emotional disturbance and cognitive impairment. Recent studies reported dysfunction of the )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(autonomic nervous system in Huntingtons disease patients, which may contribute to the increased incidence of cardiovascular )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(events in this patient population that often leads to death. We measured the baroreceptor reflex, a process dependent on proper )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(autonomic function, in the BACHD mouse model of Huntingtons disease. We found a blunted response of the baroreceptor )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(reflex as well as significantly higher daytime blood pressure in BACHD mice compared to WT controls, which are both )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(indications of autonomic dysfunction. BACHD mice had increased heart weight to tibia length ratios at 7 and 12 mo of age )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(suggesting hypertrophic changes of the heart, which we speculate is a response to the increased blood pressure and aberrant )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(baroreceptor reflex. Despite these structural changes, the hearts of BACHD mice continue to function normally as assessed by )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(echocardiographic analysis. Studies of autonomic and cardiovascular function in BACHD mice may help elucidate the )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(pathophysiology of Huntingtons disease and aid in the development of clinical strategies to offset the incidence of fatal )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(cardiovascular events in the Huntingtons disease patient population.)] TJ ET BT 26.250 422.826 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 402.872 Td /F1 9.8 Tf [(Huntingtons disease is an autosomal dominant neurodegenerative disorder characterized by apoptotic death of neurons in )] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(various brain regions that result in the progressive deterioration of movement, cognitive abilities and behavioral control )] TJ ET 0.267 0.267 0.267 rg BT 538.340 390.967 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 549.182 390.967 Td /F1 9.8 Tf [( . In )] TJ ET BT 26.250 379.062 Td /F1 9.8 Tf [(addition, Huntingtons disease patients are at increased risk for cardiovascular morbidity and are likely to succumb to )] TJ ET BT 26.250 367.158 Td /F1 9.8 Tf [(cardiovascular events)] TJ ET 0.267 0.267 0.267 rg BT 120.532 367.158 Td /F1 9.8 Tf [([2][3])] TJ ET BT 142.216 367.158 Td /F1 9.8 Tf [( .)] TJ ET 0.271 0.267 0.267 rg BT 147.637 367.158 Td /F1 9.8 Tf [( Recent studies reported that individuals with Huntingtons disease display aberrant changes in the )] TJ ET BT 26.250 355.253 Td /F1 9.8 Tf [(autonomic nervous system \(ANS\) that are detected even before the onset of other Huntingtons disease symptoms. )] TJ ET BT 26.250 343.348 Td /F1 9.8 Tf [(Misregulation of both the sympathetic and parasympathetic branches of the ANS have been described, whereby the )] TJ ET BT 26.250 331.443 Td /F1 9.8 Tf [(sympathetic nervous system \(SNS\) becomes hyperactive in presymptomatic Huntingtons disease patients while the activity of )] TJ ET BT 26.250 319.539 Td /F1 9.8 Tf [(the parasympathetic nervous system \(PNS\) progressively declines )] TJ ET 0.267 0.267 0.267 rg BT 315.591 319.539 Td /F1 9.8 Tf [([4])] TJ ET BT 326.433 319.539 Td /F1 9.8 Tf [([5])] TJ ET BT 337.275 319.539 Td /F1 9.8 Tf [([6])] TJ ET BT 348.117 319.539 Td /F1 9.8 Tf [( [7])] TJ ET BT 361.669 319.539 Td /F1 9.8 Tf [([8] )] TJ ET BT 375.222 319.539 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 386.064 319.539 Td /F1 9.8 Tf [( . These types of changes in the ANS are )] TJ ET BT 26.250 307.634 Td /F1 9.8 Tf [(associated with poor prognosis for serious cardiovascular events that many times lead to death )] TJ ET 0.267 0.267 0.267 rg BT 438.636 307.634 Td /F1 9.8 Tf [([10])] TJ ET BT 454.899 307.634 Td /F1 9.8 Tf [([11])] TJ ET BT 471.162 307.634 Td /F1 9.8 Tf [([12])] TJ ET 0.271 0.267 0.267 rg BT 487.425 307.634 Td /F1 9.8 Tf [( . Further study of )] TJ ET BT 26.250 295.729 Td /F1 9.8 Tf [(the cardiovascular system as well as autonomic activity in Huntingtons disease patients may help in better understanding )] TJ ET BT 26.250 283.824 Td /F1 9.8 Tf [(disease pathology that may lead to clinical strategies to help curb the number of cardiovascular events in the patient population.)] TJ ET BT 26.250 264.420 Td /F1 9.8 Tf [(Many mouse models of Huntingtons disease have been created to recapitulate the various characteristics of the disease to )] TJ ET BT 26.250 252.515 Td /F1 9.8 Tf [(allow for mechanistic investigations. In some of the models, a cardiovascular phenotype has been documented )] TJ ET 0.267 0.267 0.267 rg BT 506.389 252.515 Td /F1 9.8 Tf [([13] )] TJ ET BT 525.362 252.515 Td /F1 9.8 Tf [([14])] TJ ET BT 541.625 252.515 Td /F1 9.8 Tf [( [15])] TJ ET BT 560.599 252.515 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 26.250 240.610 Td /F1 9.8 Tf [(. We are particularly interested in the BACHD model: a transgenic mouse that expresses the expanded form of the human )] TJ ET BT 554.066 240.610 Td /F5 9.8 Tf [(htt)] TJ ET BT 26.250 228.705 Td /F1 9.8 Tf [(gene that encode 97 stable glutamine repeats )] TJ ET 0.267 0.267 0.267 rg BT 226.788 228.705 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 243.051 228.705 Td /F1 9.8 Tf [( . BACHD mice develop HTT aggregates similar to adult onset Huntingtons )] TJ ET BT 26.250 216.801 Td /F1 9.8 Tf [(disease and display progressive motor deficits. There is also evidence for circadian deficits along with indications that the ANS )] TJ ET BT 26.250 204.896 Td /F1 9.8 Tf [(is affected as measured by heart rate variability)] TJ ET 0.267 0.267 0.267 rg BT 230.542 204.896 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 249.515 204.896 Td /F1 9.8 Tf [( . Further investigations of this mouse model may help elucidate the )] TJ ET BT 26.250 192.991 Td /F1 9.8 Tf [(autonomic and cardiovascular pathology in Huntingtons disease.)] TJ ET BT 26.250 173.586 Td /F1 9.8 Tf [(In this study, we investigated the cardiovascular phenotype in BACHD mice and report echocardiography, heart morphology )] TJ ET BT 26.250 161.682 Td /F1 9.8 Tf [(and baroreceptor reflex properties in middle-aged mice. The baroreceptor reflex is responsible for the overall tone as well as the )] TJ ET BT 26.250 149.777 Td /F1 9.8 Tf [(acute moment-to-moment regulation of blood pressure \(BP\) by modulating cardiac output and total peripheral resistance )] TJ ET 0.267 0.267 0.267 rg BT 547.017 149.777 Td /F1 9.8 Tf [([18])] TJ ET BT 26.250 137.872 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 42.513 137.872 Td /F1 9.8 Tf [( . The central autonomic network, which includes the nucleus tractus solitarius \(NTS\) and other nuclei, receive and integrate )] TJ ET BT 26.250 125.967 Td /F1 9.8 Tf [(BP information from baroreceptor cells located in the carotid artery and aortic arch. The system responds by modulating )] TJ ET BT 26.250 114.063 Td /F1 9.8 Tf [(autonomic outflow to various tissues of the body such as the heart, blood vessels and adrenal glands, in order to adjust BP )] TJ ET BT 26.250 102.158 Td /F1 9.8 Tf [(accordingly)] TJ ET 0.267 0.267 0.267 rg BT 75.556 102.158 Td /F1 9.8 Tf [( [19])] TJ ET 0.271 0.267 0.267 rg BT 94.529 102.158 Td /F1 9.8 Tf [( . Dysregulation of this reflex in the long run, may lead to detrimental consequences on the cardiovascular )] TJ ET BT 26.250 90.253 Td /F1 9.8 Tf [(system )] TJ ET 0.267 0.267 0.267 rg BT 59.839 90.253 Td /F1 9.8 Tf [([20] )] TJ ET 0.271 0.267 0.267 rg BT 78.812 90.253 Td /F1 9.8 Tf [(. Effects on the heart can be assessed using echocardiography and morphometry measurements, which look for )] TJ ET BT 26.250 78.348 Td /F1 9.8 Tf [(changes in heart function and structure, respectively. In our study, we find evidence for abnormal heart morphometry, changes )] TJ ET BT 26.250 66.444 Td /F1 9.8 Tf [(in baseline BP, as well as a dysfunctional baroreceptor reflex response that would suggest dysregulation by the ANS.)] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Baroreceptor reflex dysfunction in the BACHD mouse model of )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Huntingtons disease.)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(September 28, 2011)] TJ ET BT 97.592 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 102.467 675.088 Td /F3 9.8 Tf [(Pathogenic Mechanism)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Analyne M. Schroeder)] TJ ET 0.271 0.267 0.267 rg BT 122.707 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 128.128 663.247 Td /F1 9.8 Tf [(Dawn H Loh)] TJ ET 0.271 0.267 0.267 rg BT 181.772 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 187.193 663.247 Td /F1 9.8 Tf [(Maria C. Jordan)] TJ ET 0.271 0.267 0.267 rg BT 256.545 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 261.966 663.247 Td /F1 9.8 Tf [(Kenneth P. Roos)] TJ ET 0.271 0.267 0.267 rg BT 335.676 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 341.097 663.247 Td /F1 9.8 Tf [(Christopher S. Colwell)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Schroeder AM, Loh DH, Jordan MC, Roos KP, Colwell CS. Baroreceptor reflex dysfunction in the BACHD mouse model of )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Huntingtons disease.. PLOS Currents Huntington Disease. 2011 Sep 28 . Edition 1. doi: 10.1371/currents.RRN1266.)] TJ ET q 15.000 19.411 577.500 617.646 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Huntingtons disease is a progressive, neurodegenerative disorder that presents with a triad of clinical symptoms, which include )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(movement abnormalities, emotional disturbance and cognitive impairment. Recent studies reported dysfunction of the )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(autonomic nervous system in Huntingtons disease patients, which may contribute to the increased incidence of cardiovascular )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(events in this patient population that often leads to death. We measured the baroreceptor reflex, a process dependent on proper )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(autonomic function, in the BACHD mouse model of Huntingtons disease. We found a blunted response of the baroreceptor )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(reflex as well as significantly higher daytime blood pressure in BACHD mice compared to WT controls, which are both )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(indications of autonomic dysfunction. BACHD mice had increased heart weight to tibia length ratios at 7 and 12 mo of age )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(suggesting hypertrophic changes of the heart, which we speculate is a response to the increased blood pressure and aberrant )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(baroreceptor reflex. Despite these structural changes, the hearts of BACHD mice continue to function normally as assessed by )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(echocardiographic analysis. Studies of autonomic and cardiovascular function in BACHD mice may help elucidate the )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(pathophysiology of Huntingtons disease and aid in the development of clinical strategies to offset the incidence of fatal )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(cardiovascular events in the Huntingtons disease patient population.)] TJ ET BT 26.250 422.826 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 402.872 Td /F1 9.8 Tf [(Huntingtons disease is an autosomal dominant neurodegenerative disorder characterized by apoptotic death of neurons in )] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(various brain regions that result in the progressive deterioration of movement, cognitive abilities and behavioral control )] TJ ET 0.267 0.267 0.267 rg BT 538.340 390.967 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 549.182 390.967 Td /F1 9.8 Tf [( . In )] TJ ET BT 26.250 379.062 Td /F1 9.8 Tf [(addition, Huntingtons disease patients are at increased risk for cardiovascular morbidity and are likely to succumb to )] TJ ET BT 26.250 367.158 Td /F1 9.8 Tf [(cardiovascular events)] TJ ET 0.267 0.267 0.267 rg BT 120.532 367.158 Td /F1 9.8 Tf [([2][3])] TJ ET BT 142.216 367.158 Td /F1 9.8 Tf [( .)] TJ ET 0.271 0.267 0.267 rg BT 147.637 367.158 Td /F1 9.8 Tf [( Recent studies reported that individuals with Huntingtons disease display aberrant changes in the )] TJ ET BT 26.250 355.253 Td /F1 9.8 Tf [(autonomic nervous system \(ANS\) that are detected even before the onset of other Huntingtons disease symptoms. )] TJ ET BT 26.250 343.348 Td /F1 9.8 Tf [(Misregulation of both the sympathetic and parasympathetic branches of the ANS have been described, whereby the )] TJ ET BT 26.250 331.443 Td /F1 9.8 Tf [(sympathetic nervous system \(SNS\) becomes hyperactive in presymptomatic Huntingtons disease patients while the activity of )] TJ ET BT 26.250 319.539 Td /F1 9.8 Tf [(the parasympathetic nervous system \(PNS\) progressively declines )] TJ ET 0.267 0.267 0.267 rg BT 315.591 319.539 Td /F1 9.8 Tf [([4])] TJ ET BT 326.433 319.539 Td /F1 9.8 Tf [([5])] TJ ET BT 337.275 319.539 Td /F1 9.8 Tf [([6])] TJ ET BT 348.117 319.539 Td /F1 9.8 Tf [( [7])] TJ ET BT 361.669 319.539 Td /F1 9.8 Tf [([8] )] TJ ET BT 375.222 319.539 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 386.064 319.539 Td /F1 9.8 Tf [( . These types of changes in the ANS are )] TJ ET BT 26.250 307.634 Td /F1 9.8 Tf [(associated with poor prognosis for serious cardiovascular events that many times lead to death )] TJ ET 0.267 0.267 0.267 rg BT 438.636 307.634 Td /F1 9.8 Tf [([10])] TJ ET BT 454.899 307.634 Td /F1 9.8 Tf [([11])] TJ ET BT 471.162 307.634 Td /F1 9.8 Tf [([12])] TJ ET 0.271 0.267 0.267 rg BT 487.425 307.634 Td /F1 9.8 Tf [( . Further study of )] TJ ET BT 26.250 295.729 Td /F1 9.8 Tf [(the cardiovascular system as well as autonomic activity in Huntingtons disease patients may help in better understanding )] TJ ET BT 26.250 283.824 Td /F1 9.8 Tf [(disease pathology that may lead to clinical strategies to help curb the number of cardiovascular events in the patient population.)] TJ ET BT 26.250 264.420 Td /F1 9.8 Tf [(Many mouse models of Huntingtons disease have been created to recapitulate the various characteristics of the disease to )] TJ ET BT 26.250 252.515 Td /F1 9.8 Tf [(allow for mechanistic investigations. In some of the models, a cardiovascular phenotype has been documented )] TJ ET 0.267 0.267 0.267 rg BT 506.389 252.515 Td /F1 9.8 Tf [([13] )] TJ ET BT 525.362 252.515 Td /F1 9.8 Tf [([14])] TJ ET BT 541.625 252.515 Td /F1 9.8 Tf [( [15])] TJ ET BT 560.599 252.515 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 26.250 240.610 Td /F1 9.8 Tf [(. We are particularly interested in the BACHD model: a transgenic mouse that expresses the expanded form of the human )] TJ ET BT 554.066 240.610 Td /F5 9.8 Tf [(htt)] TJ ET BT 26.250 228.705 Td /F1 9.8 Tf [(gene that encode 97 stable glutamine repeats )] TJ ET 0.267 0.267 0.267 rg BT 226.788 228.705 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 243.051 228.705 Td /F1 9.8 Tf [( . BACHD mice develop HTT aggregates similar to adult onset Huntingtons )] TJ ET BT 26.250 216.801 Td /F1 9.8 Tf [(disease and display progressive motor deficits. There is also evidence for circadian deficits along with indications that the ANS )] TJ ET BT 26.250 204.896 Td /F1 9.8 Tf [(is affected as measured by heart rate variability)] TJ ET 0.267 0.267 0.267 rg BT 230.542 204.896 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 249.515 204.896 Td /F1 9.8 Tf [( . Further investigations of this mouse model may help elucidate the )] TJ ET BT 26.250 192.991 Td /F1 9.8 Tf [(autonomic and cardiovascular pathology in Huntingtons disease.)] TJ ET BT 26.250 173.586 Td /F1 9.8 Tf [(In this study, we investigated the cardiovascular phenotype in BACHD mice and report echocardiography, heart morphology )] TJ ET BT 26.250 161.682 Td /F1 9.8 Tf [(and baroreceptor reflex properties in middle-aged mice. The baroreceptor reflex is responsible for the overall tone as well as the )] TJ ET BT 26.250 149.777 Td /F1 9.8 Tf [(acute moment-to-moment regulation of blood pressure \(BP\) by modulating cardiac output and total peripheral resistance )] TJ ET 0.267 0.267 0.267 rg BT 547.017 149.777 Td /F1 9.8 Tf [([18])] TJ ET BT 26.250 137.872 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 42.513 137.872 Td /F1 9.8 Tf [( . The central autonomic network, which includes the nucleus tractus solitarius \(NTS\) and other nuclei, receive and integrate )] TJ ET BT 26.250 125.967 Td /F1 9.8 Tf [(BP information from baroreceptor cells located in the carotid artery and aortic arch. The system responds by modulating )] TJ ET BT 26.250 114.063 Td /F1 9.8 Tf [(autonomic outflow to various tissues of the body such as the heart, blood vessels and adrenal glands, in order to adjust BP )] TJ ET BT 26.250 102.158 Td /F1 9.8 Tf [(accordingly)] TJ ET 0.267 0.267 0.267 rg BT 75.556 102.158 Td /F1 9.8 Tf [( [19])] TJ ET 0.271 0.267 0.267 rg BT 94.529 102.158 Td /F1 9.8 Tf [( . Dysregulation of this reflex in the long run, may lead to detrimental consequences on the cardiovascular )] TJ ET BT 26.250 90.253 Td /F1 9.8 Tf [(system )] TJ ET 0.267 0.267 0.267 rg BT 59.839 90.253 Td /F1 9.8 Tf [([20] )] TJ ET 0.271 0.267 0.267 rg BT 78.812 90.253 Td /F1 9.8 Tf [(. Effects on the heart can be assessed using echocardiography and morphometry measurements, which look for )] TJ ET BT 26.250 78.348 Td /F1 9.8 Tf [(changes in heart function and structure, respectively. In our study, we find evidence for abnormal heart morphometry, changes )] TJ ET BT 26.250 66.444 Td /F1 9.8 Tf [(in baseline BP, as well as a dysfunctional baroreceptor reflex response that would suggest dysregulation by the ANS.)] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Baroreceptor reflex dysfunction in the BACHD mouse model of )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Huntingtons disease.)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(September 28, 2011)] TJ ET BT 97.592 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 102.467 675.088 Td /F3 9.8 Tf [(Pathogenic Mechanism)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Analyne M. Schroeder)] TJ ET 0.271 0.267 0.267 rg BT 122.707 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 128.128 663.247 Td /F1 9.8 Tf [(Dawn H Loh)] TJ ET 0.271 0.267 0.267 rg BT 181.772 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 187.193 663.247 Td /F1 9.8 Tf [(Maria C. Jordan)] TJ ET 0.271 0.267 0.267 rg BT 256.545 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 261.966 663.247 Td /F1 9.8 Tf [(Kenneth P. Roos)] TJ ET 0.271 0.267 0.267 rg BT 335.676 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 341.097 663.247 Td /F1 9.8 Tf [(Christopher S. Colwell)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Schroeder AM, Loh DH, Jordan MC, Roos KP, Colwell CS. Baroreceptor reflex dysfunction in the BACHD mouse model of )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Huntingtons disease.. PLOS Currents Huntington Disease. 2011 Sep 28 . Edition 1. doi: 10.1371/currents.RRN1266.)] TJ ET q 15.000 19.411 577.500 617.646 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Huntingtons disease is a progressive, neurodegenerative disorder that presents with a triad of clinical symptoms, which include )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(movement abnormalities, emotional disturbance and cognitive impairment. Recent studies reported dysfunction of the )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(autonomic nervous system in Huntingtons disease patients, which may contribute to the increased incidence of cardiovascular )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(events in this patient population that often leads to death. We measured the baroreceptor reflex, a process dependent on proper )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(autonomic function, in the BACHD mouse model of Huntingtons disease. We found a blunted response of the baroreceptor )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(reflex as well as significantly higher daytime blood pressure in BACHD mice compared to WT controls, which are both )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(indications of autonomic dysfunction. BACHD mice had increased heart weight to tibia length ratios at 7 and 12 mo of age )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(suggesting hypertrophic changes of the heart, which we speculate is a response to the increased blood pressure and aberrant )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(baroreceptor reflex. Despite these structural changes, the hearts of BACHD mice continue to function normally as assessed by )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(echocardiographic analysis. Studies of autonomic and cardiovascular function in BACHD mice may help elucidate the )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(pathophysiology of Huntingtons disease and aid in the development of clinical strategies to offset the incidence of fatal )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(cardiovascular events in the Huntingtons disease patient population.)] TJ ET BT 26.250 422.826 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 402.872 Td /F1 9.8 Tf [(Huntingtons disease is an autosomal dominant neurodegenerative disorder characterized by apoptotic death of neurons in )] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(various brain regions that result in the progressive deterioration of movement, cognitive abilities and behavioral control )] TJ ET 0.267 0.267 0.267 rg BT 538.340 390.967 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 549.182 390.967 Td /F1 9.8 Tf [( . In )] TJ ET BT 26.250 379.062 Td /F1 9.8 Tf [(addition, Huntingtons disease patients are at increased risk for cardiovascular morbidity and are likely to succumb to )] TJ ET BT 26.250 367.158 Td /F1 9.8 Tf [(cardiovascular events)] TJ ET 0.267 0.267 0.267 rg BT 120.532 367.158 Td /F1 9.8 Tf [([2][3])] TJ ET BT 142.216 367.158 Td /F1 9.8 Tf [( .)] TJ ET 0.271 0.267 0.267 rg BT 147.637 367.158 Td /F1 9.8 Tf [( Recent studies reported that individuals with Huntingtons disease display aberrant changes in the )] TJ ET BT 26.250 355.253 Td /F1 9.8 Tf [(autonomic nervous system \(ANS\) that are detected even before the onset of other Huntingtons disease symptoms. )] TJ ET BT 26.250 343.348 Td /F1 9.8 Tf [(Misregulation of both the sympathetic and parasympathetic branches of the ANS have been described, whereby the )] TJ ET BT 26.250 331.443 Td /F1 9.8 Tf [(sympathetic nervous system \(SNS\) becomes hyperactive in presymptomatic Huntingtons disease patients while the activity of )] TJ ET BT 26.250 319.539 Td /F1 9.8 Tf [(the parasympathetic nervous system \(PNS\) progressively declines )] TJ ET 0.267 0.267 0.267 rg BT 315.591 319.539 Td /F1 9.8 Tf [([4])] TJ ET BT 326.433 319.539 Td /F1 9.8 Tf [([5])] TJ ET BT 337.275 319.539 Td /F1 9.8 Tf [([6])] TJ ET BT 348.117 319.539 Td /F1 9.8 Tf [( [7])] TJ ET BT 361.669 319.539 Td /F1 9.8 Tf [([8] )] TJ ET BT 375.222 319.539 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 386.064 319.539 Td /F1 9.8 Tf [( . These types of changes in the ANS are )] TJ ET BT 26.250 307.634 Td /F1 9.8 Tf [(associated with poor prognosis for serious cardiovascular events that many times lead to death )] TJ ET 0.267 0.267 0.267 rg BT 438.636 307.634 Td /F1 9.8 Tf [([10])] TJ ET BT 454.899 307.634 Td /F1 9.8 Tf [([11])] TJ ET BT 471.162 307.634 Td /F1 9.8 Tf [([12])] TJ ET 0.271 0.267 0.267 rg BT 487.425 307.634 Td /F1 9.8 Tf [( . Further study of )] TJ ET BT 26.250 295.729 Td /F1 9.8 Tf [(the cardiovascular system as well as autonomic activity in Huntingtons disease patients may help in better understanding )] TJ ET BT 26.250 283.824 Td /F1 9.8 Tf [(disease pathology that may lead to clinical strategies to help curb the number of cardiovascular events in the patient population.)] TJ ET BT 26.250 264.420 Td /F1 9.8 Tf [(Many mouse models of Huntingtons disease have been created to recapitulate the various characteristics of the disease to )] TJ ET BT 26.250 252.515 Td /F1 9.8 Tf [(allow for mechanistic investigations. In some of the models, a cardiovascular phenotype has been documented )] TJ ET 0.267 0.267 0.267 rg BT 506.389 252.515 Td /F1 9.8 Tf [([13] )] TJ ET BT 525.362 252.515 Td /F1 9.8 Tf [([14])] TJ ET BT 541.625 252.515 Td /F1 9.8 Tf [( [15])] TJ ET BT 560.599 252.515 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 26.250 240.610 Td /F1 9.8 Tf [(. We are particularly interested in the BACHD model: a transgenic mouse that expresses the expanded form of the human )] TJ ET BT 554.066 240.610 Td /F5 9.8 Tf [(htt)] TJ ET BT 26.250 228.705 Td /F1 9.8 Tf [(gene that encode 97 stable glutamine repeats )] TJ ET 0.267 0.267 0.267 rg BT 226.788 228.705 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 243.051 228.705 Td /F1 9.8 Tf [( . BACHD mice develop HTT aggregates similar to adult onset Huntingtons )] TJ ET BT 26.250 216.801 Td /F1 9.8 Tf [(disease and display progressive motor deficits. There is also evidence for circadian deficits along with indications that the ANS )] TJ ET BT 26.250 204.896 Td /F1 9.8 Tf [(is affected as measured by heart rate variability)] TJ ET 0.267 0.267 0.267 rg BT 230.542 204.896 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 249.515 204.896 Td /F1 9.8 Tf [( . Further investigations of this mouse model may help elucidate the )] TJ ET BT 26.250 192.991 Td /F1 9.8 Tf [(autonomic and cardiovascular pathology in Huntingtons disease.)] TJ ET BT 26.250 173.586 Td /F1 9.8 Tf [(In this study, we investigated the cardiovascular phenotype in BACHD mice and report echocardiography, heart morphology )] TJ ET BT 26.250 161.682 Td /F1 9.8 Tf [(and baroreceptor reflex properties in middle-aged mice. The baroreceptor reflex is responsible for the overall tone as well as the )] TJ ET BT 26.250 149.777 Td /F1 9.8 Tf [(acute moment-to-moment regulation of blood pressure \(BP\) by modulating cardiac output and total peripheral resistance )] TJ ET 0.267 0.267 0.267 rg BT 547.017 149.777 Td /F1 9.8 Tf [([18])] TJ ET BT 26.250 137.872 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 42.513 137.872 Td /F1 9.8 Tf [( . The central autonomic network, which includes the nucleus tractus solitarius \(NTS\) and other nuclei, receive and integrate )] TJ ET BT 26.250 125.967 Td /F1 9.8 Tf [(BP information from baroreceptor cells located in the carotid artery and aortic arch. The system responds by modulating )] TJ ET BT 26.250 114.063 Td /F1 9.8 Tf [(autonomic outflow to various tissues of the body such as the heart, blood vessels and adrenal glands, in order to adjust BP )] TJ ET BT 26.250 102.158 Td /F1 9.8 Tf [(accordingly)] TJ ET 0.267 0.267 0.267 rg BT 75.556 102.158 Td /F1 9.8 Tf [( [19])] TJ ET 0.271 0.267 0.267 rg BT 94.529 102.158 Td /F1 9.8 Tf [( . Dysregulation of this reflex in the long run, may lead to detrimental consequences on the cardiovascular )] TJ ET BT 26.250 90.253 Td /F1 9.8 Tf [(system )] TJ ET 0.267 0.267 0.267 rg BT 59.839 90.253 Td /F1 9.8 Tf [([20] )] TJ ET 0.271 0.267 0.267 rg BT 78.812 90.253 Td /F1 9.8 Tf [(. Effects on the heart can be assessed using echocardiography and morphometry measurements, which look for )] TJ ET BT 26.250 78.348 Td /F1 9.8 Tf [(changes in heart function and structure, respectively. 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[( [17] )] TJ ET 0.271 0.267 0.267 rg BT 234.344 710.919 Td /F1 9.8 Tf [(along with littermate wild-type \(WT\) controls were obtained from the mouse )] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(mutant resource at JAX \(The Jackson Laboratory, Bar Harbor, Maine\) in a colony maintained by the CHDI Foundation. In order )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(to obtain a sufficient number of animals for the baroreceptor studies, we included data from non-littermate \(n=4/8\) C57BL6/J WT )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(mice. Animals were housed in a controlled environment with a 12 hr light and 12 hr dark lighting cycle where lights-on occurred )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(at 7am. All the animals used in these studies were subject to all recommendations for animal use and welfare outlined by the )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(UCLA Division of Laboratory Animals, as well as guidelines from the National Institutes of Health. The protocols for these )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(studies were approved by the UCLA Animal Research Committee.)] TJ ET BT 26.250 620.086 Td /F4 9.8 Tf [(Baseline Measurements and Baroreceptor Reflex)] TJ ET BT 26.250 600.681 Td /F1 9.8 Tf [(The administration of Angiotensin II \(ATII\) or Nitroprusside \(NP\) leads to episodes of hypertension or hypotension, respectively. )] TJ ET BT 26.250 588.777 Td /F1 9.8 Tf [(Changes in BP as a result of drug administration should elicit a compensatory response of heart rate \(HR\) via the baroreceptor )] TJ ET BT 26.250 576.872 Td /F1 9.8 Tf [(reflex in order to normalize BP levels. Differences in the ratio of change in HR to BP \(?HR/?BP\) may indicate aberrant signaling )] TJ ET BT 26.250 564.967 Td /F1 9.8 Tf [(to the heart by the ANS. Baroreceptor function was examined in WT \(n=8\) and BACHD \(n=6\) mice \(7-9 mo of age\) between the )] TJ ET BT 26.250 553.062 Td /F1 9.8 Tf [(times of 11am \(zeitgeber time, ZT 4\) and 4pm \(ZT 9\). During the experiment, HR was determined from the R-R interval of the )] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(electrocardiogram \(EKG\). Mice were anesthetized and both femoral arteries were catheterized, whereby BP measurements )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(were collected from one artery and drugs were administered through the other artery. Following catheterization, isoflurane levels )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(were decreased to between 1-1.5% and the mice were allowed to rest for at least 10 minutes. Baseline BP and HR were then )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(recorded. Increasing concentrations of AT II \(Low Dose \(LD\): 0.5, Mid Dose \(MD\): 1.0, High Dose \(HD\): 4.0 g/kg\) were )] TJ ET BT 26.250 493.539 Td /F1 9.8 Tf [(administered, and each dose was followed by a flush of saline \(+heparin 3U/mL\) to ensure full delivery of the drugs. Increasing )] TJ ET BT 26.250 481.634 Td /F1 9.8 Tf [(concentrations of NP \(LD: 10, MD: 20, HD: 40 g/kg\) were then administered similarly. We spaced each drug infusion leaving at )] TJ ET BT 26.250 469.729 Td /F1 9.8 Tf [(least 10-15 minutes between administrations to allow BP and HR to return to baseline levels. As a control, we blocked both the )] TJ ET BT 26.250 457.824 Td /F1 9.8 Tf [(muscarinic \(75g/kg glycopyrrolate\) and ?-adrenergic \(750g/kg propranolol\) receptors before administering another HD dose )] TJ ET BT 26.250 445.920 Td /F1 9.8 Tf [(of ATII and NP. We calculated the absolute value of the maximum change in BP as well as the subsequent directional change in )] TJ ET BT 26.250 434.015 Td /F1 9.8 Tf [(HR. Ratios of these two values \(?HR/?BP\) reflect the magnitude HR change relative to the change in BP that characterizes the )] TJ ET BT 26.250 422.110 Td /F1 9.8 Tf [(sensitivity of the baroreceptor response.)] TJ ET BT 26.250 402.705 Td /F4 9.8 Tf [(Echocardiography and Heart Morphometry)] TJ ET BT 26.250 383.301 Td /F1 9.8 Tf [(In order to assess cardiac function, WT \(n=6\) and BACHD \(n=5\) mice \(11-12 mo\) were subject to a two-dimensional, M-mode )] TJ ET BT 26.250 371.396 Td /F1 9.8 Tf [(echocardiography and spectral Doppler images acquired by a Siemens Acuson Sequoia C256 equipped with a 15L8 15MHz )] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(probe \(Siemens Medical Solutions, Mountain View, CA\) as previously described)] TJ ET 0.267 0.267 0.267 rg BT 370.327 359.491 Td /F1 9.8 Tf [( [21] )] TJ ET 0.271 0.267 0.267 rg BT 392.012 359.491 Td /F1 9.8 Tf [(. Mice were lightly anesthetized with 1% )] TJ ET BT 26.250 347.586 Td /F1 9.8 Tf [(isoflurane vaporized in oxygen \(Summit Anesthesia Solutions, Bend, OR\). The HR was determined from the R-R intervals of )] TJ ET BT 26.250 335.682 Td /F1 9.8 Tf [(their EKG and was maintained at physiological levels \(between 450 and 650 bpm\) during the procedure. Parameters measured )] TJ ET BT 26.250 323.777 Td /F1 9.8 Tf [(include: Ventricular Septal Thickness \(VST\), End Diastolic Diameter \(EDD\), Posterior Wall Thickness \(PWT\), End Systolic )] TJ ET BT 26.250 311.872 Td /F1 9.8 Tf [(Diameter \(ESD\), Aortic Ejection Time \(Ao-ET\), Left Ventricular percent Fractional Shortening \(LV%FS\), Left Ventricular Ejection )] TJ ET BT 26.250 299.967 Td /F1 9.8 Tf [(Fraction \(LvEF\), Left Ventricular Mass \(LVmass\), and Early Diastole/Atrial contraction ratio \(E/A\).)] TJ ET BT 26.250 280.563 Td /F1 9.8 Tf [(Body weight \(BW\), heart weight \(HW\) and tibia length \(TL\) were measured from 7-8 mo \(WT: n=5; BACHD: n=7\) and 12 mo old )] TJ ET BT 26.250 268.658 Td /F1 9.8 Tf [(\(WT: n=6; BACHD: n=5\) mice. HW/TL or HW/BW ratios were calculated to determine if there are differences in gross heart )] TJ ET BT 26.250 256.753 Td /F1 9.8 Tf [(morphometry.)] TJ ET BT 26.250 237.348 Td /F4 9.8 Tf [(Statistics)] TJ ET BT 26.250 217.944 Td /F1 9.8 Tf [(Baseline BP, HR as well as echocardiogram parameters were compared using a Students t-test. A two-way repeated measures )] TJ ET BT 26.250 206.039 Td /F1 9.8 Tf [(ANOVA was used to analyze the Baroreceptor data \(genotype x drug concentration\) and a two-way ANOVA was used to )] TJ ET BT 26.250 194.134 Td /F1 9.8 Tf [(analyze the morphometry data \(genotype x age\).)] TJ ET BT 26.250 157.532 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 137.577 Td /F4 9.8 Tf [(Baseline BP and HR in anesthetized mice)] TJ ET Q q 15.000 36.863 577.500 740.137 re W n 0.271 0.267 0.267 rg BT 26.250 750.278 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 730.324 Td /F4 9.8 Tf [(Animals)] TJ ET BT 26.250 710.919 Td /F1 9.8 Tf [(BACHD mice on the C57BL6/J background)] TJ ET 0.267 0.267 0.267 rg BT 212.660 710.919 Td /F1 9.8 Tf [( [17] )] TJ ET 0.271 0.267 0.267 rg BT 234.344 710.919 Td /F1 9.8 Tf [(along with littermate wild-type \(WT\) controls were obtained from the mouse )] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(mutant resource at JAX \(The Jackson Laboratory, Bar Harbor, Maine\) in a colony maintained by the CHDI Foundation. In order )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(to obtain a sufficient number of animals for the baroreceptor studies, we included data from non-littermate \(n=4/8\) C57BL6/J WT )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(mice. Animals were housed in a controlled environment with a 12 hr light and 12 hr dark lighting cycle where lights-on occurred )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(at 7am. All the animals used in these studies were subject to all recommendations for animal use and welfare outlined by the )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(UCLA Division of Laboratory Animals, as well as guidelines from the National Institutes of Health. The protocols for these )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(studies were approved by the UCLA Animal Research Committee.)] TJ ET BT 26.250 620.086 Td /F4 9.8 Tf [(Baseline Measurements and Baroreceptor Reflex)] TJ ET BT 26.250 600.681 Td /F1 9.8 Tf [(The administration of Angiotensin II \(ATII\) or Nitroprusside \(NP\) leads to episodes of hypertension or hypotension, respectively. )] TJ ET BT 26.250 588.777 Td /F1 9.8 Tf [(Changes in BP as a result of drug administration should elicit a compensatory response of heart rate \(HR\) via the baroreceptor )] TJ ET BT 26.250 576.872 Td /F1 9.8 Tf [(reflex in order to normalize BP levels. Differences in the ratio of change in HR to BP \(?HR/?BP\) may indicate aberrant signaling )] TJ ET BT 26.250 564.967 Td /F1 9.8 Tf [(to the heart by the ANS. Baroreceptor function was examined in WT \(n=8\) and BACHD \(n=6\) mice \(7-9 mo of age\) between the )] TJ ET BT 26.250 553.062 Td /F1 9.8 Tf [(times of 11am \(zeitgeber time, ZT 4\) and 4pm \(ZT 9\). During the experiment, HR was determined from the R-R interval of the )] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(electrocardiogram \(EKG\). Mice were anesthetized and both femoral arteries were catheterized, whereby BP measurements )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(were collected from one artery and drugs were administered through the other artery. Following catheterization, isoflurane levels )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(were decreased to between 1-1.5% and the mice were allowed to rest for at least 10 minutes. Baseline BP and HR were then )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(recorded. Increasing concentrations of AT II \(Low Dose \(LD\): 0.5, Mid Dose \(MD\): 1.0, High Dose \(HD\): 4.0 g/kg\) were )] TJ ET BT 26.250 493.539 Td /F1 9.8 Tf [(administered, and each dose was followed by a flush of saline \(+heparin 3U/mL\) to ensure full delivery of the drugs. Increasing )] TJ ET BT 26.250 481.634 Td /F1 9.8 Tf [(concentrations of NP \(LD: 10, MD: 20, HD: 40 g/kg\) were then administered similarly. We spaced each drug infusion leaving at )] TJ ET BT 26.250 469.729 Td /F1 9.8 Tf [(least 10-15 minutes between administrations to allow BP and HR to return to baseline levels. As a control, we blocked both the )] TJ ET BT 26.250 457.824 Td /F1 9.8 Tf [(muscarinic \(75g/kg glycopyrrolate\) and ?-adrenergic \(750g/kg propranolol\) receptors before administering another HD dose )] TJ ET BT 26.250 445.920 Td /F1 9.8 Tf [(of ATII and NP. We calculated the absolute value of the maximum change in BP as well as the subsequent directional change in )] TJ ET BT 26.250 434.015 Td /F1 9.8 Tf [(HR. Ratios of these two values \(?HR/?BP\) reflect the magnitude HR change relative to the change in BP that characterizes the )] TJ ET BT 26.250 422.110 Td /F1 9.8 Tf [(sensitivity of the baroreceptor response.)] TJ ET BT 26.250 402.705 Td /F4 9.8 Tf [(Echocardiography and Heart Morphometry)] TJ ET BT 26.250 383.301 Td /F1 9.8 Tf [(In order to assess cardiac function, WT \(n=6\) and BACHD \(n=5\) mice \(11-12 mo\) were subject to a two-dimensional, M-mode )] TJ ET BT 26.250 371.396 Td /F1 9.8 Tf [(echocardiography and spectral Doppler images acquired by a Siemens Acuson Sequoia C256 equipped with a 15L8 15MHz )] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(probe \(Siemens Medical Solutions, Mountain View, CA\) as previously described)] TJ ET 0.267 0.267 0.267 rg BT 370.327 359.491 Td /F1 9.8 Tf [( [21] )] TJ ET 0.271 0.267 0.267 rg BT 392.012 359.491 Td /F1 9.8 Tf [(. Mice were lightly anesthetized with 1% )] TJ ET BT 26.250 347.586 Td /F1 9.8 Tf [(isoflurane vaporized in oxygen \(Summit Anesthesia Solutions, Bend, OR\). The HR was determined from the R-R intervals of )] TJ ET BT 26.250 335.682 Td /F1 9.8 Tf [(their EKG and was maintained at physiological levels \(between 450 and 650 bpm\) during the procedure. Parameters measured )] TJ ET BT 26.250 323.777 Td /F1 9.8 Tf [(include: Ventricular Septal Thickness \(VST\), End Diastolic Diameter \(EDD\), Posterior Wall Thickness \(PWT\), End Systolic )] TJ ET BT 26.250 311.872 Td /F1 9.8 Tf [(Diameter \(ESD\), Aortic Ejection Time \(Ao-ET\), Left Ventricular percent Fractional Shortening \(LV%FS\), Left Ventricular Ejection )] TJ ET BT 26.250 299.967 Td /F1 9.8 Tf [(Fraction \(LvEF\), Left Ventricular Mass \(LVmass\), and Early Diastole/Atrial contraction ratio \(E/A\).)] TJ ET BT 26.250 280.563 Td /F1 9.8 Tf [(Body weight \(BW\), heart weight \(HW\) and tibia length \(TL\) were measured from 7-8 mo \(WT: n=5; BACHD: n=7\) and 12 mo old )] TJ ET BT 26.250 268.658 Td /F1 9.8 Tf [(\(WT: n=6; BACHD: n=5\) mice. HW/TL or HW/BW ratios were calculated to determine if there are differences in gross heart )] TJ ET BT 26.250 256.753 Td /F1 9.8 Tf [(morphometry.)] TJ ET BT 26.250 237.348 Td /F4 9.8 Tf [(Statistics)] TJ ET BT 26.250 217.944 Td /F1 9.8 Tf [(Baseline BP, HR as well as echocardiogram parameters were compared using a Students t-test. A two-way repeated measures )] TJ ET BT 26.250 206.039 Td /F1 9.8 Tf [(ANOVA was used to analyze the Baroreceptor data \(genotype x drug concentration\) and a two-way ANOVA was used to )] TJ ET BT 26.250 194.134 Td /F1 9.8 Tf [(analyze the morphometry data \(genotype x age\).)] TJ ET BT 26.250 157.532 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 137.577 Td /F4 9.8 Tf [(Baseline BP and HR in anesthetized mice)] TJ ET Q q 15.000 36.863 577.500 740.137 re W n 0.271 0.267 0.267 rg BT 26.250 750.278 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 730.324 Td /F4 9.8 Tf [(Animals)] TJ ET BT 26.250 710.919 Td /F1 9.8 Tf [(BACHD mice on the C57BL6/J background)] TJ ET 0.267 0.267 0.267 rg BT 212.660 710.919 Td /F1 9.8 Tf [( [17] )] TJ ET 0.271 0.267 0.267 rg BT 234.344 710.919 Td /F1 9.8 Tf [(along with littermate wild-type \(WT\) controls were obtained from the mouse )] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(mutant resource at JAX \(The Jackson Laboratory, Bar Harbor, Maine\) in a colony maintained by the CHDI Foundation. In order )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(to obtain a sufficient number of animals for the baroreceptor studies, we included data from non-littermate \(n=4/8\) C57BL6/J WT )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(mice. Animals were housed in a controlled environment with a 12 hr light and 12 hr dark lighting cycle where lights-on occurred )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(at 7am. All the animals used in these studies were subject to all recommendations for animal use and welfare outlined by the )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(UCLA Division of Laboratory Animals, as well as guidelines from the National Institutes of Health. The protocols for these )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(studies were approved by the UCLA Animal Research Committee.)] TJ ET BT 26.250 620.086 Td /F4 9.8 Tf [(Baseline Measurements and Baroreceptor Reflex)] TJ ET BT 26.250 600.681 Td /F1 9.8 Tf [(The administration of Angiotensin II \(ATII\) or Nitroprusside \(NP\) leads to episodes of hypertension or hypotension, respectively. )] TJ ET BT 26.250 588.777 Td /F1 9.8 Tf [(Changes in BP as a result of drug administration should elicit a compensatory response of heart rate \(HR\) via the baroreceptor )] TJ ET BT 26.250 576.872 Td /F1 9.8 Tf [(reflex in order to normalize BP levels. Differences in the ratio of change in HR to BP \(?HR/?BP\) may indicate aberrant signaling )] TJ ET BT 26.250 564.967 Td /F1 9.8 Tf [(to the heart by the ANS. Baroreceptor function was examined in WT \(n=8\) and BACHD \(n=6\) mice \(7-9 mo of age\) between the )] TJ ET BT 26.250 553.062 Td /F1 9.8 Tf [(times of 11am \(zeitgeber time, ZT 4\) and 4pm \(ZT 9\). During the experiment, HR was determined from the R-R interval of the )] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(electrocardiogram \(EKG\). Mice were anesthetized and both femoral arteries were catheterized, whereby BP measurements )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(were collected from one artery and drugs were administered through the other artery. Following catheterization, isoflurane levels )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(were decreased to between 1-1.5% and the mice were allowed to rest for at least 10 minutes. Baseline BP and HR were then )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(recorded. Increasing concentrations of AT II \(Low Dose \(LD\): 0.5, Mid Dose \(MD\): 1.0, High Dose \(HD\): 4.0 g/kg\) were )] TJ ET BT 26.250 493.539 Td /F1 9.8 Tf [(administered, and each dose was followed by a flush of saline \(+heparin 3U/mL\) to ensure full delivery of the drugs. Increasing )] TJ ET BT 26.250 481.634 Td /F1 9.8 Tf [(concentrations of NP \(LD: 10, MD: 20, HD: 40 g/kg\) were then administered similarly. We spaced each drug infusion leaving at )] TJ ET BT 26.250 469.729 Td /F1 9.8 Tf [(least 10-15 minutes between administrations to allow BP and HR to return to baseline levels. As a control, we blocked both the )] TJ ET BT 26.250 457.824 Td /F1 9.8 Tf [(muscarinic \(75g/kg glycopyrrolate\) and ?-adrenergic \(750g/kg propranolol\) receptors before administering another HD dose )] TJ ET BT 26.250 445.920 Td /F1 9.8 Tf [(of ATII and NP. We calculated the absolute value of the maximum change in BP as well as the subsequent directional change in )] TJ ET BT 26.250 434.015 Td /F1 9.8 Tf [(HR. Ratios of these two values \(?HR/?BP\) reflect the magnitude HR change relative to the change in BP that characterizes the )] TJ ET BT 26.250 422.110 Td /F1 9.8 Tf [(sensitivity of the baroreceptor response.)] TJ ET BT 26.250 402.705 Td /F4 9.8 Tf [(Echocardiography and Heart Morphometry)] TJ ET BT 26.250 383.301 Td /F1 9.8 Tf [(In order to assess cardiac function, WT \(n=6\) and BACHD \(n=5\) mice \(11-12 mo\) were subject to a two-dimensional, M-mode )] TJ ET BT 26.250 371.396 Td /F1 9.8 Tf [(echocardiography and spectral Doppler images acquired by a Siemens Acuson Sequoia C256 equipped with a 15L8 15MHz )] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(probe \(Siemens Medical Solutions, Mountain View, CA\) as previously described)] TJ ET 0.267 0.267 0.267 rg BT 370.327 359.491 Td /F1 9.8 Tf [( [21] )] TJ ET 0.271 0.267 0.267 rg BT 392.012 359.491 Td /F1 9.8 Tf [(. Mice were lightly anesthetized with 1% )] TJ ET BT 26.250 347.586 Td /F1 9.8 Tf [(isoflurane vaporized in oxygen \(Summit Anesthesia Solutions, Bend, OR\). The HR was determined from the R-R intervals of )] TJ ET BT 26.250 335.682 Td /F1 9.8 Tf [(their EKG and was maintained at physiological levels \(between 450 and 650 bpm\) during the procedure. Parameters measured )] TJ ET BT 26.250 323.777 Td /F1 9.8 Tf [(include: Ventricular Septal Thickness \(VST\), End Diastolic Diameter \(EDD\), Posterior Wall Thickness \(PWT\), End Systolic )] TJ ET BT 26.250 311.872 Td /F1 9.8 Tf [(Diameter \(ESD\), Aortic Ejection Time \(Ao-ET\), Left Ventricular percent Fractional Shortening \(LV%FS\), Left Ventricular Ejection )] TJ ET BT 26.250 299.967 Td /F1 9.8 Tf [(Fraction \(LvEF\), Left Ventricular Mass \(LVmass\), and Early Diastole/Atrial contraction ratio \(E/A\).)] TJ ET BT 26.250 280.563 Td /F1 9.8 Tf [(Body weight \(BW\), heart weight \(HW\) and tibia length \(TL\) were measured from 7-8 mo \(WT: n=5; BACHD: n=7\) and 12 mo old )] TJ ET BT 26.250 268.658 Td /F1 9.8 Tf [(\(WT: n=6; BACHD: n=5\) mice. HW/TL or HW/BW ratios were calculated to determine if there are differences in gross heart )] TJ ET BT 26.250 256.753 Td /F1 9.8 Tf [(morphometry.)] TJ ET BT 26.250 237.348 Td /F4 9.8 Tf [(Statistics)] TJ ET BT 26.250 217.944 Td /F1 9.8 Tf [(Baseline BP, HR as well as echocardiogram parameters were compared using a Students t-test. A two-way repeated measures )] TJ ET BT 26.250 206.039 Td /F1 9.8 Tf [(ANOVA was used to analyze the Baroreceptor data \(genotype x drug concentration\) and a two-way ANOVA was used to )] TJ ET BT 26.250 194.134 Td /F1 9.8 Tf [(analyze the morphometry data \(genotype x age\).)] TJ ET BT 26.250 157.532 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 137.577 Td /F4 9.8 Tf [(Baseline BP and HR in anesthetized mice)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(2)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 203 0 obj << /Type /Annot /Subtype /Link /A 204 0 R /Border [0 0 0] /H /I /Rect [ 212.6602 710.0176 234.3442 719.9382 ] >> endobj 204 0 obj << /Type /Action >> endobj 205 0 obj << /Type /Annot /Subtype /Link /A 206 0 R /Border [0 0 0] /H /I /Rect [ 370.3275 358.5893 392.0115 368.5100 ] >> endobj 206 0 obj << /Type /Action >> endobj 207 0 obj << /Type /Annot /Subtype /Link /A 208 0 R /Border [0 0 0] /H /I /Rect [ 212.6602 710.0176 234.3442 719.9382 ] >> endobj 208 0 obj << /Type /Action >> endobj 209 0 obj << /Type /Annot /Subtype /Link /A 210 0 R /Border [0 0 0] /H /I /Rect [ 370.3275 358.5893 392.0115 368.5100 ] >> endobj 210 0 obj << /Type /Action >> endobj 211 0 obj << /Type /Annot /Subtype /Link /A 212 0 R /Border [0 0 0] /H /I /Rect [ 212.6602 710.0176 234.3442 719.9382 ] >> endobj 212 0 obj << /Type /Action >> endobj 213 0 obj << /Type /Annot /Subtype /Link /A 214 0 R /Border [0 0 0] /H /I /Rect [ 370.3275 358.5893 392.0115 368.5100 ] >> endobj 214 0 obj << /Type /Action >> endobj 215 0 obj << /Type /Page /Parent 3 0 R /Annots [ 217 0 R 219 0 R 222 0 R 224 0 R 226 0 R 228 0 R ] /Contents 216 0 R >> endobj 216 0 obj << /Length 38876 >> stream 0.271 0.267 0.267 rg q 15.000 50.774 577.500 726.226 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(To begin to determine whether BACHD mice show dysfunction in the cardiovascular system, we measured baseline BP and HR )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(in lightly anesthetized WT \( )] TJ ET BT 146.000 755.571 Td /F5 9.8 Tf [(n)] TJ ET BT 151.421 755.571 Td /F1 9.8 Tf [( =8\) and BACHD mice \( )] TJ ET BT 256.262 755.571 Td /F5 9.8 Tf [(n)] TJ ET BT 261.683 755.571 Td /F1 9.8 Tf [( =6; 7-9 mo of age\). Systolic BP was significantly higher in BACHD mice )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(\(108.0 6.9 mmHg\) compared to WT controls \(86.1 3.2 mmHg )] TJ ET BT 308.561 743.667 Td /F5 9.8 Tf [( ; t)] TJ ET BT 319.403 741.602 Td /F5 8.7 Tf [(12)] TJ ET BT 329.041 743.667 Td /F1 9.8 Tf [( =-3.13, )] TJ ET BT 365.086 743.667 Td /F5 9.8 Tf [(P)] TJ ET BT 371.590 743.667 Td /F1 9.8 Tf [( =0.009\) although BP levels were still )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(considered to be within the normal range. BACHD mice also displayed increased HRs \(615 23 bpm\) compared to WTs \(537 )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(21 bpm; T=61.0, )] TJ ET BT 100.233 719.857 Td /F5 9.8 Tf [(P=)] TJ ET BT 112.430 719.857 Td /F1 9.8 Tf [( 0.043\). The increased BP and HR measured in BACHD mice reflect a change in the regulation of the )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(cardiovascular system. Although the BP levels are still normal, the increase may be indicative of future susceptibility for )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(cardiovascular events.)] TJ ET BT 26.250 676.643 Td /F4 9.8 Tf [(Baroreceptor Reflex)] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(There is evidence that the ANS is dysfunctional in patients with Huntingtons disease. It has also been reported that BACHD )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(mice have significantly decreased HRV indicative of abnormal signal input to the heart by the ANS)] TJ ET 0.267 0.267 0.267 rg BT 448.932 645.333 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 467.906 645.333 Td /F1 9.8 Tf [( . We measured the )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(baroreceptor reflex of BACHD and WT mice to determine whether this feedback mechanism of regulating BP, which is mediated )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(by the ANS, is also disrupted. Changes in the ratios between the magnitude change in BP and HR after ATII \(vasoconstrictor\) or )] TJ ET BT 26.250 609.619 Td /F1 9.8 Tf [(NP \(vasodilator\) administration, may indicate aberrant signaling to the heart by the ANS.)] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(Increasing concentrations of ATII \(LD-0.5, MD-1.0, HD-4.0 ?g/kg\) were administered to mildly anesthetized WT and BACHD )] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(mice. By 2-way repeated measures ANOVA, we detected significant variation between genotype \( )] TJ ET BT 450.560 578.310 Td /F5 9.8 Tf [( F)] TJ ET BT 459.228 576.245 Td /F5 8.7 Tf [(1,55)] TJ ET BT 476.093 578.310 Td /F1 9.8 Tf [( =7.28, )] TJ ET BT 508.892 578.310 Td /F5 9.8 Tf [(P)] TJ ET BT 515.396 578.310 Td /F1 9.8 Tf [( =0.019\) and )] TJ ET BT 26.250 566.405 Td /F1 9.8 Tf [(concentration of ATII drug \( )] TJ ET BT 147.101 566.405 Td /F5 9.8 Tf [( F)] TJ ET BT 155.769 564.341 Td /F5 8.7 Tf [(3,55)] TJ ET BT 172.634 566.405 Td /F1 9.8 Tf [( =16.94, )] TJ ET BT 210.854 566.405 Td /F5 9.8 Tf [(P)] TJ ET BT 217.358 566.405 Td /F1 9.8 Tf [( <0.001\), but no significant interaction between genotype and drug concentration \( )] TJ ET BT 26.250 554.500 Td /F5 9.8 Tf [(F)] TJ ET BT 32.207 552.436 Td /F5 8.7 Tf [(3,55)] TJ ET BT 49.073 554.500 Td /F1 9.8 Tf [( =0.88, )] TJ ET BT 81.872 554.500 Td /F5 9.8 Tf [(P)] TJ ET BT 88.375 554.500 Td /F1 9.8 Tf [( =0.46; Fig. 1A\). Post )] TJ ET BT 182.950 554.500 Td /F5 9.8 Tf [(hoc)] TJ ET BT 198.667 554.500 Td /F1 9.8 Tf [( analysis indicate significant responses to all concentrations of AT II in WT mice when )] TJ ET BT 26.250 542.595 Td /F1 9.8 Tf [(compared to the control conditions where the ?- and muscarinic receptors were respectively blocked with propranolol and )] TJ ET BT 26.250 530.691 Td /F1 9.8 Tf [(glycopyrrolate before administration of a HD of ATII \(control vs. LD: )] TJ ET BT 318.857 530.691 Td /F5 9.8 Tf [( t)] TJ ET BT 324.278 528.626 Td /F5 8.7 Tf [(14)] TJ ET BT 333.916 530.691 Td /F5 9.8 Tf [( = )] TJ ET BT 345.031 530.691 Td /F1 9.8 Tf [( 2.32, )] TJ ET BT 372.136 530.691 Td /F5 9.8 Tf [(P)] TJ ET BT 378.639 530.691 Td /F1 9.8 Tf [( <0.01; control vs. MD: )] TJ ET BT 479.161 530.691 Td /F5 9.8 Tf [( t)] TJ ET BT 484.582 528.626 Td /F5 8.7 Tf [(14)] TJ ET BT 494.220 530.691 Td /F5 9.8 Tf [( = )] TJ ET BT 505.335 530.691 Td /F1 9.8 Tf [( 2.13, )] TJ ET BT 532.440 530.691 Td /F5 9.8 Tf [(P)] TJ ET BT 538.943 530.691 Td /F1 9.8 Tf [( <0.001; )] TJ ET BT 26.250 518.786 Td /F1 9.8 Tf [(control vs. HD: )] TJ ET BT 92.891 518.786 Td /F5 9.8 Tf [( t)] TJ ET BT 98.312 516.722 Td /F5 8.7 Tf [(14)] TJ ET BT 107.950 518.786 Td /F5 9.8 Tf [( = )] TJ ET BT 119.065 518.786 Td /F1 9.8 Tf [( 1.50, )] TJ ET BT 146.170 518.786 Td /F5 9.8 Tf [(P)] TJ ET BT 152.673 518.786 Td /F1 9.8 Tf [( <0.001\). Compared to controls, BACHD mice showed a significant difference in ?HR/?BP ratio )] TJ ET BT 26.250 506.881 Td /F1 9.8 Tf [(when administered the LD and MD of ATII, but did not have a significant response to the HD \(control vs. LD: )] TJ ET BT 494.464 506.881 Td /F5 9.8 Tf [( t)] TJ ET BT 499.885 504.817 Td /F5 8.7 Tf [(10)] TJ ET BT 509.523 506.881 Td /F5 9.8 Tf [( = )] TJ ET BT 520.638 506.881 Td /F1 9.8 Tf [( 3.49, )] TJ ET BT 547.743 506.881 Td /F5 9.8 Tf [(P)] TJ ET BT 26.250 494.976 Td /F1 9.8 Tf [(=0.008; control vs. MD: )] TJ ET BT 129.483 494.976 Td /F5 9.8 Tf [( t)] TJ ET BT 134.904 492.912 Td /F5 8.7 Tf [(10)] TJ ET BT 144.541 494.976 Td /F5 9.8 Tf [( = )] TJ ET BT 155.656 494.976 Td /F1 9.8 Tf [( 2.87, )] TJ ET BT 182.761 494.976 Td /F5 9.8 Tf [(P)] TJ ET BT 189.265 494.976 Td /F1 9.8 Tf [( =0.041; control vs. HD: )] TJ ET BT 294.126 494.976 Td /F5 9.8 Tf [( t)] TJ ET BT 299.547 492.912 Td /F5 8.7 Tf [(10)] TJ ET BT 309.184 494.976 Td /F5 9.8 Tf [( = )] TJ ET BT 320.299 494.976 Td /F1 9.8 Tf [( 2.31, )] TJ ET BT 347.404 494.976 Td /F5 9.8 Tf [(P)] TJ ET BT 353.907 494.976 Td /F1 9.8 Tf [( =0.16\). For each of the doses of ATII, the HR of )] TJ ET BT 26.250 483.072 Td /F1 9.8 Tf [(BACHD mice responded with less magnitude compared to WT mice \(LD: )] TJ ET BT 342.676 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 348.097 481.007 Td /F5 8.7 Tf [(12)] TJ ET BT 357.735 483.072 Td /F5 9.8 Tf [( = )] TJ ET BT 368.850 483.072 Td /F1 9.8 Tf [( 2.03, p=0.049; MD: )] TJ ET BT 457.468 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 462.889 481.007 Td /F5 8.7 Tf [(12)] TJ ET BT 472.526 483.072 Td /F5 9.8 Tf [( = )] TJ ET BT 483.641 483.072 Td /F1 9.8 Tf [( 2.21, p=0.033; HD: )] TJ ET BT 571.176 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 26.250 469.103 Td /F5 8.7 Tf [(12)] TJ ET BT 35.887 471.167 Td /F5 9.8 Tf [( = )] TJ ET BT 47.002 471.167 Td /F1 9.8 Tf [( 2.33, )] TJ ET BT 74.107 471.167 Td /F5 9.8 Tf [(P)] TJ ET BT 80.611 471.167 Td /F1 9.8 Tf [( =0.025\). There was no difference in the ?HR/?BP ratios between WT and BACHD mice when the ?- and )] TJ ET BT 26.250 459.262 Td /F1 9.8 Tf [(muscarinic receptors were blocked \(control: )] TJ ET BT 216.970 459.262 Td /F5 9.8 Tf [( t)] TJ ET BT 222.391 457.198 Td /F5 8.7 Tf [(14)] TJ ET BT 232.028 459.262 Td /F5 9.8 Tf [( = )] TJ ET BT 243.143 459.262 Td /F1 9.8 Tf [( 0.58, )] TJ ET BT 270.248 459.262 Td /F5 9.8 Tf [(P)] TJ ET BT 276.751 459.262 Td /F1 9.8 Tf [( =0.56\).)] TJ ET BT 26.250 439.857 Td /F1 9.8 Tf [(To test the HR response of WT and BACHD mice to decreases in BP, we administered increasing concentrations of NP \(LD- )] TJ ET BT 26.250 427.953 Td /F1 9.8 Tf [(10, MD- 20, HD- 40 ?g/kg\). By 2-way repeated measures ANOVA, we detected significant interaction between genotype and )] TJ ET BT 26.250 416.048 Td /F1 9.8 Tf [(concentrations of NP drug \( )] TJ ET BT 147.637 416.048 Td /F5 9.8 Tf [( F )] TJ ET BT 159.016 413.984 Td /F5 8.7 Tf [(3,55)] TJ ET BT 175.881 416.048 Td /F1 9.8 Tf [( =4.079, )] TJ ET BT 214.101 416.048 Td /F5 9.8 Tf [(P)] TJ ET BT 220.604 416.048 Td /F1 9.8 Tf [( =0.014, Fig. 1B\). Post )] TJ ET BT 320.600 416.048 Td /F5 9.8 Tf [(hoc)] TJ ET BT 336.317 416.048 Td /F1 9.8 Tf [( analysis detects a significant response to all )] TJ ET BT 26.250 404.143 Td /F1 9.8 Tf [(concentrations of NP in WT mice when compared to the control \(control vs. LD: )] TJ ET BT 370.337 404.143 Td /F5 9.8 Tf [( t )] TJ ET BT 378.469 402.079 Td /F5 8.7 Tf [(14)] TJ ET BT 388.106 404.143 Td /F5 9.8 Tf [( = )] TJ ET BT 399.221 404.143 Td /F1 9.8 Tf [( 5.62, )] TJ ET BT 426.326 404.143 Td /F5 9.8 Tf [(P)] TJ ET BT 432.829 404.143 Td /F1 9.8 Tf [( <0.001; control vs. MD: )] TJ ET BT 538.773 404.143 Td /F5 9.8 Tf [( t)] TJ ET BT 544.194 402.079 Td /F5 8.7 Tf [(14)] TJ ET BT 553.831 404.143 Td /F5 9.8 Tf [( = )] TJ ET BT 26.250 392.238 Td /F1 9.8 Tf [(6.35, )] TJ ET BT 50.645 392.238 Td /F5 9.8 Tf [(P)] TJ ET BT 57.148 392.238 Td /F1 9.8 Tf [( <0.001; control vs. HD: )] TJ ET BT 162.009 392.238 Td /F5 9.8 Tf [( t)] TJ ET BT 167.430 390.174 Td /F5 8.7 Tf [(14)] TJ ET BT 177.067 392.238 Td /F5 9.8 Tf [( = )] TJ ET BT 188.182 392.238 Td /F1 9.8 Tf [( 6.89, )] TJ ET BT 215.287 392.238 Td /F5 9.8 Tf [(P)] TJ ET BT 221.791 392.238 Td /F1 9.8 Tf [( <0.001\). BACHD mice, on the other hand, did not show any significant response )] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(for any of the concentrations of NP when compared to the control condition \(control vs. LD: )] TJ ET BT 420.228 380.334 Td /F5 9.8 Tf [( t )] TJ ET BT 428.360 378.269 Td /F5 8.7 Tf [(10)] TJ ET BT 437.997 380.334 Td /F5 9.8 Tf [( = )] TJ ET BT 449.112 380.334 Td /F1 9.8 Tf [( 1.43, )] TJ ET BT 476.217 380.334 Td /F5 9.8 Tf [(P)] TJ ET BT 482.720 380.334 Td /F1 9.8 Tf [( =0.96; control vs. )] TJ ET BT 26.250 368.429 Td /F1 9.8 Tf [(MD: )] TJ ET BT 46.832 368.429 Td /F5 9.8 Tf [( t)] TJ ET BT 52.253 366.365 Td /F5 8.7 Tf [(10)] TJ ET BT 61.891 368.429 Td /F5 9.8 Tf [( = )] TJ ET BT 73.006 368.429 Td /F1 9.8 Tf [( 2.26, )] TJ ET BT 100.111 368.429 Td /F5 9.8 Tf [(P)] TJ ET BT 106.614 368.429 Td /F1 9.8 Tf [( =0.18; control vs. HD: )] TJ ET BT 206.054 368.429 Td /F5 9.8 Tf [( t)] TJ ET BT 211.475 366.365 Td /F5 8.7 Tf [(10)] TJ ET BT 221.112 368.429 Td /F5 9.8 Tf [( = )] TJ ET BT 232.227 368.429 Td /F1 9.8 Tf [( 1.66, )] TJ ET BT 259.332 368.429 Td /F5 9.8 Tf [(P)] TJ ET BT 265.836 368.429 Td /F1 9.8 Tf [( =0.64\). For each of the doses of NP, BACHD had significantly lower )] TJ ET BT 26.250 356.524 Td /F1 9.8 Tf [(responses compared to WT mice \(LD: )] TJ ET BT 193.131 356.524 Td /F5 9.8 Tf [( t )] TJ ET BT 201.262 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 210.900 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 222.015 356.524 Td /F1 9.8 Tf [( 3.32, )] TJ ET BT 249.120 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 255.623 356.524 Td /F1 9.8 Tf [( =0.002; MD: )] TJ ET BT 314.425 356.524 Td /F5 9.8 Tf [( t)] TJ ET BT 319.846 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 329.484 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 340.599 356.524 Td /F1 9.8 Tf [( 3.17, )] TJ ET BT 367.704 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 374.207 356.524 Td /F1 9.8 Tf [( =0.003; HD: )] TJ ET BT 431.927 356.524 Td /F5 9.8 Tf [( t)] TJ ET BT 437.348 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 446.985 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 458.100 356.524 Td /F1 9.8 Tf [( 4.05, )] TJ ET BT 485.205 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 491.709 356.524 Td /F1 9.8 Tf [( <0.001\). When )] TJ ET BT 26.250 344.619 Td /F1 9.8 Tf [(mice were primed with ?- and muscarinic receptor blockers, there was no difference in ?HR/?BP ratios between WT and )] TJ ET BT 26.250 332.715 Td /F1 9.8 Tf [(BACHD mice after HD NP administration \(control: )] TJ ET BT 242.963 332.715 Td /F5 9.8 Tf [( t)] TJ ET BT 248.384 330.650 Td /F5 8.7 Tf [(12)] TJ ET BT 258.022 332.715 Td /F5 9.8 Tf [( = )] TJ ET BT 269.137 332.715 Td /F1 9.8 Tf [( 0.46, )] TJ ET BT 296.242 332.715 Td /F5 9.8 Tf [(P)] TJ ET BT 302.745 332.715 Td /F1 9.8 Tf [( =0.65\).)] TJ ET BT 26.250 313.310 Td /F1 9.8 Tf [(These data suggest that middle-aged BACHD mice have dysfunctional baro-receptor reflexes compared to WT controls. )] TJ ET BT 26.250 301.405 Td /F1 9.8 Tf [(BACHD mice are unable to appropriately modulate their HRs in response to either an increase or decrease in BP.)] TJ ET 0.965 0.965 0.965 rg 26.250 50.774 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 291.524 m 581.250 291.524 l 581.250 290.774 l 26.250 290.774 l f q 126.000 0 0 225.000 35.250 56.774 cm /I3 Do Q q 35.250 50.774 537.000 0.000 re W n Q Q q 15.000 50.774 577.500 726.226 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(To begin to determine whether BACHD mice show dysfunction in the cardiovascular system, we measured baseline BP and HR )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(in lightly anesthetized WT \( )] TJ ET BT 146.000 755.571 Td /F5 9.8 Tf [(n)] TJ ET BT 151.421 755.571 Td /F1 9.8 Tf [( =8\) and BACHD mice \( )] TJ ET BT 256.262 755.571 Td /F5 9.8 Tf [(n)] TJ ET BT 261.683 755.571 Td /F1 9.8 Tf [( =6; 7-9 mo of age\). Systolic BP was significantly higher in BACHD mice )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(\(108.0 6.9 mmHg\) compared to WT controls \(86.1 3.2 mmHg )] TJ ET BT 308.561 743.667 Td /F5 9.8 Tf [( ; t)] TJ ET BT 319.403 741.602 Td /F5 8.7 Tf [(12)] TJ ET BT 329.041 743.667 Td /F1 9.8 Tf [( =-3.13, )] TJ ET BT 365.086 743.667 Td /F5 9.8 Tf [(P)] TJ ET BT 371.590 743.667 Td /F1 9.8 Tf [( =0.009\) although BP levels were still )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(considered to be within the normal range. BACHD mice also displayed increased HRs \(615 23 bpm\) compared to WTs \(537 )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(21 bpm; T=61.0, )] TJ ET BT 100.233 719.857 Td /F5 9.8 Tf [(P=)] TJ ET BT 112.430 719.857 Td /F1 9.8 Tf [( 0.043\). The increased BP and HR measured in BACHD mice reflect a change in the regulation of the )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(cardiovascular system. Although the BP levels are still normal, the increase may be indicative of future susceptibility for )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(cardiovascular events.)] TJ ET BT 26.250 676.643 Td /F4 9.8 Tf [(Baroreceptor Reflex)] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(There is evidence that the ANS is dysfunctional in patients with Huntingtons disease. It has also been reported that BACHD )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(mice have significantly decreased HRV indicative of abnormal signal input to the heart by the ANS)] TJ ET 0.267 0.267 0.267 rg BT 448.932 645.333 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 467.906 645.333 Td /F1 9.8 Tf [( . We measured the )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(baroreceptor reflex of BACHD and WT mice to determine whether this feedback mechanism of regulating BP, which is mediated )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(by the ANS, is also disrupted. Changes in the ratios between the magnitude change in BP and HR after ATII \(vasoconstrictor\) or )] TJ ET BT 26.250 609.619 Td /F1 9.8 Tf [(NP \(vasodilator\) administration, may indicate aberrant signaling to the heart by the ANS.)] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(Increasing concentrations of ATII \(LD-0.5, MD-1.0, HD-4.0 ?g/kg\) were administered to mildly anesthetized WT and BACHD )] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(mice. By 2-way repeated measures ANOVA, we detected significant variation between genotype \( )] TJ ET BT 450.560 578.310 Td /F5 9.8 Tf [( F)] TJ ET BT 459.228 576.245 Td /F5 8.7 Tf [(1,55)] TJ ET BT 476.093 578.310 Td /F1 9.8 Tf [( =7.28, )] TJ ET BT 508.892 578.310 Td /F5 9.8 Tf [(P)] TJ ET BT 515.396 578.310 Td /F1 9.8 Tf [( =0.019\) and )] TJ ET BT 26.250 566.405 Td /F1 9.8 Tf [(concentration of ATII drug \( )] TJ ET BT 147.101 566.405 Td /F5 9.8 Tf [( F)] TJ ET BT 155.769 564.341 Td /F5 8.7 Tf [(3,55)] TJ ET BT 172.634 566.405 Td /F1 9.8 Tf [( =16.94, )] TJ ET BT 210.854 566.405 Td /F5 9.8 Tf [(P)] TJ ET BT 217.358 566.405 Td /F1 9.8 Tf [( <0.001\), but no significant interaction between genotype and drug concentration \( )] TJ ET BT 26.250 554.500 Td /F5 9.8 Tf [(F)] TJ ET BT 32.207 552.436 Td /F5 8.7 Tf [(3,55)] TJ ET BT 49.073 554.500 Td /F1 9.8 Tf [( =0.88, )] TJ ET BT 81.872 554.500 Td /F5 9.8 Tf [(P)] TJ ET BT 88.375 554.500 Td /F1 9.8 Tf [( =0.46; Fig. 1A\). Post )] TJ ET BT 182.950 554.500 Td /F5 9.8 Tf [(hoc)] TJ ET BT 198.667 554.500 Td /F1 9.8 Tf [( analysis indicate significant responses to all concentrations of AT II in WT mice when )] TJ ET BT 26.250 542.595 Td /F1 9.8 Tf [(compared to the control conditions where the ?- and muscarinic receptors were respectively blocked with propranolol and )] TJ ET BT 26.250 530.691 Td /F1 9.8 Tf [(glycopyrrolate before administration of a HD of ATII \(control vs. LD: )] TJ ET BT 318.857 530.691 Td /F5 9.8 Tf [( t)] TJ ET BT 324.278 528.626 Td /F5 8.7 Tf [(14)] TJ ET BT 333.916 530.691 Td /F5 9.8 Tf [( = )] TJ ET BT 345.031 530.691 Td /F1 9.8 Tf [( 2.32, )] TJ ET BT 372.136 530.691 Td /F5 9.8 Tf [(P)] TJ ET BT 378.639 530.691 Td /F1 9.8 Tf [( <0.01; control vs. MD: )] TJ ET BT 479.161 530.691 Td /F5 9.8 Tf [( t)] TJ ET BT 484.582 528.626 Td /F5 8.7 Tf [(14)] TJ ET BT 494.220 530.691 Td /F5 9.8 Tf [( = )] TJ ET BT 505.335 530.691 Td /F1 9.8 Tf [( 2.13, )] TJ ET BT 532.440 530.691 Td /F5 9.8 Tf [(P)] TJ ET BT 538.943 530.691 Td /F1 9.8 Tf [( <0.001; )] TJ ET BT 26.250 518.786 Td /F1 9.8 Tf [(control vs. HD: )] TJ ET BT 92.891 518.786 Td /F5 9.8 Tf [( t)] TJ ET BT 98.312 516.722 Td /F5 8.7 Tf [(14)] TJ ET BT 107.950 518.786 Td /F5 9.8 Tf [( = )] TJ ET BT 119.065 518.786 Td /F1 9.8 Tf [( 1.50, )] TJ ET BT 146.170 518.786 Td /F5 9.8 Tf [(P)] TJ ET BT 152.673 518.786 Td /F1 9.8 Tf [( <0.001\). Compared to controls, BACHD mice showed a significant difference in ?HR/?BP ratio )] TJ ET BT 26.250 506.881 Td /F1 9.8 Tf [(when administered the LD and MD of ATII, but did not have a significant response to the HD \(control vs. LD: )] TJ ET BT 494.464 506.881 Td /F5 9.8 Tf [( t)] TJ ET BT 499.885 504.817 Td /F5 8.7 Tf [(10)] TJ ET BT 509.523 506.881 Td /F5 9.8 Tf [( = )] TJ ET BT 520.638 506.881 Td /F1 9.8 Tf [( 3.49, )] TJ ET BT 547.743 506.881 Td /F5 9.8 Tf [(P)] TJ ET BT 26.250 494.976 Td /F1 9.8 Tf [(=0.008; control vs. MD: )] TJ ET BT 129.483 494.976 Td /F5 9.8 Tf [( t)] TJ ET BT 134.904 492.912 Td /F5 8.7 Tf [(10)] TJ ET BT 144.541 494.976 Td /F5 9.8 Tf [( = )] TJ ET BT 155.656 494.976 Td /F1 9.8 Tf [( 2.87, )] TJ ET BT 182.761 494.976 Td /F5 9.8 Tf [(P)] TJ ET BT 189.265 494.976 Td /F1 9.8 Tf [( =0.041; control vs. HD: )] TJ ET BT 294.126 494.976 Td /F5 9.8 Tf [( t)] TJ ET BT 299.547 492.912 Td /F5 8.7 Tf [(10)] TJ ET BT 309.184 494.976 Td /F5 9.8 Tf [( = )] TJ ET BT 320.299 494.976 Td /F1 9.8 Tf [( 2.31, )] TJ ET BT 347.404 494.976 Td /F5 9.8 Tf [(P)] TJ ET BT 353.907 494.976 Td /F1 9.8 Tf [( =0.16\). For each of the doses of ATII, the HR of )] TJ ET BT 26.250 483.072 Td /F1 9.8 Tf [(BACHD mice responded with less magnitude compared to WT mice \(LD: )] TJ ET BT 342.676 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 348.097 481.007 Td /F5 8.7 Tf [(12)] TJ ET BT 357.735 483.072 Td /F5 9.8 Tf [( = )] TJ ET BT 368.850 483.072 Td /F1 9.8 Tf [( 2.03, p=0.049; MD: )] TJ ET BT 457.468 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 462.889 481.007 Td /F5 8.7 Tf [(12)] TJ ET BT 472.526 483.072 Td /F5 9.8 Tf [( = )] TJ ET BT 483.641 483.072 Td /F1 9.8 Tf [( 2.21, p=0.033; HD: )] TJ ET BT 571.176 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 26.250 469.103 Td /F5 8.7 Tf [(12)] TJ ET BT 35.887 471.167 Td /F5 9.8 Tf [( = )] TJ ET BT 47.002 471.167 Td /F1 9.8 Tf [( 2.33, )] TJ ET BT 74.107 471.167 Td /F5 9.8 Tf [(P)] TJ ET BT 80.611 471.167 Td /F1 9.8 Tf [( =0.025\). There was no difference in the ?HR/?BP ratios between WT and BACHD mice when the ?- and )] TJ ET BT 26.250 459.262 Td /F1 9.8 Tf [(muscarinic receptors were blocked \(control: )] TJ ET BT 216.970 459.262 Td /F5 9.8 Tf [( t)] TJ ET BT 222.391 457.198 Td /F5 8.7 Tf [(14)] TJ ET BT 232.028 459.262 Td /F5 9.8 Tf [( = )] TJ ET BT 243.143 459.262 Td /F1 9.8 Tf [( 0.58, )] TJ ET BT 270.248 459.262 Td /F5 9.8 Tf [(P)] TJ ET BT 276.751 459.262 Td /F1 9.8 Tf [( =0.56\).)] TJ ET BT 26.250 439.857 Td /F1 9.8 Tf [(To test the HR response of WT and BACHD mice to decreases in BP, we administered increasing concentrations of NP \(LD- )] TJ ET BT 26.250 427.953 Td /F1 9.8 Tf [(10, MD- 20, HD- 40 ?g/kg\). By 2-way repeated measures ANOVA, we detected significant interaction between genotype and )] TJ ET BT 26.250 416.048 Td /F1 9.8 Tf [(concentrations of NP drug \( )] TJ ET BT 147.637 416.048 Td /F5 9.8 Tf [( F )] TJ ET BT 159.016 413.984 Td /F5 8.7 Tf [(3,55)] TJ ET BT 175.881 416.048 Td /F1 9.8 Tf [( =4.079, )] TJ ET BT 214.101 416.048 Td /F5 9.8 Tf [(P)] TJ ET BT 220.604 416.048 Td /F1 9.8 Tf [( =0.014, Fig. 1B\). Post )] TJ ET BT 320.600 416.048 Td /F5 9.8 Tf [(hoc)] TJ ET BT 336.317 416.048 Td /F1 9.8 Tf [( analysis detects a significant response to all )] TJ ET BT 26.250 404.143 Td /F1 9.8 Tf [(concentrations of NP in WT mice when compared to the control \(control vs. LD: )] TJ ET BT 370.337 404.143 Td /F5 9.8 Tf [( t )] TJ ET BT 378.469 402.079 Td /F5 8.7 Tf [(14)] TJ ET BT 388.106 404.143 Td /F5 9.8 Tf [( = )] TJ ET BT 399.221 404.143 Td /F1 9.8 Tf [( 5.62, )] TJ ET BT 426.326 404.143 Td /F5 9.8 Tf [(P)] TJ ET BT 432.829 404.143 Td /F1 9.8 Tf [( <0.001; control vs. MD: )] TJ ET BT 538.773 404.143 Td /F5 9.8 Tf [( t)] TJ ET BT 544.194 402.079 Td /F5 8.7 Tf [(14)] TJ ET BT 553.831 404.143 Td /F5 9.8 Tf [( = )] TJ ET BT 26.250 392.238 Td /F1 9.8 Tf [(6.35, )] TJ ET BT 50.645 392.238 Td /F5 9.8 Tf [(P)] TJ ET BT 57.148 392.238 Td /F1 9.8 Tf [( <0.001; control vs. HD: )] TJ ET BT 162.009 392.238 Td /F5 9.8 Tf [( t)] TJ ET BT 167.430 390.174 Td /F5 8.7 Tf [(14)] TJ ET BT 177.067 392.238 Td /F5 9.8 Tf [( = )] TJ ET BT 188.182 392.238 Td /F1 9.8 Tf [( 6.89, )] TJ ET BT 215.287 392.238 Td /F5 9.8 Tf [(P)] TJ ET BT 221.791 392.238 Td /F1 9.8 Tf [( <0.001\). BACHD mice, on the other hand, did not show any significant response )] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(for any of the concentrations of NP when compared to the control condition \(control vs. LD: )] TJ ET BT 420.228 380.334 Td /F5 9.8 Tf [( t )] TJ ET BT 428.360 378.269 Td /F5 8.7 Tf [(10)] TJ ET BT 437.997 380.334 Td /F5 9.8 Tf [( = )] TJ ET BT 449.112 380.334 Td /F1 9.8 Tf [( 1.43, )] TJ ET BT 476.217 380.334 Td /F5 9.8 Tf [(P)] TJ ET BT 482.720 380.334 Td /F1 9.8 Tf [( =0.96; control vs. )] TJ ET BT 26.250 368.429 Td /F1 9.8 Tf [(MD: )] TJ ET BT 46.832 368.429 Td /F5 9.8 Tf [( t)] TJ ET BT 52.253 366.365 Td /F5 8.7 Tf [(10)] TJ ET BT 61.891 368.429 Td /F5 9.8 Tf [( = )] TJ ET BT 73.006 368.429 Td /F1 9.8 Tf [( 2.26, )] TJ ET BT 100.111 368.429 Td /F5 9.8 Tf [(P)] TJ ET BT 106.614 368.429 Td /F1 9.8 Tf [( =0.18; control vs. HD: )] TJ ET BT 206.054 368.429 Td /F5 9.8 Tf [( t)] TJ ET BT 211.475 366.365 Td /F5 8.7 Tf [(10)] TJ ET BT 221.112 368.429 Td /F5 9.8 Tf [( = )] TJ ET BT 232.227 368.429 Td /F1 9.8 Tf [( 1.66, )] TJ ET BT 259.332 368.429 Td /F5 9.8 Tf [(P)] TJ ET BT 265.836 368.429 Td /F1 9.8 Tf [( =0.64\). For each of the doses of NP, BACHD had significantly lower )] TJ ET BT 26.250 356.524 Td /F1 9.8 Tf [(responses compared to WT mice \(LD: )] TJ ET BT 193.131 356.524 Td /F5 9.8 Tf [( t )] TJ ET BT 201.262 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 210.900 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 222.015 356.524 Td /F1 9.8 Tf [( 3.32, )] TJ ET BT 249.120 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 255.623 356.524 Td /F1 9.8 Tf [( =0.002; MD: )] TJ ET BT 314.425 356.524 Td /F5 9.8 Tf [( t)] TJ ET BT 319.846 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 329.484 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 340.599 356.524 Td /F1 9.8 Tf [( 3.17, )] TJ ET BT 367.704 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 374.207 356.524 Td /F1 9.8 Tf [( =0.003; HD: )] TJ ET BT 431.927 356.524 Td /F5 9.8 Tf [( t)] TJ ET BT 437.348 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 446.985 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 458.100 356.524 Td /F1 9.8 Tf [( 4.05, )] TJ ET BT 485.205 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 491.709 356.524 Td /F1 9.8 Tf [( <0.001\). When )] TJ ET BT 26.250 344.619 Td /F1 9.8 Tf [(mice were primed with ?- and muscarinic receptor blockers, there was no difference in ?HR/?BP ratios between WT and )] TJ ET BT 26.250 332.715 Td /F1 9.8 Tf [(BACHD mice after HD NP administration \(control: )] TJ ET BT 242.963 332.715 Td /F5 9.8 Tf [( t)] TJ ET BT 248.384 330.650 Td /F5 8.7 Tf [(12)] TJ ET BT 258.022 332.715 Td /F5 9.8 Tf [( = )] TJ ET BT 269.137 332.715 Td /F1 9.8 Tf [( 0.46, )] TJ ET BT 296.242 332.715 Td /F5 9.8 Tf [(P)] TJ ET BT 302.745 332.715 Td /F1 9.8 Tf [( =0.65\).)] TJ ET BT 26.250 313.310 Td /F1 9.8 Tf [(These data suggest that middle-aged BACHD mice have dysfunctional baro-receptor reflexes compared to WT controls. )] TJ ET BT 26.250 301.405 Td /F1 9.8 Tf [(BACHD mice are unable to appropriately modulate their HRs in response to either an increase or decrease in BP.)] TJ ET 0.965 0.965 0.965 rg 26.250 50.774 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 291.524 m 581.250 291.524 l 581.250 290.774 l 26.250 290.774 l f q 126.000 0 0 225.000 35.250 56.774 cm /I3 Do Q q 35.250 50.774 537.000 0.000 re W n Q Q q 15.000 50.774 577.500 726.226 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(To begin to determine whether BACHD mice show dysfunction in the cardiovascular system, we measured baseline BP and HR )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(in lightly anesthetized WT \( )] TJ ET BT 146.000 755.571 Td /F5 9.8 Tf [(n)] TJ ET BT 151.421 755.571 Td /F1 9.8 Tf [( =8\) and BACHD mice \( )] TJ ET BT 256.262 755.571 Td /F5 9.8 Tf [(n)] TJ ET BT 261.683 755.571 Td /F1 9.8 Tf [( =6; 7-9 mo of age\). Systolic BP was significantly higher in BACHD mice )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(\(108.0 6.9 mmHg\) compared to WT controls \(86.1 3.2 mmHg )] TJ ET BT 308.561 743.667 Td /F5 9.8 Tf [( ; t)] TJ ET BT 319.403 741.602 Td /F5 8.7 Tf [(12)] TJ ET BT 329.041 743.667 Td /F1 9.8 Tf [( =-3.13, )] TJ ET BT 365.086 743.667 Td /F5 9.8 Tf [(P)] TJ ET BT 371.590 743.667 Td /F1 9.8 Tf [( =0.009\) although BP levels were still )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(considered to be within the normal range. BACHD mice also displayed increased HRs \(615 23 bpm\) compared to WTs \(537 )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(21 bpm; T=61.0, )] TJ ET BT 100.233 719.857 Td /F5 9.8 Tf [(P=)] TJ ET BT 112.430 719.857 Td /F1 9.8 Tf [( 0.043\). The increased BP and HR measured in BACHD mice reflect a change in the regulation of the )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(cardiovascular system. Although the BP levels are still normal, the increase may be indicative of future susceptibility for )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(cardiovascular events.)] TJ ET BT 26.250 676.643 Td /F4 9.8 Tf [(Baroreceptor Reflex)] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(There is evidence that the ANS is dysfunctional in patients with Huntingtons disease. It has also been reported that BACHD )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(mice have significantly decreased HRV indicative of abnormal signal input to the heart by the ANS)] TJ ET 0.267 0.267 0.267 rg BT 448.932 645.333 Td /F1 9.8 Tf [( [16])] TJ ET 0.271 0.267 0.267 rg BT 467.906 645.333 Td /F1 9.8 Tf [( . We measured the )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(baroreceptor reflex of BACHD and WT mice to determine whether this feedback mechanism of regulating BP, which is mediated )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(by the ANS, is also disrupted. Changes in the ratios between the magnitude change in BP and HR after ATII \(vasoconstrictor\) or )] TJ ET BT 26.250 609.619 Td /F1 9.8 Tf [(NP \(vasodilator\) administration, may indicate aberrant signaling to the heart by the ANS.)] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(Increasing concentrations of ATII \(LD-0.5, MD-1.0, HD-4.0 ?g/kg\) were administered to mildly anesthetized WT and BACHD )] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(mice. By 2-way repeated measures ANOVA, we detected significant variation between genotype \( )] TJ ET BT 450.560 578.310 Td /F5 9.8 Tf [( F)] TJ ET BT 459.228 576.245 Td /F5 8.7 Tf [(1,55)] TJ ET BT 476.093 578.310 Td /F1 9.8 Tf [( =7.28, )] TJ ET BT 508.892 578.310 Td /F5 9.8 Tf [(P)] TJ ET BT 515.396 578.310 Td /F1 9.8 Tf [( =0.019\) and )] TJ ET BT 26.250 566.405 Td /F1 9.8 Tf [(concentration of ATII drug \( )] TJ ET BT 147.101 566.405 Td /F5 9.8 Tf [( F)] TJ ET BT 155.769 564.341 Td /F5 8.7 Tf [(3,55)] TJ ET BT 172.634 566.405 Td /F1 9.8 Tf [( =16.94, )] TJ ET BT 210.854 566.405 Td /F5 9.8 Tf [(P)] TJ ET BT 217.358 566.405 Td /F1 9.8 Tf [( <0.001\), but no significant interaction between genotype and drug concentration \( )] TJ ET BT 26.250 554.500 Td /F5 9.8 Tf [(F)] TJ ET BT 32.207 552.436 Td /F5 8.7 Tf [(3,55)] TJ ET BT 49.073 554.500 Td /F1 9.8 Tf [( =0.88, )] TJ ET BT 81.872 554.500 Td /F5 9.8 Tf [(P)] TJ ET BT 88.375 554.500 Td /F1 9.8 Tf [( =0.46; Fig. 1A\). Post )] TJ ET BT 182.950 554.500 Td /F5 9.8 Tf [(hoc)] TJ ET BT 198.667 554.500 Td /F1 9.8 Tf [( analysis indicate significant responses to all concentrations of AT II in WT mice when )] TJ ET BT 26.250 542.595 Td /F1 9.8 Tf [(compared to the control conditions where the ?- and muscarinic receptors were respectively blocked with propranolol and )] TJ ET BT 26.250 530.691 Td /F1 9.8 Tf [(glycopyrrolate before administration of a HD of ATII \(control vs. LD: )] TJ ET BT 318.857 530.691 Td /F5 9.8 Tf [( t)] TJ ET BT 324.278 528.626 Td /F5 8.7 Tf [(14)] TJ ET BT 333.916 530.691 Td /F5 9.8 Tf [( = )] TJ ET BT 345.031 530.691 Td /F1 9.8 Tf [( 2.32, )] TJ ET BT 372.136 530.691 Td /F5 9.8 Tf [(P)] TJ ET BT 378.639 530.691 Td /F1 9.8 Tf [( <0.01; control vs. MD: )] TJ ET BT 479.161 530.691 Td /F5 9.8 Tf [( t)] TJ ET BT 484.582 528.626 Td /F5 8.7 Tf [(14)] TJ ET BT 494.220 530.691 Td /F5 9.8 Tf [( = )] TJ ET BT 505.335 530.691 Td /F1 9.8 Tf [( 2.13, )] TJ ET BT 532.440 530.691 Td /F5 9.8 Tf [(P)] TJ ET BT 538.943 530.691 Td /F1 9.8 Tf [( <0.001; )] TJ ET BT 26.250 518.786 Td /F1 9.8 Tf [(control vs. HD: )] TJ ET BT 92.891 518.786 Td /F5 9.8 Tf [( t)] TJ ET BT 98.312 516.722 Td /F5 8.7 Tf [(14)] TJ ET BT 107.950 518.786 Td /F5 9.8 Tf [( = )] TJ ET BT 119.065 518.786 Td /F1 9.8 Tf [( 1.50, )] TJ ET BT 146.170 518.786 Td /F5 9.8 Tf [(P)] TJ ET BT 152.673 518.786 Td /F1 9.8 Tf [( <0.001\). Compared to controls, BACHD mice showed a significant difference in ?HR/?BP ratio )] TJ ET BT 26.250 506.881 Td /F1 9.8 Tf [(when administered the LD and MD of ATII, but did not have a significant response to the HD \(control vs. LD: )] TJ ET BT 494.464 506.881 Td /F5 9.8 Tf [( t)] TJ ET BT 499.885 504.817 Td /F5 8.7 Tf [(10)] TJ ET BT 509.523 506.881 Td /F5 9.8 Tf [( = )] TJ ET BT 520.638 506.881 Td /F1 9.8 Tf [( 3.49, )] TJ ET BT 547.743 506.881 Td /F5 9.8 Tf [(P)] TJ ET BT 26.250 494.976 Td /F1 9.8 Tf [(=0.008; control vs. MD: )] TJ ET BT 129.483 494.976 Td /F5 9.8 Tf [( t)] TJ ET BT 134.904 492.912 Td /F5 8.7 Tf [(10)] TJ ET BT 144.541 494.976 Td /F5 9.8 Tf [( = )] TJ ET BT 155.656 494.976 Td /F1 9.8 Tf [( 2.87, )] TJ ET BT 182.761 494.976 Td /F5 9.8 Tf [(P)] TJ ET BT 189.265 494.976 Td /F1 9.8 Tf [( =0.041; control vs. HD: )] TJ ET BT 294.126 494.976 Td /F5 9.8 Tf [( t)] TJ ET BT 299.547 492.912 Td /F5 8.7 Tf [(10)] TJ ET BT 309.184 494.976 Td /F5 9.8 Tf [( = )] TJ ET BT 320.299 494.976 Td /F1 9.8 Tf [( 2.31, )] TJ ET BT 347.404 494.976 Td /F5 9.8 Tf [(P)] TJ ET BT 353.907 494.976 Td /F1 9.8 Tf [( =0.16\). For each of the doses of ATII, the HR of )] TJ ET BT 26.250 483.072 Td /F1 9.8 Tf [(BACHD mice responded with less magnitude compared to WT mice \(LD: )] TJ ET BT 342.676 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 348.097 481.007 Td /F5 8.7 Tf [(12)] TJ ET BT 357.735 483.072 Td /F5 9.8 Tf [( = )] TJ ET BT 368.850 483.072 Td /F1 9.8 Tf [( 2.03, p=0.049; MD: )] TJ ET BT 457.468 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 462.889 481.007 Td /F5 8.7 Tf [(12)] TJ ET BT 472.526 483.072 Td /F5 9.8 Tf [( = )] TJ ET BT 483.641 483.072 Td /F1 9.8 Tf [( 2.21, p=0.033; HD: )] TJ ET BT 571.176 483.072 Td /F5 9.8 Tf [( t)] TJ ET BT 26.250 469.103 Td /F5 8.7 Tf [(12)] TJ ET BT 35.887 471.167 Td /F5 9.8 Tf [( = )] TJ ET BT 47.002 471.167 Td /F1 9.8 Tf [( 2.33, )] TJ ET BT 74.107 471.167 Td /F5 9.8 Tf [(P)] TJ ET BT 80.611 471.167 Td /F1 9.8 Tf [( =0.025\). There was no difference in the ?HR/?BP ratios between WT and BACHD mice when the ?- and )] TJ ET BT 26.250 459.262 Td /F1 9.8 Tf [(muscarinic receptors were blocked \(control: )] TJ ET BT 216.970 459.262 Td /F5 9.8 Tf [( t)] TJ ET BT 222.391 457.198 Td /F5 8.7 Tf [(14)] TJ ET BT 232.028 459.262 Td /F5 9.8 Tf [( = )] TJ ET BT 243.143 459.262 Td /F1 9.8 Tf [( 0.58, )] TJ ET BT 270.248 459.262 Td /F5 9.8 Tf [(P)] TJ ET BT 276.751 459.262 Td /F1 9.8 Tf [( =0.56\).)] TJ ET BT 26.250 439.857 Td /F1 9.8 Tf [(To test the HR response of WT and BACHD mice to decreases in BP, we administered increasing concentrations of NP \(LD- )] TJ ET BT 26.250 427.953 Td /F1 9.8 Tf [(10, MD- 20, HD- 40 ?g/kg\). By 2-way repeated measures ANOVA, we detected significant interaction between genotype and )] TJ ET BT 26.250 416.048 Td /F1 9.8 Tf [(concentrations of NP drug \( )] TJ ET BT 147.637 416.048 Td /F5 9.8 Tf [( F )] TJ ET BT 159.016 413.984 Td /F5 8.7 Tf [(3,55)] TJ ET BT 175.881 416.048 Td /F1 9.8 Tf [( =4.079, )] TJ ET BT 214.101 416.048 Td /F5 9.8 Tf [(P)] TJ ET BT 220.604 416.048 Td /F1 9.8 Tf [( =0.014, Fig. 1B\). Post )] TJ ET BT 320.600 416.048 Td /F5 9.8 Tf [(hoc)] TJ ET BT 336.317 416.048 Td /F1 9.8 Tf [( analysis detects a significant response to all )] TJ ET BT 26.250 404.143 Td /F1 9.8 Tf [(concentrations of NP in WT mice when compared to the control \(control vs. LD: )] TJ ET BT 370.337 404.143 Td /F5 9.8 Tf [( t )] TJ ET BT 378.469 402.079 Td /F5 8.7 Tf [(14)] TJ ET BT 388.106 404.143 Td /F5 9.8 Tf [( = )] TJ ET BT 399.221 404.143 Td /F1 9.8 Tf [( 5.62, )] TJ ET BT 426.326 404.143 Td /F5 9.8 Tf [(P)] TJ ET BT 432.829 404.143 Td /F1 9.8 Tf [( <0.001; control vs. MD: )] TJ ET BT 538.773 404.143 Td /F5 9.8 Tf [( t)] TJ ET BT 544.194 402.079 Td /F5 8.7 Tf [(14)] TJ ET BT 553.831 404.143 Td /F5 9.8 Tf [( = )] TJ ET BT 26.250 392.238 Td /F1 9.8 Tf [(6.35, )] TJ ET BT 50.645 392.238 Td /F5 9.8 Tf [(P)] TJ ET BT 57.148 392.238 Td /F1 9.8 Tf [( <0.001; control vs. HD: )] TJ ET BT 162.009 392.238 Td /F5 9.8 Tf [( t)] TJ ET BT 167.430 390.174 Td /F5 8.7 Tf [(14)] TJ ET BT 177.067 392.238 Td /F5 9.8 Tf [( = )] TJ ET BT 188.182 392.238 Td /F1 9.8 Tf [( 6.89, )] TJ ET BT 215.287 392.238 Td /F5 9.8 Tf [(P)] TJ ET BT 221.791 392.238 Td /F1 9.8 Tf [( <0.001\). BACHD mice, on the other hand, did not show any significant response )] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(for any of the concentrations of NP when compared to the control condition \(control vs. LD: )] TJ ET BT 420.228 380.334 Td /F5 9.8 Tf [( t )] TJ ET BT 428.360 378.269 Td /F5 8.7 Tf [(10)] TJ ET BT 437.997 380.334 Td /F5 9.8 Tf [( = )] TJ ET BT 449.112 380.334 Td /F1 9.8 Tf [( 1.43, )] TJ ET BT 476.217 380.334 Td /F5 9.8 Tf [(P)] TJ ET BT 482.720 380.334 Td /F1 9.8 Tf [( =0.96; control vs. )] TJ ET BT 26.250 368.429 Td /F1 9.8 Tf [(MD: )] TJ ET BT 46.832 368.429 Td /F5 9.8 Tf [( t)] TJ ET BT 52.253 366.365 Td /F5 8.7 Tf [(10)] TJ ET BT 61.891 368.429 Td /F5 9.8 Tf [( = )] TJ ET BT 73.006 368.429 Td /F1 9.8 Tf [( 2.26, )] TJ ET BT 100.111 368.429 Td /F5 9.8 Tf [(P)] TJ ET BT 106.614 368.429 Td /F1 9.8 Tf [( =0.18; control vs. HD: )] TJ ET BT 206.054 368.429 Td /F5 9.8 Tf [( t)] TJ ET BT 211.475 366.365 Td /F5 8.7 Tf [(10)] TJ ET BT 221.112 368.429 Td /F5 9.8 Tf [( = )] TJ ET BT 232.227 368.429 Td /F1 9.8 Tf [( 1.66, )] TJ ET BT 259.332 368.429 Td /F5 9.8 Tf [(P)] TJ ET BT 265.836 368.429 Td /F1 9.8 Tf [( =0.64\). For each of the doses of NP, BACHD had significantly lower )] TJ ET BT 26.250 356.524 Td /F1 9.8 Tf [(responses compared to WT mice \(LD: )] TJ ET BT 193.131 356.524 Td /F5 9.8 Tf [( t )] TJ ET BT 201.262 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 210.900 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 222.015 356.524 Td /F1 9.8 Tf [( 3.32, )] TJ ET BT 249.120 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 255.623 356.524 Td /F1 9.8 Tf [( =0.002; MD: )] TJ ET BT 314.425 356.524 Td /F5 9.8 Tf [( t)] TJ ET BT 319.846 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 329.484 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 340.599 356.524 Td /F1 9.8 Tf [( 3.17, )] TJ ET BT 367.704 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 374.207 356.524 Td /F1 9.8 Tf [( =0.003; HD: )] TJ ET BT 431.927 356.524 Td /F5 9.8 Tf [( t)] TJ ET BT 437.348 354.460 Td /F5 8.7 Tf [(12)] TJ ET BT 446.985 356.524 Td /F5 9.8 Tf [( = )] TJ ET BT 458.100 356.524 Td /F1 9.8 Tf [( 4.05, )] TJ ET BT 485.205 356.524 Td /F5 9.8 Tf [(P)] TJ ET BT 491.709 356.524 Td /F1 9.8 Tf [( <0.001\). When )] TJ ET BT 26.250 344.619 Td /F1 9.8 Tf [(mice were primed with ?- and muscarinic receptor blockers, there was no difference in ?HR/?BP ratios between WT and )] TJ ET BT 26.250 332.715 Td /F1 9.8 Tf [(BACHD mice after HD NP administration \(control: )] TJ ET BT 242.963 332.715 Td /F5 9.8 Tf [( t)] TJ ET BT 248.384 330.650 Td /F5 8.7 Tf [(12)] TJ ET BT 258.022 332.715 Td /F5 9.8 Tf [( = )] TJ ET BT 269.137 332.715 Td /F1 9.8 Tf [( 0.46, )] TJ ET BT 296.242 332.715 Td /F5 9.8 Tf [(P)] TJ ET BT 302.745 332.715 Td /F1 9.8 Tf [( =0.65\).)] TJ ET BT 26.250 313.310 Td /F1 9.8 Tf [(These data suggest that middle-aged BACHD mice have dysfunctional baro-receptor reflexes compared to WT controls. )] TJ ET BT 26.250 301.405 Td /F1 9.8 Tf [(BACHD mice are unable to appropriately modulate their HRs in response to either an increase or decrease in BP.)] TJ ET 0.965 0.965 0.965 rg 26.250 50.774 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 291.524 m 581.250 291.524 l 581.250 290.774 l 26.250 290.774 l f q 126.000 0 0 225.000 35.250 56.774 cm /I3 Do Q q 35.250 50.774 537.000 0.000 re W n Q Q q 126.000 0 0 225.000 35.250 56.774 cm /I3 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(3)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 217 0 obj << /Type /Annot /Subtype /Link /A 218 0 R /Border [0 0 0] /H /I /Rect [ 448.9320 644.4316 467.9055 654.3522 ] >> endobj 218 0 obj << /Type /Action >> endobj 219 0 obj << /Type /Annot /Subtype /Link /A 220 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 56.7743 161.2500 281.7743 ] >> endobj 220 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/ayalyne061311a.tif) >> endobj 221 0 obj << /Type /XObject /Subtype /Image /Width 168 /Height 300 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 12684>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?~7 iD#dBmN ?8}znnLqNwG?YgktYwG_AzhsIz(Ͻ>gފ(3Kz(> џz(Ͻ.}袀>3EPU KZVwakY_b#{+<zj 5xO^Z<Z]=Βڬw\F DF L9/]k^94ٶB\f2p;W__ru[ZOJtB,g(Ɠ5~3ў#^hw]ae 1Y >ei[YTQyW^^xYz } 1F?x~34k1ouM?]9Ki,a#?J} XztA|5xSulb-`%p6 Fހ?A3Kx_u;ڝ-h-e 0PǕ+,-u57ů#PQQֿ?go MѦ-c3pw<$<s1@O~UƿSxXiG 2A?ֆ5U7yVUsqyjY~J>*%V€?L+-xxG:g<@4&I\l}p? 1qF(ǵc;PҤZUona2,)gi|y;̠lF*xڴz,wDW6rA{eL͍S pĀquQ֡Rjl#k(ԠFq KU"(TnаbF >cr{>Qc/*Rk*XGJ)uZMG?+_%ѭ@_q?j&'뎡SWm|' /ZΟV2KO҅>oHk?+Wo%B ~"|QcLIk_uOvDe4S5۾i,N׊(?j?<-!^:<3sR;LvSRI!-ʓ[hFH%)#PsNGNJn 9'aاg7umEZַx?DZZ@'!M32zgWQ/^su2\\l3(G3IaںAÖv7-%ͫN1"c%''eqZ@QOr8:4f>R4PgފZ(oǶ֓ÏsXֺwoymBX~rdn+J~9'KѮF{VYg7oI.r>/%u.sj,Mp$d4@@1J #ru:?~#V 7J)uZGy?yk*_f^<ܾ2c__(>'j ߶Of qtA_SxWxK k7r[ĸǛs޿_|>}KH'ܫ=>U.O_?—վyo{q{дJɊ ,s]8?e" _dWV2KO҅, ߲F>."&.?΀>//ľdLWB'Yр4s<ғį,bsNGNJn"^0赭}+(hZ(ҊJ(y}((W^qZK}+Ntm-P7Tko|&~{֟T7O$JYYG J7~(CAG"ԡ,j:6G<*Uwo-F+ƀ9G/+_%ѭ_&#땯A AMM_s^\klyGjU/ q;ŃWI!G0/M!U/,{c;p-V!$-2zh++Wo%B?s:}ᯉAfcWI$a̧*J2"?)ɲx "|4eO1o&{#4,I?5?>i'7Ri o)URUgEu4R4~4ؓgTL:_؛F7K+nj?<|dƐ캹lS[fq8Z#7'8\٥}'jY$D#꬧8 Ol|7$f1jvW)?+ {Ž/|.5}V[ r!(muv:5 ~)h? rjTz|V+.:cGсʐ1^w! PZF8G{bS!c\G| CnxV G@MjwrGtx~Q,kcx+^޷ZjpAArmT[<8}g^^q&jksu:41$8cF u9i.y & VF[e^nc46M'Ū-ٻݟ)b9?y ꫜOvڊ^('.!y!8c8RKגqX;O?\YկcԓUw7d,"2LYPyd(I$A!E/k?F?A [[f_*0ܫXdk7oo |:5jwF8gӢI%Ďtq'TPAWx4r:|Iщm1-ŝŸI/Yn2+A[2{W[.>w_s,socHSs;dn{ڇsEh9gklj:ehZɍF# kG_Azhu_r}v>no9WP4- :pHu\QE ZJ9𥢀AG>RsG>((R@ ϠAE-'>–N}Q@E.(sXm5KK8XVݑnNA*ڍ&ڷU;@l}8#>`x{Ķc-2JnAwr|вr1s@ c N}j =} Q+ny ExABťRw8LHѹIwB2QV85|7a h|rZ_Kq *lDx {{MfWЭu}7Xk1N$3ҔU*wvrK9lpHBhHe:0 ؐAA=$Zqgx@P:~.mo:"wg5m!†t*2@4V7Ag#Akh$)4e* \* tohkhoX)AZ`r1H#A/E/e|6WxCUjwW־=,% .m̕+ЮƺO;q+im~N`Ojźմ5H4Mn-hVѐ0 \;M5MK>q=)dn3 ?gXxEk7vhڵ/,jkpr$cޘ3b6hVkݕZ1|p]rO ry [Uƹ/.6pR85x7V9լJOBRK~c; ,FᏅnm&{ܒIq$h" z6%̳xR18Mٷqg]n=~ |ռ_j̶6`KHd-ɖ_9BNhnb]Uu$%)í7Y״oF$վ+.33ۇ!TB>e23\ß+΁}h6]HZfhɍ~y/6U.O\Ե-]H mCq{([wCF1 ,;X.kZ̋,SD,! -AG\{k Ŵo* #& d2r8g7x@XdCq,?2 H%[rJlmtX=(=)1F=J?JOŒ{P&=(J?JL{TUZ[k$q,x,,,Ŝ"=A0}/^)O8S^X_ "}Ͳƥ#.a>p%{{QP{:ՍeP-ׯ^;9tbllؙYwӳ sǐ]\\;;:&T m0THH^(ǵs_ <7u߆E%ZXNѴBI8v\{Q@ E~<|'ZOJRYcHDRX* l @ 6FE\6FE(4f (4 =z-x5+vh Iq[iMs]7Zְvtii3Y|$ SnH$QE09+ eɴ;7GdNGs]dz~hv^ak`$5 vɂhz @-t6 >PZ۠HAUGp*f ( (QEbn~ O!ao xeM $rA.0Ʌd-dau=׾$jKK n<eC #}<5 zx9}Ii os%,}u B zl1 [moEUu/gԴyg x._hzLd[bIr ;zVwmt 6[G_hFI6*7) }hq@ 1Ir?,So|]]Thx{o,GdJr]p_:_]L?f|e/ĕ6]$غ[>y+~ |?}|>Lj4+eq8d sր=b8u"sF_ڗXmCOo΀?\Q>UZ8ԁF3U7 554Pċn|;ʟ~ 7@}`~QYS_0X\\\y\;/Dtel ظo -{zod"?WZIk}nBD&_}^@ )8>^% MgPj%'Xȋ" Y۹חQ |yepߵ àYFfini.c6}da wRvit|eΣo:;? j\,Ÿ}5Rxd r!L4K@cn?PBgnvv mzH+!L8g8th8k& byX^}%{҇;x?pk^#|ϲإFO.6i!UDs=kݿ \|4. &G?ӿ*Cɑ,?+_&I-eo~7ހ?C )ho-O7Mx__-hi$¿ +]\O'UZ1@g[Z爼?y6ַHm&t#~ZUz /Im_×kWlq@$7Inz$>c# } 1@ "uꚅj7ku}Cu5IQ#0!K[;S<{!:ڏ$"tx˧̭wX9Om[٭܋HYH8軶UAQ@/xgA?WedSv&+xi'W*V`W_PWʿb־NGeMs>kH-ţKE6.}_ >.>WU2?ޝWי૟d~3;K"Z&ɽƇKzio"wߍh$Š3Fh_ S'Mm?t6Ko8JIW5Ÿ?JIz) LZ3@/Iz2h )3E|os:ٔ[2Ohr{%L.^#)d9v3/U׵ 5=g{L[dž[$/ [_|Mtx6~(. 9|Rn6++ ܪFsr5ė|E[Im" 1D_:csdCa%[m'vJ= q'lʿ}_ >.|\#}Y}y|\#}Y~ WAǎX w'_UmᏀ37YJ}SP`}25uKW guI,ND*=?>ʏʌqGGE(?Sv>;%[1I:8<naQN+۹_|S:啁$K녔'`{‘n*1IڬaXlm5_?x÷P'<9|FiSO4ea-Tǽ<~x⧌m1[M^iHw!A?K>MOMU}g#Hqqx&w3Y 6Á#&| wK;Ehl+t͍]ewb̫) JPќU,w'<)GXM^hW7_):nB]&htɖw w1*aB mW'*Хo&N< gv~$?˯HxF`FG> ^&GgH8^)xiȚ8 /#$ B>ңĺ:H++_!A+ S'MmП+Sz|G+hHI/ 0 zßeBٿ=Ÿ$EJhx ;|*18z.3BֵKm>ķ:m +90ڬz/t _z :ӭ{ՕJ =n2oi\W4쳮IE{4; _4h0Uiσ[ǁՁv`(9M~kWkkMuD6@v-o*:hb af(F5(Nz(s>(sVӵNi.lH\IJXTT""`GtfǽzJ`w]k0w]=sFi1F=sFi1F=sFi1F=sFi1F=sFi1G@ 3I!Kļ>̒p2@$gF=mrk ƺGqc:}[͵OW\m? 7-Oeu >TT%=\Z'ZoɦEkr:j/>_]YԵ='KcPʆ5,e,p8PmEy_?uˋm"[e`dXYn1>0jaINJ^=.A.˴^C+H7@ pxW 9]sLu.f-4JDuG{?:/t\qך5]?Muu3m_'.W#ε{kmgxQtw]m7FA\"Wu-c$ 9.FuhWt9,5Zk[L~L0A'$`| @A|G6Xz\sF'd2!#< QsW1_#E] u}DB&)ĜszO5֐5 *X߷Rf=?>m46+>% F ;fkff&/Bg2+|s=h,eNSѼS:r}L30Y%cGwJ"+u;[MYsjevEzyH!F!PdWv@)Hԓkڽ>7z1no {W'q@o~i^k0{i4,!炸Cָ/7,=HtRKh*e2dಆ(m2JB&NU5oPZts_m[p؝y$m۪H P8 }uЇgqG#BкV$h?q |=@Nx endstream endobj 222 0 obj << /Type /Annot /Subtype /Link /A 223 0 R /Border [0 0 0] /H /I /Rect [ 448.9320 644.4316 467.9055 654.3522 ] >> endobj 223 0 obj << /Type /Action >> endobj 224 0 obj << /Type /Annot /Subtype /Link /A 225 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 56.7743 161.2500 281.7743 ] >> endobj 225 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/ayalyne061311a.tif) >> endobj 226 0 obj << /Type /Annot /Subtype /Link /A 227 0 R /Border [0 0 0] /H /I /Rect [ 448.9320 644.4316 467.9055 654.3522 ] >> endobj 227 0 obj << /Type /Action >> endobj 228 0 obj << /Type /Annot /Subtype /Link /A 229 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 56.7743 161.2500 281.7743 ] >> endobj 229 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/ayalyne061311a.tif) >> endobj 230 0 obj << /Type /Page /Parent 3 0 R /Annots [ 233 0 R 236 0 R 239 0 R 241 0 R 243 0 R 245 0 R ] /Contents 231 0 R >> endobj 231 0 obj << /Length 31278 >> stream q 15.000 27.868 577.500 749.132 re W n 0.965 0.965 0.965 rg 26.250 657.928 555.000 119.072 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 657.928 m 581.250 657.928 l 581.250 658.678 l 26.250 658.678 l f q 35.250 669.178 537.000 107.822 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Baroreceptor Reflex in WT and BACHD mice.)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(Mice were administered increasing concentrations of ATII \(A\) and NP \(B\). For control conditions, mice were primed with )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(muscarinic and ?- blockers before administration of the HD of ATII and NP. The maximum change in HR \(?HR\) and the )] TJ ET BT 35.250 720.634 Td /F1 9.8 Tf [(absolute value of the maximum change in BP \(?BP\) following drug administration was measured. We compared ?HR/?BP )] TJ ET BT 35.250 706.897 Td /F1 9.8 Tf [(among the different groups using a 2-way repeated measures ANOVA. # significant response compared to control )] TJ ET BT 35.250 693.161 Td /F1 9.8 Tf [(conditions in WT mice. ^ significant response compared to control conditions in BACHD mice. * significant difference )] TJ ET BT 35.250 679.425 Td /F1 9.8 Tf [(between WT and BACHD mice.)] TJ ET Q BT 26.250 640.904 Td /F4 9.8 Tf [(Morphometry)] TJ ET BT 26.250 621.499 Td /F1 9.8 Tf [(Increased BP and changes in baroreceptor reflex function may lead to cardiac hypertrophy. We used a standard measure of )] TJ ET BT 26.250 609.594 Td /F1 9.8 Tf [(heart morphometry by calculating the ratio of heart weight \(HW\) relative to body weight \(BW\) or tibia length \(TL\) in 7-8 mo and )] TJ ET BT 26.250 597.690 Td /F1 9.8 Tf [(12 mo old WT and BACHD mice.)] TJ ET BT 26.250 578.285 Td /F1 9.8 Tf [(In comparing the morphometry parameters among the various groups by 2-way ANOVA, we detected a significant effect of )] TJ ET BT 26.250 566.380 Td /F1 9.8 Tf [(genotype on BW \( )] TJ ET BT 106.999 566.380 Td /F5 9.8 Tf [( F)] TJ ET BT 115.667 564.316 Td /F5 8.7 Tf [(1,22)] TJ ET BT 132.533 566.380 Td /F1 9.8 Tf [( =11.36, )] TJ ET BT 170.753 566.380 Td /F5 9.8 Tf [(P)] TJ ET BT 177.256 566.380 Td /F1 9.8 Tf [( =0.003\), with BACHD mice displaying increased BW at 7mo. of age \( )] TJ ET BT 479.350 566.380 Td /F5 9.8 Tf [( t)] TJ ET BT 484.771 564.316 Td /F5 8.7 Tf [(12)] TJ ET BT 494.408 566.380 Td /F5 9.8 Tf [( =3.31, P= )] TJ ET BT 542.115 566.380 Td /F1 9.8 Tf [( 0.004\) )] TJ ET BT 26.250 554.475 Td /F1 9.8 Tf [(when compared to WT mice, but this difference is no longer detected between genotypes at 12 mo of age \( )] TJ ET BT 489.609 554.475 Td /F5 9.8 Tf [( t)] TJ ET BT 495.030 552.411 Td /F5 8.7 Tf [(12)] TJ ET BT 504.667 554.475 Td /F5 9.8 Tf [( =1.49, P )] TJ ET BT 546.680 554.475 Td /F1 9.8 Tf [( =0.15; )] TJ ET BT 26.250 542.571 Td /F1 9.8 Tf [(Table 1\). When comparing the HWs, we found a significant effect of genotype \( )] TJ ET BT 369.284 542.571 Td /F5 9.8 Tf [( F)] TJ ET BT 377.952 540.506 Td /F5 8.7 Tf [(1,22)] TJ ET BT 394.817 542.571 Td /F1 9.8 Tf [( =13.20, )] TJ ET BT 433.037 542.571 Td /F5 9.8 Tf [(P)] TJ ET BT 439.541 542.571 Td /F1 9.8 Tf [( =0.002\) and age \( )] TJ ET BT 522.201 542.571 Td /F5 9.8 Tf [( F)] TJ ET BT 530.869 540.506 Td /F5 8.7 Tf [(1,22)] TJ ET BT 547.734 542.571 Td /F1 9.8 Tf [( =8.78, )] TJ ET BT 26.250 530.666 Td /F5 9.8 Tf [(P)] TJ ET BT 32.753 530.666 Td /F1 9.8 Tf [( =0.008\), but no significant interaction between genotype and age \( )] TJ ET BT 324.073 530.666 Td /F5 9.8 Tf [( F)] TJ ET BT 332.741 528.602 Td /F5 8.7 Tf [(1,22)] TJ ET BT 349.607 530.666 Td /F1 9.8 Tf [( =0.13, )] TJ ET BT 382.406 530.666 Td /F5 9.8 Tf [(P)] TJ ET BT 388.909 530.666 Td /F1 9.8 Tf [( =0.72; Table 1\). The HWs of WT mice )] TJ ET BT 26.250 518.761 Td /F1 9.8 Tf [(increased as they aged \( )] TJ ET BT 135.723 518.761 Td /F5 9.8 Tf [( t)] TJ ET BT 141.144 516.697 Td /F5 8.7 Tf [(14)] TJ ET BT 150.781 518.761 Td /F1 9.8 Tf [( =1.31, )] TJ ET BT 183.580 518.761 Td /F5 9.8 Tf [(P)] TJ ET BT 190.084 518.761 Td /F1 9.8 Tf [( =0.032\), but at both age groups, the HW of BACHD mice were significantly higher when )] TJ ET BT 26.250 506.856 Td /F1 9.8 Tf [(compared to WT mice \(7mo.: )] TJ ET BT 154.657 506.856 Td /F5 9.8 Tf [(t)] TJ ET BT 157.368 504.792 Td /F1 8.7 Tf [(12)] TJ ET BT 167.005 506.856 Td /F5 9.8 Tf [(=2.87,)] TJ ET BT 194.383 506.856 Td /F1 9.8 Tf [( P )] TJ ET BT 206.308 506.856 Td /F5 9.8 Tf [(=0.01;)] TJ ET BT 233.686 506.856 Td /F1 9.8 Tf [( 12mo )] TJ ET BT 263.491 506.856 Td /F5 9.8 Tf [(:)] TJ ET BT 266.202 506.856 Td /F5 9.8 Tf [( t)] TJ ET BT 271.623 504.792 Td /F5 8.7 Tf [(12)] TJ ET BT 281.260 506.856 Td /F1 9.8 Tf [( =2.28, )] TJ ET BT 314.059 506.856 Td /F5 9.8 Tf [(P)] TJ ET BT 320.562 506.856 Td /F1 9.8 Tf [( =0.035\). Lastly, we found a significant effect of age \( )] TJ ET BT 551.715 506.856 Td /F5 9.8 Tf [( F)] TJ ET BT 560.383 504.792 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 494.952 Td /F1 9.8 Tf [(=7.16, )] TJ ET BT 56.338 494.952 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 494.952 Td /F1 9.8 Tf [( =0.015\) when comparing TL \(Table 1\). The TL of WT mice increased as they aged \( )] TJ ET BT 429.432 494.952 Td /F5 9.8 Tf [( t)] TJ ET BT 434.853 492.887 Td /F5 8.7 Tf [(14)] TJ ET BT 444.490 494.952 Td /F1 9.8 Tf [( =2.88, )] TJ ET BT 477.289 494.952 Td /F5 9.8 Tf [(P)] TJ ET BT 483.793 494.952 Td /F1 9.8 Tf [( =0.01\), but this trend )] TJ ET BT 26.250 483.047 Td /F1 9.8 Tf [(was not detected in BACHD mice. Similar to BW, the TLs of BACHD mice were longer at 7mo. \( )] TJ ET BT 441.298 483.047 Td /F5 9.8 Tf [( t)] TJ ET BT 446.719 480.983 Td /F5 8.7 Tf [(12)] TJ ET BT 456.356 483.047 Td /F1 9.8 Tf [( = 2.43, )] TJ ET BT 491.866 483.047 Td /F5 9.8 Tf [(P)] TJ ET BT 498.369 483.047 Td /F1 9.8 Tf [( =0.025\) )] TJ ET BT 26.250 471.142 Td /F1 9.8 Tf [(compared to WT mice, but not at 12 mo of age \( )] TJ ET BT 235.972 471.142 Td /F5 9.8 Tf [( t)] TJ ET BT 241.393 469.078 Td /F5 8.7 Tf [(12)] TJ ET BT 251.031 471.142 Td /F1 9.8 Tf [( = 0.32, )] TJ ET BT 286.540 471.142 Td /F5 9.8 Tf [(P)] TJ ET BT 293.044 471.142 Td /F1 9.8 Tf [( =0.76\).)] TJ ET 0.965 0.965 0.965 rg 26.250 371.261 555.000 90.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 461.261 m 581.250 461.261 l 581.250 460.511 l 26.250 460.511 l f 26.250 371.261 m 581.250 371.261 l 581.250 372.011 l 26.250 372.011 l f q 225.000 0 0 70.500 35.250 381.011 cm /I4 Do Q q 35.250 375.011 537.000 0.000 re W n Q 0.271 0.267 0.267 rg BT 26.250 354.237 Td /F6 9.8 Tf [(Table 1:)] TJ ET BT 63.095 354.237 Td /F5 9.8 Tf [( Morphometry measurements of WT and BACHD mice. * significance between genotypes. )] TJ ET BT 453.778 354.237 Td /F5 9.8 Tf [(# significance between ages.)] TJ ET BT 26.250 334.833 Td /F1 9.8 Tf [(We did not find significant differences in the HW/BW ratios between WT and BACHD mice by 2-way ANOVA \(age: )] TJ ET BT 520.965 334.833 Td /F5 9.8 Tf [( F )] TJ ET BT 532.343 332.768 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 322.928 Td /F1 9.8 Tf [(=0.66, )] TJ ET BT 56.338 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 322.928 Td /F1 9.8 Tf [( =0.43; genotype: )] TJ ET BT 141.173 322.928 Td /F5 9.8 Tf [( F )] TJ ET BT 152.551 320.864 Td /F5 8.7 Tf [(1,22)] TJ ET BT 169.417 322.928 Td /F1 9.8 Tf [( =2.85, )] TJ ET BT 202.216 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 208.719 322.928 Td /F1 9.8 Tf [( =0.108; age X genotype: )] TJ ET BT 320.659 322.928 Td /F5 9.8 Tf [( F )] TJ ET BT 332.037 320.864 Td /F5 8.7 Tf [(1,22)] TJ ET BT 348.902 322.928 Td /F1 9.8 Tf [( =2.22, )] TJ ET BT 381.701 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 388.205 322.928 Td /F1 9.8 Tf [( =0.15\), but measured significant )] TJ ET BT 26.250 311.023 Td /F1 9.8 Tf [(differences in the HW/TL ratios between the two genotypes \(Fig. 2\). By 2-way ANOVA, we find a significant effect of genotype \( )] TJ ET BT 26.250 299.118 Td /F5 9.8 Tf [(F )] TJ ET BT 34.918 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 51.783 299.118 Td /F1 9.8 Tf [( =10.50, )] TJ ET BT 90.003 299.118 Td /F5 9.8 Tf [(P)] TJ ET BT 96.506 299.118 Td /F1 9.8 Tf [( =0.004\) and age \( )] TJ ET BT 179.167 299.118 Td /F5 9.8 Tf [( F )] TJ ET BT 190.545 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 207.410 299.118 Td /F1 9.8 Tf [( =5.31, )] TJ ET BT 240.209 299.118 Td /F5 9.8 Tf [(P)] TJ ET BT 246.713 299.118 Td /F1 9.8 Tf [( =0.033\), but do not detect an interaction between genotype and age \( )] TJ ET BT 551.059 299.118 Td /F5 9.8 Tf [( F )] TJ ET BT 562.437 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 287.214 Td /F1 9.8 Tf [(=0.001, )] TJ ET BT 61.760 287.214 Td /F5 9.8 Tf [(P)] TJ ET BT 68.263 287.214 Td /F1 9.8 Tf [( =0.97\). The HW/TL ratios did not change as BACHD or WT mice aged \(WT: )] TJ ET BT 400.689 287.214 Td /F5 9.8 Tf [( t )] TJ ET BT 408.820 285.149 Td /F5 8.7 Tf [(9)] TJ ET BT 413.639 287.214 Td /F1 9.8 Tf [( =0.131, )] TJ ET BT 451.859 287.214 Td /F5 9.8 Tf [(P)] TJ ET BT 458.362 287.214 Td /F1 9.8 Tf [( >0.05; BACHD: )] TJ ET BT 530.707 287.214 Td /F5 9.8 Tf [( t )] TJ ET BT 538.839 285.149 Td /F5 8.7 Tf [(10)] TJ ET BT 26.250 275.309 Td /F1 9.8 Tf [(=0.108, )] TJ ET BT 61.760 275.309 Td /F5 9.8 Tf [(P)] TJ ET BT 68.263 275.309 Td /F1 9.8 Tf [( >0.05\), but the HW/TL ratios were significantly higher in BACHD mice compared to WT mice at both ages \(7mo: )] TJ ET BT 555.665 275.309 Td /F5 9.8 Tf [( t )] TJ ET BT 563.797 273.245 Td /F5 8.7 Tf [(10)] TJ ET BT 26.250 263.404 Td /F1 9.8 Tf [(=2.30, )] TJ ET BT 56.338 263.404 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 263.404 Td /F1 9.8 Tf [( =0.033; 12mo: )] TJ ET BT 130.868 263.404 Td /F5 9.8 Tf [( t )] TJ ET BT 138.999 261.340 Td /F5 8.7 Tf [(9)] TJ ET BT 143.818 263.404 Td /F1 9.8 Tf [( =2.28, )] TJ ET BT 176.617 263.404 Td /F5 9.8 Tf [(P)] TJ ET BT 183.120 263.404 Td /F1 9.8 Tf [( =0.034\). These data indicate that the hearts of BACHD mice are increased in mass in )] TJ ET BT 26.250 251.499 Td /F1 9.8 Tf [(relation to body frame and likely result in some form of cardiac remodeling.)] TJ ET 0.965 0.965 0.965 rg 26.250 27.868 555.000 213.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 241.618 m 581.250 241.618 l 581.250 240.868 l 26.250 240.868 l f q 225.000 0 0 198.000 35.250 33.868 cm /I5 Do Q q 35.250 27.868 537.000 0.000 re W n Q Q q 15.000 27.868 577.500 749.132 re W n 0.965 0.965 0.965 rg 26.250 657.928 555.000 119.072 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 657.928 m 581.250 657.928 l 581.250 658.678 l 26.250 658.678 l f q 35.250 669.178 537.000 107.822 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Baroreceptor Reflex in WT and BACHD mice.)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(Mice were administered increasing concentrations of ATII \(A\) and NP \(B\). For control conditions, mice were primed with )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(muscarinic and ?- blockers before administration of the HD of ATII and NP. The maximum change in HR \(?HR\) and the )] TJ ET BT 35.250 720.634 Td /F1 9.8 Tf [(absolute value of the maximum change in BP \(?BP\) following drug administration was measured. We compared ?HR/?BP )] TJ ET BT 35.250 706.897 Td /F1 9.8 Tf [(among the different groups using a 2-way repeated measures ANOVA. # significant response compared to control )] TJ ET BT 35.250 693.161 Td /F1 9.8 Tf [(conditions in WT mice. ^ significant response compared to control conditions in BACHD mice. * significant difference )] TJ ET BT 35.250 679.425 Td /F1 9.8 Tf [(between WT and BACHD mice.)] TJ ET Q BT 26.250 640.904 Td /F4 9.8 Tf [(Morphometry)] TJ ET BT 26.250 621.499 Td /F1 9.8 Tf [(Increased BP and changes in baroreceptor reflex function may lead to cardiac hypertrophy. We used a standard measure of )] TJ ET BT 26.250 609.594 Td /F1 9.8 Tf [(heart morphometry by calculating the ratio of heart weight \(HW\) relative to body weight \(BW\) or tibia length \(TL\) in 7-8 mo and )] TJ ET BT 26.250 597.690 Td /F1 9.8 Tf [(12 mo old WT and BACHD mice.)] TJ ET BT 26.250 578.285 Td /F1 9.8 Tf [(In comparing the morphometry parameters among the various groups by 2-way ANOVA, we detected a significant effect of )] TJ ET BT 26.250 566.380 Td /F1 9.8 Tf [(genotype on BW \( )] TJ ET BT 106.999 566.380 Td /F5 9.8 Tf [( F)] TJ ET BT 115.667 564.316 Td /F5 8.7 Tf [(1,22)] TJ ET BT 132.533 566.380 Td /F1 9.8 Tf [( =11.36, )] TJ ET BT 170.753 566.380 Td /F5 9.8 Tf [(P)] TJ ET BT 177.256 566.380 Td /F1 9.8 Tf [( =0.003\), with BACHD mice displaying increased BW at 7mo. of age \( )] TJ ET BT 479.350 566.380 Td /F5 9.8 Tf [( t)] TJ ET BT 484.771 564.316 Td /F5 8.7 Tf [(12)] TJ ET BT 494.408 566.380 Td /F5 9.8 Tf [( =3.31, P= )] TJ ET BT 542.115 566.380 Td /F1 9.8 Tf [( 0.004\) )] TJ ET BT 26.250 554.475 Td /F1 9.8 Tf [(when compared to WT mice, but this difference is no longer detected between genotypes at 12 mo of age \( )] TJ ET BT 489.609 554.475 Td /F5 9.8 Tf [( t)] TJ ET BT 495.030 552.411 Td /F5 8.7 Tf [(12)] TJ ET BT 504.667 554.475 Td /F5 9.8 Tf [( =1.49, P )] TJ ET BT 546.680 554.475 Td /F1 9.8 Tf [( =0.15; )] TJ ET BT 26.250 542.571 Td /F1 9.8 Tf [(Table 1\). When comparing the HWs, we found a significant effect of genotype \( )] TJ ET BT 369.284 542.571 Td /F5 9.8 Tf [( F)] TJ ET BT 377.952 540.506 Td /F5 8.7 Tf [(1,22)] TJ ET BT 394.817 542.571 Td /F1 9.8 Tf [( =13.20, )] TJ ET BT 433.037 542.571 Td /F5 9.8 Tf [(P)] TJ ET BT 439.541 542.571 Td /F1 9.8 Tf [( =0.002\) and age \( )] TJ ET BT 522.201 542.571 Td /F5 9.8 Tf [( F)] TJ ET BT 530.869 540.506 Td /F5 8.7 Tf [(1,22)] TJ ET BT 547.734 542.571 Td /F1 9.8 Tf [( =8.78, )] TJ ET BT 26.250 530.666 Td /F5 9.8 Tf [(P)] TJ ET BT 32.753 530.666 Td /F1 9.8 Tf [( =0.008\), but no significant interaction between genotype and age \( )] TJ ET BT 324.073 530.666 Td /F5 9.8 Tf [( F)] TJ ET BT 332.741 528.602 Td /F5 8.7 Tf [(1,22)] TJ ET BT 349.607 530.666 Td /F1 9.8 Tf [( =0.13, )] TJ ET BT 382.406 530.666 Td /F5 9.8 Tf [(P)] TJ ET BT 388.909 530.666 Td /F1 9.8 Tf [( =0.72; Table 1\). The HWs of WT mice )] TJ ET BT 26.250 518.761 Td /F1 9.8 Tf [(increased as they aged \( )] TJ ET BT 135.723 518.761 Td /F5 9.8 Tf [( t)] TJ ET BT 141.144 516.697 Td /F5 8.7 Tf [(14)] TJ ET BT 150.781 518.761 Td /F1 9.8 Tf [( =1.31, )] TJ ET BT 183.580 518.761 Td /F5 9.8 Tf [(P)] TJ ET BT 190.084 518.761 Td /F1 9.8 Tf [( =0.032\), but at both age groups, the HW of BACHD mice were significantly higher when )] TJ ET BT 26.250 506.856 Td /F1 9.8 Tf [(compared to WT mice \(7mo.: )] TJ ET BT 154.657 506.856 Td /F5 9.8 Tf [(t)] TJ ET BT 157.368 504.792 Td /F1 8.7 Tf [(12)] TJ ET BT 167.005 506.856 Td /F5 9.8 Tf [(=2.87,)] TJ ET BT 194.383 506.856 Td /F1 9.8 Tf [( P )] TJ ET BT 206.308 506.856 Td /F5 9.8 Tf [(=0.01;)] TJ ET BT 233.686 506.856 Td /F1 9.8 Tf [( 12mo )] TJ ET BT 263.491 506.856 Td /F5 9.8 Tf [(:)] TJ ET BT 266.202 506.856 Td /F5 9.8 Tf [( t)] TJ ET BT 271.623 504.792 Td /F5 8.7 Tf [(12)] TJ ET BT 281.260 506.856 Td /F1 9.8 Tf [( =2.28, )] TJ ET BT 314.059 506.856 Td /F5 9.8 Tf [(P)] TJ ET BT 320.562 506.856 Td /F1 9.8 Tf [( =0.035\). Lastly, we found a significant effect of age \( )] TJ ET BT 551.715 506.856 Td /F5 9.8 Tf [( F)] TJ ET BT 560.383 504.792 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 494.952 Td /F1 9.8 Tf [(=7.16, )] TJ ET BT 56.338 494.952 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 494.952 Td /F1 9.8 Tf [( =0.015\) when comparing TL \(Table 1\). The TL of WT mice increased as they aged \( )] TJ ET BT 429.432 494.952 Td /F5 9.8 Tf [( t)] TJ ET BT 434.853 492.887 Td /F5 8.7 Tf [(14)] TJ ET BT 444.490 494.952 Td /F1 9.8 Tf [( =2.88, )] TJ ET BT 477.289 494.952 Td /F5 9.8 Tf [(P)] TJ ET BT 483.793 494.952 Td /F1 9.8 Tf [( =0.01\), but this trend )] TJ ET BT 26.250 483.047 Td /F1 9.8 Tf [(was not detected in BACHD mice. Similar to BW, the TLs of BACHD mice were longer at 7mo. \( )] TJ ET BT 441.298 483.047 Td /F5 9.8 Tf [( t)] TJ ET BT 446.719 480.983 Td /F5 8.7 Tf [(12)] TJ ET BT 456.356 483.047 Td /F1 9.8 Tf [( = 2.43, )] TJ ET BT 491.866 483.047 Td /F5 9.8 Tf [(P)] TJ ET BT 498.369 483.047 Td /F1 9.8 Tf [( =0.025\) )] TJ ET BT 26.250 471.142 Td /F1 9.8 Tf [(compared to WT mice, but not at 12 mo of age \( )] TJ ET BT 235.972 471.142 Td /F5 9.8 Tf [( t)] TJ ET BT 241.393 469.078 Td /F5 8.7 Tf [(12)] TJ ET BT 251.031 471.142 Td /F1 9.8 Tf [( = 0.32, )] TJ ET BT 286.540 471.142 Td /F5 9.8 Tf [(P)] TJ ET BT 293.044 471.142 Td /F1 9.8 Tf [( =0.76\).)] TJ ET 0.965 0.965 0.965 rg 26.250 371.261 555.000 90.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 461.261 m 581.250 461.261 l 581.250 460.511 l 26.250 460.511 l f 26.250 371.261 m 581.250 371.261 l 581.250 372.011 l 26.250 372.011 l f q 225.000 0 0 70.500 35.250 381.011 cm /I4 Do Q q 35.250 375.011 537.000 0.000 re W n Q 0.271 0.267 0.267 rg BT 26.250 354.237 Td /F6 9.8 Tf [(Table 1:)] TJ ET BT 63.095 354.237 Td /F5 9.8 Tf [( Morphometry measurements of WT and BACHD mice. * significance between genotypes. )] TJ ET BT 453.778 354.237 Td /F5 9.8 Tf [(# significance between ages.)] TJ ET BT 26.250 334.833 Td /F1 9.8 Tf [(We did not find significant differences in the HW/BW ratios between WT and BACHD mice by 2-way ANOVA \(age: )] TJ ET BT 520.965 334.833 Td /F5 9.8 Tf [( F )] TJ ET BT 532.343 332.768 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 322.928 Td /F1 9.8 Tf [(=0.66, )] TJ ET BT 56.338 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 322.928 Td /F1 9.8 Tf [( =0.43; genotype: )] TJ ET BT 141.173 322.928 Td /F5 9.8 Tf [( F )] TJ ET BT 152.551 320.864 Td /F5 8.7 Tf [(1,22)] TJ ET BT 169.417 322.928 Td /F1 9.8 Tf [( =2.85, )] TJ ET BT 202.216 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 208.719 322.928 Td /F1 9.8 Tf [( =0.108; age X genotype: )] TJ ET BT 320.659 322.928 Td /F5 9.8 Tf [( F )] TJ ET BT 332.037 320.864 Td /F5 8.7 Tf [(1,22)] TJ ET BT 348.902 322.928 Td /F1 9.8 Tf [( =2.22, )] TJ ET BT 381.701 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 388.205 322.928 Td /F1 9.8 Tf [( =0.15\), but measured significant )] TJ ET BT 26.250 311.023 Td /F1 9.8 Tf [(differences in the HW/TL ratios between the two genotypes \(Fig. 2\). By 2-way ANOVA, we find a significant effect of genotype \( )] TJ ET BT 26.250 299.118 Td /F5 9.8 Tf [(F )] TJ ET BT 34.918 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 51.783 299.118 Td /F1 9.8 Tf [( =10.50, )] TJ ET BT 90.003 299.118 Td /F5 9.8 Tf [(P)] TJ ET BT 96.506 299.118 Td /F1 9.8 Tf [( =0.004\) and age \( )] TJ ET BT 179.167 299.118 Td /F5 9.8 Tf [( F )] TJ ET BT 190.545 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 207.410 299.118 Td /F1 9.8 Tf [( =5.31, )] TJ ET BT 240.209 299.118 Td /F5 9.8 Tf [(P)] TJ ET BT 246.713 299.118 Td /F1 9.8 Tf [( =0.033\), but do not detect an interaction between genotype and age \( )] TJ ET BT 551.059 299.118 Td /F5 9.8 Tf [( F )] TJ ET BT 562.437 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 287.214 Td /F1 9.8 Tf [(=0.001, )] TJ ET BT 61.760 287.214 Td /F5 9.8 Tf [(P)] TJ ET BT 68.263 287.214 Td /F1 9.8 Tf [( =0.97\). The HW/TL ratios did not change as BACHD or WT mice aged \(WT: )] TJ ET BT 400.689 287.214 Td /F5 9.8 Tf [( t )] TJ ET BT 408.820 285.149 Td /F5 8.7 Tf [(9)] TJ ET BT 413.639 287.214 Td /F1 9.8 Tf [( =0.131, )] TJ ET BT 451.859 287.214 Td /F5 9.8 Tf [(P)] TJ ET BT 458.362 287.214 Td /F1 9.8 Tf [( >0.05; BACHD: )] TJ ET BT 530.707 287.214 Td /F5 9.8 Tf [( t )] TJ ET BT 538.839 285.149 Td /F5 8.7 Tf [(10)] TJ ET BT 26.250 275.309 Td /F1 9.8 Tf [(=0.108, )] TJ ET BT 61.760 275.309 Td /F5 9.8 Tf [(P)] TJ ET BT 68.263 275.309 Td /F1 9.8 Tf [( >0.05\), but the HW/TL ratios were significantly higher in BACHD mice compared to WT mice at both ages \(7mo: )] TJ ET BT 555.665 275.309 Td /F5 9.8 Tf [( t )] TJ ET BT 563.797 273.245 Td /F5 8.7 Tf [(10)] TJ ET BT 26.250 263.404 Td /F1 9.8 Tf [(=2.30, )] TJ ET BT 56.338 263.404 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 263.404 Td /F1 9.8 Tf [( =0.033; 12mo: )] TJ ET BT 130.868 263.404 Td /F5 9.8 Tf [( t )] TJ ET BT 138.999 261.340 Td /F5 8.7 Tf [(9)] TJ ET BT 143.818 263.404 Td /F1 9.8 Tf [( =2.28, )] TJ ET BT 176.617 263.404 Td /F5 9.8 Tf [(P)] TJ ET BT 183.120 263.404 Td /F1 9.8 Tf [( =0.034\). These data indicate that the hearts of BACHD mice are increased in mass in )] TJ ET BT 26.250 251.499 Td /F1 9.8 Tf [(relation to body frame and likely result in some form of cardiac remodeling.)] TJ ET 0.965 0.965 0.965 rg 26.250 27.868 555.000 213.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 241.618 m 581.250 241.618 l 581.250 240.868 l 26.250 240.868 l f q 225.000 0 0 198.000 35.250 33.868 cm /I5 Do Q q 35.250 27.868 537.000 0.000 re W n Q Q q 15.000 27.868 577.500 749.132 re W n 0.965 0.965 0.965 rg 26.250 657.928 555.000 119.072 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 657.928 m 581.250 657.928 l 581.250 658.678 l 26.250 658.678 l f q 35.250 669.178 537.000 107.822 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Baroreceptor Reflex in WT and BACHD mice.)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(Mice were administered increasing concentrations of ATII \(A\) and NP \(B\). For control conditions, mice were primed with )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(muscarinic and ?- blockers before administration of the HD of ATII and NP. The maximum change in HR \(?HR\) and the )] TJ ET BT 35.250 720.634 Td /F1 9.8 Tf [(absolute value of the maximum change in BP \(?BP\) following drug administration was measured. We compared ?HR/?BP )] TJ ET BT 35.250 706.897 Td /F1 9.8 Tf [(among the different groups using a 2-way repeated measures ANOVA. # significant response compared to control )] TJ ET BT 35.250 693.161 Td /F1 9.8 Tf [(conditions in WT mice. ^ significant response compared to control conditions in BACHD mice. * significant difference )] TJ ET BT 35.250 679.425 Td /F1 9.8 Tf [(between WT and BACHD mice.)] TJ ET Q BT 26.250 640.904 Td /F4 9.8 Tf [(Morphometry)] TJ ET BT 26.250 621.499 Td /F1 9.8 Tf [(Increased BP and changes in baroreceptor reflex function may lead to cardiac hypertrophy. We used a standard measure of )] TJ ET BT 26.250 609.594 Td /F1 9.8 Tf [(heart morphometry by calculating the ratio of heart weight \(HW\) relative to body weight \(BW\) or tibia length \(TL\) in 7-8 mo and )] TJ ET BT 26.250 597.690 Td /F1 9.8 Tf [(12 mo old WT and BACHD mice.)] TJ ET BT 26.250 578.285 Td /F1 9.8 Tf [(In comparing the morphometry parameters among the various groups by 2-way ANOVA, we detected a significant effect of )] TJ ET BT 26.250 566.380 Td /F1 9.8 Tf [(genotype on BW \( )] TJ ET BT 106.999 566.380 Td /F5 9.8 Tf [( F)] TJ ET BT 115.667 564.316 Td /F5 8.7 Tf [(1,22)] TJ ET BT 132.533 566.380 Td /F1 9.8 Tf [( =11.36, )] TJ ET BT 170.753 566.380 Td /F5 9.8 Tf [(P)] TJ ET BT 177.256 566.380 Td /F1 9.8 Tf [( =0.003\), with BACHD mice displaying increased BW at 7mo. of age \( )] TJ ET BT 479.350 566.380 Td /F5 9.8 Tf [( t)] TJ ET BT 484.771 564.316 Td /F5 8.7 Tf [(12)] TJ ET BT 494.408 566.380 Td /F5 9.8 Tf [( =3.31, P= )] TJ ET BT 542.115 566.380 Td /F1 9.8 Tf [( 0.004\) )] TJ ET BT 26.250 554.475 Td /F1 9.8 Tf [(when compared to WT mice, but this difference is no longer detected between genotypes at 12 mo of age \( )] TJ ET BT 489.609 554.475 Td /F5 9.8 Tf [( t)] TJ ET BT 495.030 552.411 Td /F5 8.7 Tf [(12)] TJ ET BT 504.667 554.475 Td /F5 9.8 Tf [( =1.49, P )] TJ ET BT 546.680 554.475 Td /F1 9.8 Tf [( =0.15; )] TJ ET BT 26.250 542.571 Td /F1 9.8 Tf [(Table 1\). When comparing the HWs, we found a significant effect of genotype \( )] TJ ET BT 369.284 542.571 Td /F5 9.8 Tf [( F)] TJ ET BT 377.952 540.506 Td /F5 8.7 Tf [(1,22)] TJ ET BT 394.817 542.571 Td /F1 9.8 Tf [( =13.20, )] TJ ET BT 433.037 542.571 Td /F5 9.8 Tf [(P)] TJ ET BT 439.541 542.571 Td /F1 9.8 Tf [( =0.002\) and age \( )] TJ ET BT 522.201 542.571 Td /F5 9.8 Tf [( F)] TJ ET BT 530.869 540.506 Td /F5 8.7 Tf [(1,22)] TJ ET BT 547.734 542.571 Td /F1 9.8 Tf [( =8.78, )] TJ ET BT 26.250 530.666 Td /F5 9.8 Tf [(P)] TJ ET BT 32.753 530.666 Td /F1 9.8 Tf [( =0.008\), but no significant interaction between genotype and age \( )] TJ ET BT 324.073 530.666 Td /F5 9.8 Tf [( F)] TJ ET BT 332.741 528.602 Td /F5 8.7 Tf [(1,22)] TJ ET BT 349.607 530.666 Td /F1 9.8 Tf [( =0.13, )] TJ ET BT 382.406 530.666 Td /F5 9.8 Tf [(P)] TJ ET BT 388.909 530.666 Td /F1 9.8 Tf [( =0.72; Table 1\). The HWs of WT mice )] TJ ET BT 26.250 518.761 Td /F1 9.8 Tf [(increased as they aged \( )] TJ ET BT 135.723 518.761 Td /F5 9.8 Tf [( t)] TJ ET BT 141.144 516.697 Td /F5 8.7 Tf [(14)] TJ ET BT 150.781 518.761 Td /F1 9.8 Tf [( =1.31, )] TJ ET BT 183.580 518.761 Td /F5 9.8 Tf [(P)] TJ ET BT 190.084 518.761 Td /F1 9.8 Tf [( =0.032\), but at both age groups, the HW of BACHD mice were significantly higher when )] TJ ET BT 26.250 506.856 Td /F1 9.8 Tf [(compared to WT mice \(7mo.: )] TJ ET BT 154.657 506.856 Td /F5 9.8 Tf [(t)] TJ ET BT 157.368 504.792 Td /F1 8.7 Tf [(12)] TJ ET BT 167.005 506.856 Td /F5 9.8 Tf [(=2.87,)] TJ ET BT 194.383 506.856 Td /F1 9.8 Tf [( P )] TJ ET BT 206.308 506.856 Td /F5 9.8 Tf [(=0.01;)] TJ ET BT 233.686 506.856 Td /F1 9.8 Tf [( 12mo )] TJ ET BT 263.491 506.856 Td /F5 9.8 Tf [(:)] TJ ET BT 266.202 506.856 Td /F5 9.8 Tf [( t)] TJ ET BT 271.623 504.792 Td /F5 8.7 Tf [(12)] TJ ET BT 281.260 506.856 Td /F1 9.8 Tf [( =2.28, )] TJ ET BT 314.059 506.856 Td /F5 9.8 Tf [(P)] TJ ET BT 320.562 506.856 Td /F1 9.8 Tf [( =0.035\). Lastly, we found a significant effect of age \( )] TJ ET BT 551.715 506.856 Td /F5 9.8 Tf [( F)] TJ ET BT 560.383 504.792 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 494.952 Td /F1 9.8 Tf [(=7.16, )] TJ ET BT 56.338 494.952 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 494.952 Td /F1 9.8 Tf [( =0.015\) when comparing TL \(Table 1\). The TL of WT mice increased as they aged \( )] TJ ET BT 429.432 494.952 Td /F5 9.8 Tf [( t)] TJ ET BT 434.853 492.887 Td /F5 8.7 Tf [(14)] TJ ET BT 444.490 494.952 Td /F1 9.8 Tf [( =2.88, )] TJ ET BT 477.289 494.952 Td /F5 9.8 Tf [(P)] TJ ET BT 483.793 494.952 Td /F1 9.8 Tf [( =0.01\), but this trend )] TJ ET BT 26.250 483.047 Td /F1 9.8 Tf [(was not detected in BACHD mice. Similar to BW, the TLs of BACHD mice were longer at 7mo. \( )] TJ ET BT 441.298 483.047 Td /F5 9.8 Tf [( t)] TJ ET BT 446.719 480.983 Td /F5 8.7 Tf [(12)] TJ ET BT 456.356 483.047 Td /F1 9.8 Tf [( = 2.43, )] TJ ET BT 491.866 483.047 Td /F5 9.8 Tf [(P)] TJ ET BT 498.369 483.047 Td /F1 9.8 Tf [( =0.025\) )] TJ ET BT 26.250 471.142 Td /F1 9.8 Tf [(compared to WT mice, but not at 12 mo of age \( )] TJ ET BT 235.972 471.142 Td /F5 9.8 Tf [( t)] TJ ET BT 241.393 469.078 Td /F5 8.7 Tf [(12)] TJ ET BT 251.031 471.142 Td /F1 9.8 Tf [( = 0.32, )] TJ ET BT 286.540 471.142 Td /F5 9.8 Tf [(P)] TJ ET BT 293.044 471.142 Td /F1 9.8 Tf [( =0.76\).)] TJ ET 0.965 0.965 0.965 rg 26.250 371.261 555.000 90.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 461.261 m 581.250 461.261 l 581.250 460.511 l 26.250 460.511 l f 26.250 371.261 m 581.250 371.261 l 581.250 372.011 l 26.250 372.011 l f q 225.000 0 0 70.500 35.250 381.011 cm /I4 Do Q q 35.250 375.011 537.000 0.000 re W n Q 0.271 0.267 0.267 rg BT 26.250 354.237 Td /F6 9.8 Tf [(Table 1:)] TJ ET BT 63.095 354.237 Td /F5 9.8 Tf [( Morphometry measurements of WT and BACHD mice. * significance between genotypes. )] TJ ET BT 453.778 354.237 Td /F5 9.8 Tf [(# significance between ages.)] TJ ET BT 26.250 334.833 Td /F1 9.8 Tf [(We did not find significant differences in the HW/BW ratios between WT and BACHD mice by 2-way ANOVA \(age: )] TJ ET BT 520.965 334.833 Td /F5 9.8 Tf [( F )] TJ ET BT 532.343 332.768 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 322.928 Td /F1 9.8 Tf [(=0.66, )] TJ ET BT 56.338 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 322.928 Td /F1 9.8 Tf [( =0.43; genotype: )] TJ ET BT 141.173 322.928 Td /F5 9.8 Tf [( F )] TJ ET BT 152.551 320.864 Td /F5 8.7 Tf [(1,22)] TJ ET BT 169.417 322.928 Td /F1 9.8 Tf [( =2.85, )] TJ ET BT 202.216 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 208.719 322.928 Td /F1 9.8 Tf [( =0.108; age X genotype: )] TJ ET BT 320.659 322.928 Td /F5 9.8 Tf [( F )] TJ ET BT 332.037 320.864 Td /F5 8.7 Tf [(1,22)] TJ ET BT 348.902 322.928 Td /F1 9.8 Tf [( =2.22, )] TJ ET BT 381.701 322.928 Td /F5 9.8 Tf [(P)] TJ ET BT 388.205 322.928 Td /F1 9.8 Tf [( =0.15\), but measured significant )] TJ ET BT 26.250 311.023 Td /F1 9.8 Tf [(differences in the HW/TL ratios between the two genotypes \(Fig. 2\). By 2-way ANOVA, we find a significant effect of genotype \( )] TJ ET BT 26.250 299.118 Td /F5 9.8 Tf [(F )] TJ ET BT 34.918 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 51.783 299.118 Td /F1 9.8 Tf [( =10.50, )] TJ ET BT 90.003 299.118 Td /F5 9.8 Tf [(P)] TJ ET BT 96.506 299.118 Td /F1 9.8 Tf [( =0.004\) and age \( )] TJ ET BT 179.167 299.118 Td /F5 9.8 Tf [( F )] TJ ET BT 190.545 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 207.410 299.118 Td /F1 9.8 Tf [( =5.31, )] TJ ET BT 240.209 299.118 Td /F5 9.8 Tf [(P)] TJ ET BT 246.713 299.118 Td /F1 9.8 Tf [( =0.033\), but do not detect an interaction between genotype and age \( )] TJ ET BT 551.059 299.118 Td /F5 9.8 Tf [( F )] TJ ET BT 562.437 297.054 Td /F5 8.7 Tf [(1,22)] TJ ET BT 26.250 287.214 Td /F1 9.8 Tf [(=0.001, )] TJ ET BT 61.760 287.214 Td /F5 9.8 Tf [(P)] TJ ET BT 68.263 287.214 Td /F1 9.8 Tf [( =0.97\). The HW/TL ratios did not change as BACHD or WT mice aged \(WT: )] TJ ET BT 400.689 287.214 Td /F5 9.8 Tf [( t )] TJ ET BT 408.820 285.149 Td /F5 8.7 Tf [(9)] TJ ET BT 413.639 287.214 Td /F1 9.8 Tf [( =0.131, )] TJ ET BT 451.859 287.214 Td /F5 9.8 Tf [(P)] TJ ET BT 458.362 287.214 Td /F1 9.8 Tf [( >0.05; BACHD: )] TJ ET BT 530.707 287.214 Td /F5 9.8 Tf [( t )] TJ ET BT 538.839 285.149 Td /F5 8.7 Tf [(10)] TJ ET BT 26.250 275.309 Td /F1 9.8 Tf [(=0.108, )] TJ ET BT 61.760 275.309 Td /F5 9.8 Tf [(P)] TJ ET BT 68.263 275.309 Td /F1 9.8 Tf [( >0.05\), but the HW/TL ratios were significantly higher in BACHD mice compared to WT mice at both ages \(7mo: )] TJ ET BT 555.665 275.309 Td /F5 9.8 Tf [( t )] TJ ET BT 563.797 273.245 Td /F5 8.7 Tf [(10)] TJ ET BT 26.250 263.404 Td /F1 9.8 Tf [(=2.30, )] TJ ET BT 56.338 263.404 Td /F5 9.8 Tf [(P)] TJ ET BT 62.842 263.404 Td /F1 9.8 Tf [( =0.033; 12mo: )] TJ ET BT 130.868 263.404 Td /F5 9.8 Tf [( t )] TJ ET BT 138.999 261.340 Td /F5 8.7 Tf [(9)] TJ ET BT 143.818 263.404 Td /F1 9.8 Tf [( =2.28, )] TJ ET BT 176.617 263.404 Td /F5 9.8 Tf [(P)] TJ ET BT 183.120 263.404 Td /F1 9.8 Tf [( =0.034\). These data indicate that the hearts of BACHD mice are increased in mass in )] TJ ET BT 26.250 251.499 Td /F1 9.8 Tf [(relation to body frame and likely result in some form of cardiac remodeling.)] TJ ET 0.965 0.965 0.965 rg 26.250 27.868 555.000 213.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 241.618 m 581.250 241.618 l 581.250 240.868 l 26.250 240.868 l f q 225.000 0 0 198.000 35.250 33.868 cm /I5 Do Q q 35.250 27.868 537.000 0.000 re W n Q Q q 225.000 0 0 70.500 35.250 381.011 cm /I4 Do Q q 225.000 0 0 198.000 35.250 33.868 cm /I5 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(4)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 232 0 obj << /Type /Font /Subtype /Type1 /Name /F6 /BaseFont /Helvetica-BoldOblique /Encoding /WinAnsiEncoding >> endobj 233 0 obj << /Type /Annot /Subtype /Link /A 234 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 381.0112 260.2500 451.5112 ] >> endobj 234 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/analynetable1.tif) >> endobj 235 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 94 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 13021>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ^," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?_?ZY [iŚ߈u>K.e1q@'ON7O-՗A}o{qw'XD6lUon9_܍[pPدi?x{⦹j׆Mr.CH `/=4]N_n4ԻVW_]%Ӊ.D6m7ne=ޡhG jRLԱUVuUbOw:f]D.7`^>nc6~7dRdh1]z3Oo ֧i\j.eʺq I'rxӧYxԴVŸG ~ukK+U9T߶nm~#3}Kt.ȪYT82+ֿb.|C{D9?}N95K'ԥ @@gY?kÿ݄<]j-i"س K@ ":3 9/ex'㗎dƇ Ė/K!E#I!HYUפx1ټeX&oO> nE,]֢YX$k1p>Bۊ]?g[_l<T3.&a--aiX85疔USͦGIu_&oC$m]͔n8|}/D6oiC՝~i!u H\(fiz~K=3MK SM_jזrV]EvP~gg?(uHtVMF$'9,{4uM&Vׄ1Q5-f OLoWN{k]N[u fy8Th` @ qu + CxJOE5Q:.ddeFFk}_r:<_V!?*}11bTtzQu}`x&7Z;%BxS?Moi G6O]vVy}|5ۓĞ= i uV{-;`衂w'mC8UYx*qk4oٛԛU7܂r&;~aޔ򿇿'ռ}RJX(R5 f[HGaLO;c\5E⥷G$CD;%9L}9J˺'-b@oO{Юu&fv|7H= s-s[:PookBwsbs(ث4 RҫwW F_z<7,`y%&b[ˌ$5x7 Nrׯm|[cOOq7Xr;ք',54xQ/}qw$m(oS1hv&3VTyj?@)5_ '_Gğ^TvxgcyaݕIxk=sṴGe> l]I9=[ۏo[]BI">rZg8o8zeqr;3i ^I?SPxK%볢8T@?PxK%EqgFP8?QG%?mo^/w~&5OkMi:=n3q_9/>(O࿌5 WQ`jRu";>使"h<`ci\v>E D]r~W{x)4F<~Pm!$}Rkdz㿋wuGkNuA1R/jjv)#x,,ۧ EL Ivp(_?+KE,p7\_g(4,:K?Ρx\kmcC:vF>j~.O w$Ӯ-7yCL/ȊWnZF';6{QvA!u\~(vKy/%_:|9Ҵ mK 6ܮpb7M&-ozŨxN⟆5_eq*[)Ni&,BZyPQ V,H¢Bc'|HYEY%C+>('l[1ɨ=ݾ+$ك;*n!A9Q~KAZ.oe}WPM֔ٹi"._;7$ Q]JWP?:EW WL2O^gJd:efMsR+# bJ?-CZ,*Kŝ%V_LI_)* ɠRW3deL/* !]|8Z?WX٢jZIHskl stoBBw}ضZ-m' VHcei&c\J`0 4Gr>=<$er3C~j6? j>}5ݿ,qXLe&.kG66w,k[O^QM'cc_0.#TO¯es}Y|8oy';/^Ծ xÚ_uoj:^X:09F<\*XǏ~sR hwQ6V ~`i qccq-@EhQ@^[jVowoջtS tl j開x.ŬBG3fsw\gt4P6M3[LILheO\s- F]AҒ/u,!>yۜg|H4^ h76֭ijzF o!%PX@)Gv w7Ŀxo5hSmY\iU-= 2b0vJhPNk-CB ]/LtՅ'uD0Ǻ7H%N W|?:E=ֺGk})-iQ~.2^ HC6xOVY7_8x?'~X{ያiK0y%w˖$& }@0hڄ8\d漫?Χ\xFTO%$+$E8xʜ0+/Wg_\iGmn +kqw'q%c˺RܖA o o5deeaio4zs,ݷ\[8z45.u#m;K(ZD/%d2.岺 %@=lm=Gzp8 |C__O 7wᡦx|zڋBݏxwT4 7RkKh!Du F hޓ ^eIxŞ7mk~YMvw𙼨ܘӣHHP7|$|_X|D`bH˱Jܫ&oh'''Q2 ^GC޼$k~о uСll!̑F坂@p-žχuKm~9yYi6qX> ܄5GDf2f-(hԂA,~K+O jVcn"$"`F0O54^V-OmMi LcSsX {FJQ0:W;N?f_A{F]jfSrѿLY]2`;Ha?g^/;[WkW 0duDAŒ(㟩@uŠ5GMH$7dH\$q@~\{PUq85|T|5i>wz֍xK./P};Р_&RN1r x7}vĶ^%F-%&۲QDU%_YJ^TEB@;RP:q^U_^ Լ k:Gy<ݤPjƥE7;>Tܛ jO,[k}S@m?TI/ X"xdHF8=@*n$֗ _;*[ԵmnK;ƩњL6)g0#n0v|]4m/IT2kM .(eY ȑC6BoxO#.KEqYeI}KR=gqRTњz ?[ xĚnaymZu7I$P̌K4Iyt|:n<3a\^3s!x{Mz9(Trs=gqRT=gqRT?$+kpjڞ^FD]ErxRxN䲉`=7#~/G#~TUUV}]۸nHnf C;ˆz_}fm6yoa{yJpaX,i*I^r?[ ?Y*_*9| KKo]C vHm"Fgw? iZ}̉gs][Btq %Y0bsZYTUYTUQπtOEkm%ia ,Jf*\121G텞mʀ;>YbI1:la?~y&0oԱbłM V$XOrk?[ ~/Q4ۋ{B g1j7* KqubػšrEEk>5e:w,-75 ]Oߌ)|#WwXMmu^Izd7 # 9E~šDGaknAdXT 1Չ-adF0BHT\3OS$oS[DYj3vpN*wqY1G|)^Y@ĜW_&k EcmSʉ eӭg$m w_|M4xR,~jϩ:ql, -s*N٘R28}]{a #=:NFK[hm0Ux/G?BHC4߆zUy-b^]J$2~;#37>Em跞Kѡc7-kGDG'ҽHRP_kpGCD$]A  Ao4LeڭͮhKXZgRPZ *xPyO'S7_9- M56"v=ةĒ(?8Y>lO} D1 \!S>=:M@X$SG%bߥ|~+gs;Ե ptou.\ &6䧚dؾf6=3@-7]xOޟpOn˛MR*i"uffmIvE}rmVtӈ򾅺ڀ>dDži7 \O3K[yJf+He-gmb):}5w" BsS!G1@_\[i64p?Js:>-: n;@LLSx?i#P @k9}oeєm<^^DZM#B>yxr}šFFlwIc_1`JHa?Puk cg5%Λky42m Bۢy# P=Ҁ>In5Q/;`YpˊdAkdž5I-u[蚷H~ r\C({:}BM-&NgkK;{R aP@&|+~ds[k?H=fb7 [.kczׂIGXZMkkʤ Dz]%3HĒ}6415Ģ%;yKF18N7"Zo%wt9huGJ h/Z(yH[[E a}W=@۴>.񼄂%i|e+:n⿈UŮ>5&P@Lq]P3ի| M!5_%ŋ-3\$*dtVU+)}+{^ oi]'۝JZ6 û hV4O~hO [I.tYdA,ldv.]Tzsxf.U]?Kմ5vX,"V L|?~%k:u Bm6WtD%*]#i x7ӑ[v7nswn*V_(jl tt(㛩gdžJPѭntys7vzXlUwωXKLD24HvA2|}gǺ'Ay_]^UִdS@EjDh$pD&ß 3X#LPiYfG冖Gra0\^8w>xWƁ9m+>(Ӿ"6^eԺ՛Yx^f_\޻+8O,V 0EPk7}7{{}Eui_XxbKLc6nx~x7ZNjnl/>uݶyC4qʨB\rsoo3~ V4OVCEӛiy]6=:º>%7+qnc:ܡ spy_?|┋OKv܁*\G!I|3'8D {(4(--aX%ڈ0b<6şH,hկ.4x, ]#`B׿/x|Q4֖A 5Č(J#Wn9? |A^V(Yg!4;y2`%w;r99hVOqYүգO F+h G^@W}'Uм!i -;RH3u0;@s^|6?h#SXQ,2aBHݪB#85Ѩޝ6;gN+˿o;sU| ? 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M]O:'ċkL}>[w#de``` / d V{FQIuuq34TP] @.iG sHݍXѕр*rSQ(U@ 0{~TQEQE%Q@ IEW9$u$W@:娢>' 7Z%>E]Xb-h <%5aw[ºīѓ Y67W$]xB kbMK罒(&=ϊ[BMFB?o>鶾 `mmlrB"^c??<`2N_w:Np5m\[YaRDvWt7O5TG7ß~C[?Uw0CБ=ޢ()h J(((m)ٻ^kiTIZHլu yq"7h:oxMgTOk6|q@>pmmal1# |)>!i<C<74BٯDS0uIgz>=?tLdIQJ+G]:%>{(]Nl2c?*_/?y 1yӼa;÷^./(㑹gMPHDVS# (( endstream endobj 239 0 obj << /Type /Annot /Subtype /Link /A 240 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 381.0112 260.2500 451.5112 ] >> endobj 240 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/analynetable1.tif) >> endobj 241 0 obj << /Type /Annot /Subtype /Link /A 242 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 33.8685 260.2500 231.8685 ] >> endobj 242 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/ayalyne061311b.jpg) >> endobj 243 0 obj << /Type /Annot /Subtype /Link /A 244 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 381.0112 260.2500 451.5112 ] >> endobj 244 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/analynetable1.tif) >> endobj 245 0 obj << /Type /Annot /Subtype /Link /A 246 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 33.8685 260.2500 231.8685 ] >> endobj 246 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/ayalyne061311b.jpg) >> endobj 247 0 obj << /Type /Page /Parent 3 0 R /Annots [ 249 0 R 252 0 R 254 0 R 256 0 R 258 0 R 260 0 R 262 0 R 264 0 R 266 0 R 268 0 R 270 0 R 272 0 R 274 0 R 276 0 R 278 0 R 280 0 R 282 0 R 284 0 R 286 0 R 288 0 R 290 0 R 292 0 R 294 0 R 296 0 R 298 0 R 300 0 R 302 0 R 304 0 R 306 0 R 308 0 R 310 0 R 312 0 R 314 0 R ] /Contents 248 0 R >> endobj 248 0 obj << /Length 20673 >> stream q 15.000 41.923 577.500 735.077 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 2: Heart Morphometry comparisons between WT and BACHD mice at 7 mo and 12 mo of age.)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(HW/BW or HW/TL were calculated for all genotypes and age groups and compared using a 2-way ANOVA. * significant )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(difference between genotypes.)] TJ ET Q BT 26.250 695.849 Td /F4 9.8 Tf [(Echocardiographic Analysis)] TJ ET BT 26.250 676.444 Td /F1 9.8 Tf [(Changes in the morphology of the hearts of BACHD mice, could cause aberrant modifications in heart function. Therefore, we )] TJ ET BT 26.250 664.539 Td /F1 9.8 Tf [(subjected BACHD and WT mice to echocardiographic analysis at about 12 mo of age in order to assess heart function. We )] TJ ET BT 26.250 652.635 Td /F1 9.8 Tf [(found no significant differences in any of the parameters measured \(Table 2\). Though not statistically significant, the wall )] TJ ET BT 26.250 640.730 Td /F1 9.8 Tf [(thicknesses and LV mass were slightly higher in the BACHD mice consistent with the morphometry data. Despite indications of )] TJ ET BT 26.250 628.825 Td /F1 9.8 Tf [(abnormal regulation of BP and baroreflex, the hearts of BACHD mice continue to function normally at this age as assessed by )] TJ ET BT 26.250 616.920 Td /F1 9.8 Tf [(echocardiogram)] TJ ET 0.965 0.965 0.965 rg 26.250 394.789 555.000 212.250 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 607.039 m 581.250 607.039 l 581.250 606.289 l 26.250 606.289 l f 26.250 394.789 m 581.250 394.789 l 581.250 395.539 l 26.250 395.539 l f q 225.000 0 0 192.750 35.250 404.539 cm /I6 Do Q q 35.250 398.539 537.000 0.000 re W n Q 0.271 0.267 0.267 rg BT 26.250 377.766 Td /F6 9.8 Tf [(Table 2:)] TJ ET BT 63.095 377.766 Td /F5 9.8 Tf [( Echocardiogram parameters in 12 mo old WT and BACHD mice.No significant differences were detected between )] TJ ET BT 26.250 365.861 Td /F5 9.8 Tf [(genotypes using a Students t-test. HR- Heart Rate; VST-Ventricular Septal Thickness, EDD- End Diastolic Diameter, PWT- )] TJ ET BT 26.250 353.956 Td /F5 9.8 Tf [(Posterior Wall Thickness, ESD- End Systolic Diameter, Ao-ET- Aortic Ejection Time, LV%FS- Left Ventricular percent Fractional )] TJ ET BT 26.250 342.051 Td /F5 9.8 Tf [(Shortening, LvEF- Left Ventricular Ejection Fraction, LVMass- Left Ventricular Mass, and E/A- Early Diastole/Atrial contraction )] TJ ET BT 26.250 330.147 Td /F5 9.8 Tf [(ratio.)] TJ ET BT 26.250 293.544 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 273.590 Td /F1 9.8 Tf [(We report dysfunction of the ANS in BACHD mice, as measured by the baroreceptor reflex. Furthermore, baseline )] TJ ET BT 26.250 261.685 Td /F1 9.8 Tf [(measurements of BP and HR were higher in BACHD mice compared to WT controls. Lastly, we find changes in the )] TJ ET BT 26.250 249.780 Td /F1 9.8 Tf [(morphometry of the heart, but echocardiography did not detect any functional changes at 12 mo of age.)] TJ ET BT 26.250 230.376 Td /F1 9.8 Tf [(The increased baseline BP levels measured in lightly anesthetized BACHD mice indicate changes in the overall regulation of BP )] TJ ET BT 26.250 218.471 Td /F1 9.8 Tf [(tone. Importantly, these BP recordings were taken during the day, a time in the resting period of mice when BP is expected to )] TJ ET BT 26.250 206.566 Td /F1 9.8 Tf [(be low. These increased BP levels parallel the reported increase in HR of BACHD mice also measured during the day )] TJ ET 0.267 0.267 0.267 rg BT 536.156 206.566 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 552.418 206.566 Td /F1 9.8 Tf [( , )] TJ ET BT 26.250 194.661 Td /F1 9.8 Tf [(suggesting a global dysregulation of the cardiovascular system causing it to be hyperactive during the rest period. The blunted )] TJ ET BT 26.250 182.757 Td /F1 9.8 Tf [(depression in BP levels during rest would be similar to a nondipping pressure profile observed in humans, which in many cases )] TJ ET BT 26.250 170.852 Td /F1 9.8 Tf [(is an indication of dysautonomia)] TJ ET 0.267 0.267 0.267 rg BT 164.983 170.852 Td /F1 9.8 Tf [( [22])] TJ ET BT 183.956 170.852 Td /F1 9.8 Tf [( [23])] TJ ET 0.271 0.267 0.267 rg BT 202.930 170.852 Td /F1 9.8 Tf [( . Nondippers have a higher risk for future cardiovascular events, as well as damage to )] TJ ET BT 26.250 158.947 Td /F1 9.8 Tf [(other organs )] TJ ET 0.267 0.267 0.267 rg BT 83.697 158.947 Td /F1 9.8 Tf [([23])] TJ ET BT 99.960 158.947 Td /F1 9.8 Tf [([24])] TJ ET 0.271 0.267 0.267 rg BT 116.223 158.947 Td /F1 9.8 Tf [( . Published reports of BP in Huntingtons disease patients do not detect significant differences compared )] TJ ET BT 26.250 147.042 Td /F1 9.8 Tf [(to control groups, however BP measurements were taken during the day when patients are in a more active state, which could )] TJ ET BT 26.250 135.138 Td /F1 9.8 Tf [(mask the higher levels of BP tone)] TJ ET 0.267 0.267 0.267 rg BT 171.486 135.138 Td /F1 9.8 Tf [( [5])] TJ ET BT 185.038 135.138 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 195.881 135.138 Td /F1 9.8 Tf [( . This appears to be the case for HR in BACHD mice, as HR levels are not significantly )] TJ ET BT 26.250 123.233 Td /F1 9.8 Tf [(different between WT and BACHD mice during the active period)] TJ ET 0.267 0.267 0.267 rg BT 302.068 123.233 Td /F1 9.8 Tf [( [16] )] TJ ET 0.271 0.267 0.267 rg BT 323.752 123.233 Td /F1 9.8 Tf [(. Therefore, it may be valuable to examine nighttime BP )] TJ ET BT 26.250 111.328 Td /F1 9.8 Tf [(and HR in Huntingtons disease patients, as well as pursue circadian studies of BP in awake and freely moving BACHD mice, )] TJ ET BT 26.250 99.423 Td /F1 9.8 Tf [(which would further explore the extent of dysregulation in BP. It is important to note that the BWs of BACHD mice are )] TJ ET BT 26.250 87.519 Td /F1 9.8 Tf [(significantly increased at 7 mo of age compared to WT mice, possibly due to hypoactivity )] TJ ET 0.267 0.267 0.267 rg BT 411.531 87.519 Td /F1 9.8 Tf [([16] )] TJ ET BT 430.505 87.519 Td /F1 9.8 Tf [([25])] TJ ET 0.271 0.267 0.267 rg BT 446.767 87.519 Td /F1 9.8 Tf [(, which may contribute to the )] TJ ET BT 26.250 75.614 Td /F1 9.8 Tf [(observed increase in BP in BACHD mice. This increased BW is transient, as the BWs are no longer significantly different at 12 )] TJ ET BT 26.250 63.709 Td /F1 9.8 Tf [(mo of age. Comparisons of BP at this older age may indicate whether heavier BW and/or other mechanisms of BP regulation )] TJ ET BT 26.250 51.804 Td /F1 9.8 Tf [(are factors involved in the increase of BP observed in BACHD mice.)] TJ ET Q q 15.000 41.923 577.500 735.077 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 2: Heart Morphometry comparisons between WT and BACHD mice at 7 mo and 12 mo of age.)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(HW/BW or HW/TL were calculated for all genotypes and age groups and compared using a 2-way ANOVA. * significant )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(difference between genotypes.)] TJ ET Q BT 26.250 695.849 Td /F4 9.8 Tf [(Echocardiographic Analysis)] TJ ET BT 26.250 676.444 Td /F1 9.8 Tf [(Changes in the morphology of the hearts of BACHD mice, could cause aberrant modifications in heart function. Therefore, we )] TJ ET BT 26.250 664.539 Td /F1 9.8 Tf [(subjected BACHD and WT mice to echocardiographic analysis at about 12 mo of age in order to assess heart function. We )] TJ ET BT 26.250 652.635 Td /F1 9.8 Tf [(found no significant differences in any of the parameters measured \(Table 2\). Though not statistically significant, the wall )] TJ ET BT 26.250 640.730 Td /F1 9.8 Tf [(thicknesses and LV mass were slightly higher in the BACHD mice consistent with the morphometry data. Despite indications of )] TJ ET BT 26.250 628.825 Td /F1 9.8 Tf [(abnormal regulation of BP and baroreflex, the hearts of BACHD mice continue to function normally at this age as assessed by )] TJ ET BT 26.250 616.920 Td /F1 9.8 Tf [(echocardiogram)] TJ ET 0.965 0.965 0.965 rg 26.250 394.789 555.000 212.250 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 607.039 m 581.250 607.039 l 581.250 606.289 l 26.250 606.289 l f 26.250 394.789 m 581.250 394.789 l 581.250 395.539 l 26.250 395.539 l f q 225.000 0 0 192.750 35.250 404.539 cm /I6 Do Q q 35.250 398.539 537.000 0.000 re W n Q 0.271 0.267 0.267 rg BT 26.250 377.766 Td /F6 9.8 Tf [(Table 2:)] TJ ET BT 63.095 377.766 Td /F5 9.8 Tf [( Echocardiogram parameters in 12 mo old WT and BACHD mice.No significant differences were detected between )] TJ ET BT 26.250 365.861 Td /F5 9.8 Tf [(genotypes using a Students t-test. HR- Heart Rate; VST-Ventricular Septal Thickness, EDD- End Diastolic Diameter, PWT- )] TJ ET BT 26.250 353.956 Td /F5 9.8 Tf [(Posterior Wall Thickness, ESD- End Systolic Diameter, Ao-ET- Aortic Ejection Time, LV%FS- Left Ventricular percent Fractional )] TJ ET BT 26.250 342.051 Td /F5 9.8 Tf [(Shortening, LvEF- Left Ventricular Ejection Fraction, LVMass- Left Ventricular Mass, and E/A- Early Diastole/Atrial contraction )] TJ ET BT 26.250 330.147 Td /F5 9.8 Tf [(ratio.)] TJ ET BT 26.250 293.544 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 273.590 Td /F1 9.8 Tf [(We report dysfunction of the ANS in BACHD mice, as measured by the baroreceptor reflex. Furthermore, baseline )] TJ ET BT 26.250 261.685 Td /F1 9.8 Tf [(measurements of BP and HR were higher in BACHD mice compared to WT controls. Lastly, we find changes in the )] TJ ET BT 26.250 249.780 Td /F1 9.8 Tf [(morphometry of the heart, but echocardiography did not detect any functional changes at 12 mo of age.)] TJ ET BT 26.250 230.376 Td /F1 9.8 Tf [(The increased baseline BP levels measured in lightly anesthetized BACHD mice indicate changes in the overall regulation of BP )] TJ ET BT 26.250 218.471 Td /F1 9.8 Tf [(tone. Importantly, these BP recordings were taken during the day, a time in the resting period of mice when BP is expected to )] TJ ET BT 26.250 206.566 Td /F1 9.8 Tf [(be low. These increased BP levels parallel the reported increase in HR of BACHD mice also measured during the day )] TJ ET 0.267 0.267 0.267 rg BT 536.156 206.566 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 552.418 206.566 Td /F1 9.8 Tf [( , )] TJ ET BT 26.250 194.661 Td /F1 9.8 Tf [(suggesting a global dysregulation of the cardiovascular system causing it to be hyperactive during the rest period. The blunted )] TJ ET BT 26.250 182.757 Td /F1 9.8 Tf [(depression in BP levels during rest would be similar to a nondipping pressure profile observed in humans, which in many cases )] TJ ET BT 26.250 170.852 Td /F1 9.8 Tf [(is an indication of dysautonomia)] TJ ET 0.267 0.267 0.267 rg BT 164.983 170.852 Td /F1 9.8 Tf [( [22])] TJ ET BT 183.956 170.852 Td /F1 9.8 Tf [( [23])] TJ ET 0.271 0.267 0.267 rg BT 202.930 170.852 Td /F1 9.8 Tf [( . Nondippers have a higher risk for future cardiovascular events, as well as damage to )] TJ ET BT 26.250 158.947 Td /F1 9.8 Tf [(other organs )] TJ ET 0.267 0.267 0.267 rg BT 83.697 158.947 Td /F1 9.8 Tf [([23])] TJ ET BT 99.960 158.947 Td /F1 9.8 Tf [([24])] TJ ET 0.271 0.267 0.267 rg BT 116.223 158.947 Td /F1 9.8 Tf [( . Published reports of BP in Huntingtons disease patients do not detect significant differences compared )] TJ ET BT 26.250 147.042 Td /F1 9.8 Tf [(to control groups, however BP measurements were taken during the day when patients are in a more active state, which could )] TJ ET BT 26.250 135.138 Td /F1 9.8 Tf [(mask the higher levels of BP tone)] TJ ET 0.267 0.267 0.267 rg BT 171.486 135.138 Td /F1 9.8 Tf [( [5])] TJ ET BT 185.038 135.138 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 195.881 135.138 Td /F1 9.8 Tf [( . This appears to be the case for HR in BACHD mice, as HR levels are not significantly )] TJ ET BT 26.250 123.233 Td /F1 9.8 Tf [(different between WT and BACHD mice during the active period)] TJ ET 0.267 0.267 0.267 rg BT 302.068 123.233 Td /F1 9.8 Tf [( [16] )] TJ ET 0.271 0.267 0.267 rg BT 323.752 123.233 Td /F1 9.8 Tf [(. Therefore, it may be valuable to examine nighttime BP )] TJ ET BT 26.250 111.328 Td /F1 9.8 Tf [(and HR in Huntingtons disease patients, as well as pursue circadian studies of BP in awake and freely moving BACHD mice, )] TJ ET BT 26.250 99.423 Td /F1 9.8 Tf [(which would further explore the extent of dysregulation in BP. It is important to note that the BWs of BACHD mice are )] TJ ET BT 26.250 87.519 Td /F1 9.8 Tf [(significantly increased at 7 mo of age compared to WT mice, possibly due to hypoactivity )] TJ ET 0.267 0.267 0.267 rg BT 411.531 87.519 Td /F1 9.8 Tf [([16] )] TJ ET BT 430.505 87.519 Td /F1 9.8 Tf [([25])] TJ ET 0.271 0.267 0.267 rg BT 446.767 87.519 Td /F1 9.8 Tf [(, which may contribute to the )] TJ ET BT 26.250 75.614 Td /F1 9.8 Tf [(observed increase in BP in BACHD mice. This increased BW is transient, as the BWs are no longer significantly different at 12 )] TJ ET BT 26.250 63.709 Td /F1 9.8 Tf [(mo of age. Comparisons of BP at this older age may indicate whether heavier BW and/or other mechanisms of BP regulation )] TJ ET BT 26.250 51.804 Td /F1 9.8 Tf [(are factors involved in the increase of BP observed in BACHD mice.)] TJ ET Q q 15.000 41.923 577.500 735.077 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 2: Heart Morphometry comparisons between WT and BACHD mice at 7 mo and 12 mo of age.)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(HW/BW or HW/TL were calculated for all genotypes and age groups and compared using a 2-way ANOVA. * significant )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(difference between genotypes.)] TJ ET Q BT 26.250 695.849 Td /F4 9.8 Tf [(Echocardiographic Analysis)] TJ ET BT 26.250 676.444 Td /F1 9.8 Tf [(Changes in the morphology of the hearts of BACHD mice, could cause aberrant modifications in heart function. Therefore, we )] TJ ET BT 26.250 664.539 Td /F1 9.8 Tf [(subjected BACHD and WT mice to echocardiographic analysis at about 12 mo of age in order to assess heart function. We )] TJ ET BT 26.250 652.635 Td /F1 9.8 Tf [(found no significant differences in any of the parameters measured \(Table 2\). Though not statistically significant, the wall )] TJ ET BT 26.250 640.730 Td /F1 9.8 Tf [(thicknesses and LV mass were slightly higher in the BACHD mice consistent with the morphometry data. Despite indications of )] TJ ET BT 26.250 628.825 Td /F1 9.8 Tf [(abnormal regulation of BP and baroreflex, the hearts of BACHD mice continue to function normally at this age as assessed by )] TJ ET BT 26.250 616.920 Td /F1 9.8 Tf [(echocardiogram)] TJ ET 0.965 0.965 0.965 rg 26.250 394.789 555.000 212.250 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 607.039 m 581.250 607.039 l 581.250 606.289 l 26.250 606.289 l f 26.250 394.789 m 581.250 394.789 l 581.250 395.539 l 26.250 395.539 l f q 225.000 0 0 192.750 35.250 404.539 cm /I6 Do Q q 35.250 398.539 537.000 0.000 re W n Q 0.271 0.267 0.267 rg BT 26.250 377.766 Td /F6 9.8 Tf [(Table 2:)] TJ ET BT 63.095 377.766 Td /F5 9.8 Tf [( Echocardiogram parameters in 12 mo old WT and BACHD mice.No significant differences were detected between )] TJ ET BT 26.250 365.861 Td /F5 9.8 Tf [(genotypes using a Students t-test. HR- Heart Rate; VST-Ventricular Septal Thickness, EDD- End Diastolic Diameter, PWT- )] TJ ET BT 26.250 353.956 Td /F5 9.8 Tf [(Posterior Wall Thickness, ESD- End Systolic Diameter, Ao-ET- Aortic Ejection Time, LV%FS- Left Ventricular percent Fractional )] TJ ET BT 26.250 342.051 Td /F5 9.8 Tf [(Shortening, LvEF- Left Ventricular Ejection Fraction, LVMass- Left Ventricular Mass, and E/A- Early Diastole/Atrial contraction )] TJ ET BT 26.250 330.147 Td /F5 9.8 Tf [(ratio.)] TJ ET BT 26.250 293.544 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 273.590 Td /F1 9.8 Tf [(We report dysfunction of the ANS in BACHD mice, as measured by the baroreceptor reflex. Furthermore, baseline )] TJ ET BT 26.250 261.685 Td /F1 9.8 Tf [(measurements of BP and HR were higher in BACHD mice compared to WT controls. Lastly, we find changes in the )] TJ ET BT 26.250 249.780 Td /F1 9.8 Tf [(morphometry of the heart, but echocardiography did not detect any functional changes at 12 mo of age.)] TJ ET BT 26.250 230.376 Td /F1 9.8 Tf [(The increased baseline BP levels measured in lightly anesthetized BACHD mice indicate changes in the overall regulation of BP )] TJ ET BT 26.250 218.471 Td /F1 9.8 Tf [(tone. Importantly, these BP recordings were taken during the day, a time in the resting period of mice when BP is expected to )] TJ ET BT 26.250 206.566 Td /F1 9.8 Tf [(be low. These increased BP levels parallel the reported increase in HR of BACHD mice also measured during the day )] TJ ET 0.267 0.267 0.267 rg BT 536.156 206.566 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 552.418 206.566 Td /F1 9.8 Tf [( , )] TJ ET BT 26.250 194.661 Td /F1 9.8 Tf [(suggesting a global dysregulation of the cardiovascular system causing it to be hyperactive during the rest period. The blunted )] TJ ET BT 26.250 182.757 Td /F1 9.8 Tf [(depression in BP levels during rest would be similar to a nondipping pressure profile observed in humans, which in many cases )] TJ ET BT 26.250 170.852 Td /F1 9.8 Tf [(is an indication of dysautonomia)] TJ ET 0.267 0.267 0.267 rg BT 164.983 170.852 Td /F1 9.8 Tf [( [22])] TJ ET BT 183.956 170.852 Td /F1 9.8 Tf [( [23])] TJ ET 0.271 0.267 0.267 rg BT 202.930 170.852 Td /F1 9.8 Tf [( . Nondippers have a higher risk for future cardiovascular events, as well as damage to )] TJ ET BT 26.250 158.947 Td /F1 9.8 Tf [(other organs )] TJ ET 0.267 0.267 0.267 rg BT 83.697 158.947 Td /F1 9.8 Tf [([23])] TJ ET BT 99.960 158.947 Td /F1 9.8 Tf [([24])] TJ ET 0.271 0.267 0.267 rg BT 116.223 158.947 Td /F1 9.8 Tf [( . Published reports of BP in Huntingtons disease patients do not detect significant differences compared )] TJ ET BT 26.250 147.042 Td /F1 9.8 Tf [(to control groups, however BP measurements were taken during the day when patients are in a more active state, which could )] TJ ET BT 26.250 135.138 Td /F1 9.8 Tf [(mask the higher levels of BP tone)] TJ ET 0.267 0.267 0.267 rg BT 171.486 135.138 Td /F1 9.8 Tf [( [5])] TJ ET BT 185.038 135.138 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 195.881 135.138 Td /F1 9.8 Tf [( . This appears to be the case for HR in BACHD mice, as HR levels are not significantly )] TJ ET BT 26.250 123.233 Td /F1 9.8 Tf [(different between WT and BACHD mice during the active period)] TJ ET 0.267 0.267 0.267 rg BT 302.068 123.233 Td /F1 9.8 Tf [( [16] )] TJ ET 0.271 0.267 0.267 rg BT 323.752 123.233 Td /F1 9.8 Tf [(. Therefore, it may be valuable to examine nighttime BP )] TJ ET BT 26.250 111.328 Td /F1 9.8 Tf [(and HR in Huntingtons disease patients, as well as pursue circadian studies of BP in awake and freely moving BACHD mice, )] TJ ET BT 26.250 99.423 Td /F1 9.8 Tf [(which would further explore the extent of dysregulation in BP. It is important to note that the BWs of BACHD mice are )] TJ ET BT 26.250 87.519 Td /F1 9.8 Tf [(significantly increased at 7 mo of age compared to WT mice, possibly due to hypoactivity )] TJ ET 0.267 0.267 0.267 rg BT 411.531 87.519 Td /F1 9.8 Tf [([16] )] TJ ET BT 430.505 87.519 Td /F1 9.8 Tf [([25])] TJ ET 0.271 0.267 0.267 rg BT 446.767 87.519 Td /F1 9.8 Tf [(, which may contribute to the )] TJ ET BT 26.250 75.614 Td /F1 9.8 Tf [(observed increase in BP in BACHD mice. This increased BW is transient, as the BWs are no longer significantly different at 12 )] TJ ET BT 26.250 63.709 Td /F1 9.8 Tf [(mo of age. Comparisons of BP at this older age may indicate whether heavier BW and/or other mechanisms of BP regulation )] TJ ET BT 26.250 51.804 Td /F1 9.8 Tf [(are factors involved in the increase of BP observed in BACHD mice.)] TJ ET Q q 225.000 0 0 192.750 35.250 404.539 cm /I6 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(5)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 249 0 obj << /Type /Annot /Subtype /Link /A 250 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 404.5395 260.2500 597.2895 ] >> endobj 250 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2011/11/analynetable2.tif) >> endobj 251 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 257 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 33627>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?4qT*.Ktr;_~?O>0j ]n(}<#q 34b,`.wtn ?}mi5.b݌9E|c`F׆-%m!2\[A Ԑ~&.:'hc~*NF./7,c9`7/blpMa~? x>~QxmbO[}2a@n݃T$bxE'dR<:dq[p>0| SRZQӾ麗4Jr¶~Q(׊??^_ZisZf]9mmK8Wt۲|X+mo?/TmK] vowk+Z3092GziIoB`lv-koqK"3GM><]cƽbEiYi٭JVYڂ2rah~ ž3ֵ_D7:}^@ocՁ9ݹprBG=uKϣd_1!<Uy l=V34Gionljq$$ NIlz?cT\G|w7'נdwo(їuG]9#45Iּ7ƚQ&_-%n%pwsl?m.⋯'5߇'ҼK,wN4I8i 2f\OS&⛛:OAd!6+ )Gx~"~ǚֿ76[w_CVηDZc*,J;+zM\7u-~Uaqk$$(3H`TZ_v~(o4ۈgm414c"FuEW(sW^"~ęyyM\cKZ\cXGiPg35^_^}.-W7113@xLz^)4 :iWh^7 g6;~3W晥k6aco"Kn/,ϕqFn-y},F'F>x4Jڣ Ńcxצ>#'ŶxK [1a6gmOu#vo/v۞3q]p?\,^JbPEPEbpRdz-f@zk)Jxsٯʣ'aWu\)DPE@ E #QzzPZLj3@ Fh(}/Qo|RԮ_-lk{=" :=_3W6f <k ?>4[4Rp!FN@8'~>~|2< >X&+L*B|=z?֭x EjYGe&: ? ,4k-zT:dzόmR[s'*;dW'=rA][iznZEkix%TB2yc$+o@o]fItRhNU0U "m?b_ؠ.KLUמ_[>|x~q~"__ؠ ~/R}~"NÂ+?[{|cxEB9H@O⼣ǁIo$C}>Rxų+ .F J_^(l{NA.u۝%:ܓɝq50x>񯊾$<&,&4 O\rx[)=x#[ 2U{wm?b'n/R5(a!/W1s!wo1>3w'%, C{mZoRUKF:"څ&+wox?<%x8"5i~Z$aF29|O Ɵ3x~VZCyem !' 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0 R 460 0 R 462 0 R 464 0 R 466 0 R ] /Contents 317 0 R >> endobj 317 0 obj << /Length 30679 >> stream 0.271 0.267 0.267 rg q 15.000 38.521 577.500 738.479 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(The BACHD mice showed deficits in the baroreceptor reflex, whereby the response in HR to the transient hyper- and )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(hypotension induced by ATII and NP, respectively, is blunted compared to WTs. 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As the disease advances, parasympathetic activity )] TJ ET BT 26.250 588.905 Td /F1 9.8 Tf [(progressively decreases )] TJ ET 0.267 0.267 0.267 rg BT 134.075 588.905 Td /F1 9.8 Tf [([4] [5] )] TJ ET BT 161.180 588.905 Td /F1 9.8 Tf [([7] )] TJ ET 0.271 0.267 0.267 rg BT 174.733 588.905 Td /F1 9.8 Tf [(. In our experiments, the blunted increase in HR after NP administration in BACHD mice may )] TJ ET BT 26.250 577.000 Td /F1 9.8 Tf [(be a result of a ceiling effect for sympathetic activity, in that the range for further activation is limited due to an already )] TJ ET BT 26.250 565.095 Td /F1 9.8 Tf [(hyperactive sympathetic nervous system. The blunted decrease in HR after ATII administration may be a result of the )] TJ ET BT 26.250 553.191 Td /F1 9.8 Tf [(dysfunction of both branches of the autonomic nervous system. The hyperactivity of the sympathetic nervous system may not )] TJ ET BT 26.250 541.286 Td /F1 9.8 Tf [(allow the HR to fully depress and in addition, the progressive dysfunction of the parasympathetic nervous system may be )] TJ ET BT 26.250 529.381 Td /F1 9.8 Tf [(inadequate to slow HR. Tests to measure both the sympathetic and parasympathetic nervous system activity in BACHD mice )] TJ ET BT 26.250 517.476 Td /F1 9.8 Tf [(would be able to determine the extent of the dysfunction of each of the branches.)] TJ ET BT 26.250 498.072 Td /F1 9.8 Tf [(There is a high prevalence of autonomic dysfunction in Huntingtons disease patients that manifest as various clinical symptoms )] TJ ET BT 26.250 486.167 Td /F1 9.8 Tf [(and signs such as gastrointestinal complaints, urinary difficulties and postural dizziness )] TJ ET 0.267 0.267 0.267 rg BT 404.482 486.167 Td /F1 9.8 Tf [([8] )] TJ ET 0.271 0.267 0.267 rg BT 418.034 486.167 Td /F1 9.8 Tf [(. More profound may be the )] TJ ET BT 26.250 474.262 Td /F1 9.8 Tf [(increased risk of cardiac arrhythmias, and the development of coronary heart disease, that result in a significant number of )] TJ ET BT 26.250 462.357 Td /F1 9.8 Tf [(deaths within the Huntingtons disease population )] TJ ET 0.267 0.267 0.267 rg BT 243.031 462.357 Td /F1 9.8 Tf [([2] [3] [5] [33])] TJ ET 0.271 0.267 0.267 rg BT 299.952 462.357 Td /F1 9.8 Tf [( . Importantly, these autonomic symptoms occur before any )] TJ ET BT 26.250 450.453 Td /F1 9.8 Tf [(motor deficits, therefore measures of autonomic dysfunction could be a valuable tool in Huntingtons disease diagnosis and )] TJ ET BT 26.250 438.548 Td /F1 9.8 Tf [(staging)] TJ ET 0.267 0.267 0.267 rg BT 57.684 438.548 Td /F1 9.8 Tf [( [8] [9] )] TJ ET 0.271 0.267 0.267 rg BT 87.499 438.548 Td /F1 9.8 Tf [(. Upon diagnosis, vigilant monitoring of the cardiovascular system may help deter the incidence of fatal events. )] TJ ET BT 26.250 426.643 Td /F1 9.8 Tf [(We were able to measure changes in the morphometry of the heart in BACHD mice relative to body frame size \(TL\), which )] TJ ET BT 26.250 414.738 Td /F1 9.8 Tf [(could indicate the start of cardiac remodeling in response to the increased BP and aberrant autonomic signaling. )] TJ ET BT 26.250 402.834 Td /F1 9.8 Tf [(Echocardiogram results do not show functional changes in the hearts of BACHD mice, suggesting that the hearts at this stage )] TJ ET BT 26.250 390.929 Td /F1 9.8 Tf [(of the disease are still able to compensate despite the morphological and physiological changes in the cardiovascular system. )] TJ ET BT 26.250 379.024 Td /F1 9.8 Tf [(The R6/2 Huntington disease mouse model, which display a more rapid disease progression, develop serious cardiac )] TJ ET BT 26.250 367.119 Td /F1 9.8 Tf [(dysfunction suggesting a cardiotoxic effect of )] TJ ET BT 222.976 367.119 Td /F5 9.8 Tf [(htt)] TJ ET BT 233.818 367.119 Td /F1 9.8 Tf [( deposits in the heart)] TJ ET 0.267 0.267 0.267 rg BT 324.327 367.119 Td /F1 9.8 Tf [( [15])] TJ ET 0.271 0.267 0.267 rg BT 343.300 367.119 Td /F1 9.8 Tf [( , and we speculate that BACHD mice may develop )] TJ ET BT 26.250 355.215 Td /F1 9.8 Tf [(cardiac dysfunction at an older age. Future work can be directed to study the susceptibility of this BACHD model to )] TJ ET BT 26.250 343.310 Td /F1 9.8 Tf [(cardiovascular stresses as well as design management strategies focused on cardiovascular health to offset and reduce the )] TJ ET BT 26.250 331.405 Td /F1 9.8 Tf [(chances of serious cardiovascular events in HD patients.)] TJ ET BT 26.250 294.803 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 274.848 Td /F1 9.8 Tf [(Work supported by NRSA award F31NS070529 to AMS as well as CHDI Foundation Grant A-4339 and a Stein Oppenheimer )] TJ ET BT 26.250 262.944 Td /F1 9.8 Tf [(award to CSC.)] TJ ET BT 26.250 226.341 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 206.387 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 169.784 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 142.330 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 142.330 Td /F1 9.8 Tf [(Margolis RL, Ross CA. Diagnosis of Huntington disease. Clin Chem. 2003 Oct;49\(10\):1726-32. Review. PubMed PMID: )] TJ ET BT 26.250 130.425 Td /F1 9.8 Tf [(14500613.)] TJ ET BT 26.250 111.021 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 111.021 Td /F1 9.8 Tf [(Chiu E, Alexander L. Causes of death in Huntington's disease. Med J Aust. 1982 Feb 20;1\(4\):153. PubMed PMID: 6210834.)] TJ ET BT 26.250 91.616 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 91.616 Td /F1 9.8 Tf [(Lanska DJ, Lavine L, Lanska MJ, Schoenberg BS. Huntington's disease mortality in the United States. Neurology. 1988 )] TJ ET BT 26.250 79.711 Td /F1 9.8 Tf [(May;38\(5\):769-72. PubMed PMID: 2966305.)] TJ ET BT 26.250 60.306 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 60.306 Td /F1 9.8 Tf [(Sharma KR, Romano JG, Ayyar DR, Rotta FT, Facca A, Sanchez-Ramos J. Sympathetic skin response and heart rate )] TJ ET BT 26.250 48.402 Td /F1 9.8 Tf [(variability in patients with Huntington disease. Arch Neurol. 1999 Oct;56\(10\):1248-52. PubMed PMID: 10520941.)] TJ ET Q q 15.000 38.521 577.500 738.479 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(The BACHD mice showed deficits in the baroreceptor reflex, whereby the response in HR to the transient hyper- and )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(hypotension induced by ATII and NP, respectively, is blunted compared to WTs. This blunted response in both directions of the )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(reflex suggests that both branches of the ANS may be affected. The primary deficit in the baroreceptor reflex in BACHD mice is )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(unknown, as this process is mediated by various regions of the brain that include the brainstem and hypothalamus, along with )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(possible deficits in the outputs from the central autonomic nervous system)] TJ ET 0.267 0.267 0.267 rg BT 345.426 719.857 Td /F1 9.8 Tf [( [6])] TJ ET BT 358.978 719.857 Td /F1 9.8 Tf [([18])] TJ ET BT 375.241 719.857 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 391.504 719.857 Td /F1 9.8 Tf [( . )] TJ ET BT 399.636 719.857 Td /F5 9.8 Tf [(Htt)] TJ ET BT 412.096 719.857 Td /F1 9.8 Tf [( deposits are found globally in BACHD )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(mice, which could disrupt function among cells in the baroreceptor pathway, even without evidence for gross degeneration of )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(these brain regions )] TJ ET 0.267 0.267 0.267 rg BT 111.874 696.048 Td /F1 9.8 Tf [([17] )] TJ ET 0.271 0.267 0.267 rg BT 130.848 696.048 Td /F1 9.8 Tf [(. In HD patients, the detection of alterations in the baroreceptor pathway, such as the vagal nuclei and )] TJ ET BT 26.250 684.143 Td /F1 9.8 Tf [(cerebral cortex, are establishing structural cause for the dysfunction)] TJ ET 0.267 0.267 0.267 rg BT 318.331 684.143 Td /F1 9.8 Tf [( [5])] TJ ET BT 331.883 684.143 Td /F1 9.8 Tf [( [6])] TJ ET BT 345.436 684.143 Td /F1 9.8 Tf [([27])] TJ ET BT 361.699 684.143 Td /F1 9.8 Tf [( [28])] TJ ET BT 380.672 684.143 Td /F1 9.8 Tf [([29])] TJ ET 0.271 0.267 0.267 rg BT 396.935 684.143 Td /F1 9.8 Tf [( . Ideally, identification of the site of )] TJ ET BT 26.250 672.238 Td /F1 9.8 Tf [(dysfunction could be used to devise an appropriate therapeutic approach to manage symptomatic HD patients)] TJ ET 0.267 0.267 0.267 rg BT 500.441 672.238 Td /F1 9.8 Tf [( [30])] TJ ET 0.271 0.267 0.267 rg BT 519.415 672.238 Td /F1 9.8 Tf [( . In humans, )] TJ ET BT 26.250 660.333 Td /F1 9.8 Tf [(similar studies have been conducted to test the response of the baroreceptor reflex. Results have been mixed, however recent )] TJ ET BT 26.250 648.429 Td /F1 9.8 Tf [(studies report deficits during the Valsalva maneuver, hand-grip test, and the head up tilt test)] TJ ET 0.267 0.267 0.267 rg BT 421.866 648.429 Td /F1 9.8 Tf [( [4] [7])] TJ ET BT 448.971 648.429 Td /F1 9.8 Tf [([31])] TJ ET BT 465.234 648.429 Td /F1 9.8 Tf [([32])] TJ ET 0.271 0.267 0.267 rg BT 481.497 648.429 Td /F1 9.8 Tf [(. Furthermore, )] TJ ET BT 26.250 636.524 Td /F1 9.8 Tf [(patients complain of dizziness and light-headedness upon standing, which are symptoms of baroreceptor dysregulation )] TJ ET BT 26.250 624.619 Td /F1 9.8 Tf [(resulting in orthostatic hypotension )] TJ ET 0.267 0.267 0.267 rg BT 179.071 624.619 Td /F1 9.8 Tf [([6])] TJ ET BT 189.913 624.619 Td /F1 9.8 Tf [( [8])] TJ ET 0.271 0.267 0.267 rg BT 203.466 624.619 Td /F1 9.8 Tf [(. Other measurements such as Heart Rate Variability and sympathetic skin response )] TJ ET BT 26.250 612.714 Td /F1 9.8 Tf [(suggest that both branches of the ANS are disrupted in HD patients)] TJ ET 0.267 0.267 0.267 rg BT 317.278 612.714 Td /F1 9.8 Tf [( [4])] TJ ET BT 330.830 612.714 Td /F1 9.8 Tf [( [5])] TJ ET BT 344.383 612.714 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 355.225 612.714 Td /F1 9.8 Tf [(. During the very early stages of HD, the )] TJ ET BT 26.250 600.810 Td /F1 9.8 Tf [(sympathetic nervous system appears to be hyperactive )] TJ ET 0.267 0.267 0.267 rg BT 266.851 600.810 Td /F1 9.8 Tf [([6] [7] [9] )] TJ ET 0.271 0.267 0.267 rg BT 307.508 600.810 Td /F1 9.8 Tf [(. As the disease advances, parasympathetic activity )] TJ ET BT 26.250 588.905 Td /F1 9.8 Tf [(progressively decreases )] TJ ET 0.267 0.267 0.267 rg BT 134.075 588.905 Td /F1 9.8 Tf [([4] [5] )] TJ ET BT 161.180 588.905 Td /F1 9.8 Tf [([7] )] TJ ET 0.271 0.267 0.267 rg BT 174.733 588.905 Td /F1 9.8 Tf [(. In our experiments, the blunted increase in HR after NP administration in BACHD mice may )] TJ ET BT 26.250 577.000 Td /F1 9.8 Tf [(be a result of a ceiling effect for sympathetic activity, in that the range for further activation is limited due to an already )] TJ ET BT 26.250 565.095 Td /F1 9.8 Tf [(hyperactive sympathetic nervous system. The blunted decrease in HR after ATII administration may be a result of the )] TJ ET BT 26.250 553.191 Td /F1 9.8 Tf [(dysfunction of both branches of the autonomic nervous system. The hyperactivity of the sympathetic nervous system may not )] TJ ET BT 26.250 541.286 Td /F1 9.8 Tf [(allow the HR to fully depress and in addition, the progressive dysfunction of the parasympathetic nervous system may be )] TJ ET BT 26.250 529.381 Td /F1 9.8 Tf [(inadequate to slow HR. Tests to measure both the sympathetic and parasympathetic nervous system activity in BACHD mice )] TJ ET BT 26.250 517.476 Td /F1 9.8 Tf [(would be able to determine the extent of the dysfunction of each of the branches.)] TJ ET BT 26.250 498.072 Td /F1 9.8 Tf [(There is a high prevalence of autonomic dysfunction in Huntingtons disease patients that manifest as various clinical symptoms )] TJ ET BT 26.250 486.167 Td /F1 9.8 Tf [(and signs such as gastrointestinal complaints, urinary difficulties and postural dizziness )] TJ ET 0.267 0.267 0.267 rg BT 404.482 486.167 Td /F1 9.8 Tf [([8] )] TJ ET 0.271 0.267 0.267 rg BT 418.034 486.167 Td /F1 9.8 Tf [(. More profound may be the )] TJ ET BT 26.250 474.262 Td /F1 9.8 Tf [(increased risk of cardiac arrhythmias, and the development of coronary heart disease, that result in a significant number of )] TJ ET BT 26.250 462.357 Td /F1 9.8 Tf [(deaths within the Huntingtons disease population )] TJ ET 0.267 0.267 0.267 rg BT 243.031 462.357 Td /F1 9.8 Tf [([2] [3] [5] [33])] TJ ET 0.271 0.267 0.267 rg BT 299.952 462.357 Td /F1 9.8 Tf [( . Importantly, these autonomic symptoms occur before any )] TJ ET BT 26.250 450.453 Td /F1 9.8 Tf [(motor deficits, therefore measures of autonomic dysfunction could be a valuable tool in Huntingtons disease diagnosis and )] TJ ET BT 26.250 438.548 Td /F1 9.8 Tf [(staging)] TJ ET 0.267 0.267 0.267 rg BT 57.684 438.548 Td /F1 9.8 Tf [( [8] [9] )] TJ ET 0.271 0.267 0.267 rg BT 87.499 438.548 Td /F1 9.8 Tf [(. Upon diagnosis, vigilant monitoring of the cardiovascular system may help deter the incidence of fatal events. )] TJ ET BT 26.250 426.643 Td /F1 9.8 Tf [(We were able to measure changes in the morphometry of the heart in BACHD mice relative to body frame size \(TL\), which )] TJ ET BT 26.250 414.738 Td /F1 9.8 Tf [(could indicate the start of cardiac remodeling in response to the increased BP and aberrant autonomic signaling. )] TJ ET BT 26.250 402.834 Td /F1 9.8 Tf [(Echocardiogram results do not show functional changes in the hearts of BACHD mice, suggesting that the hearts at this stage )] TJ ET BT 26.250 390.929 Td /F1 9.8 Tf [(of the disease are still able to compensate despite the morphological and physiological changes in the cardiovascular system. )] TJ ET BT 26.250 379.024 Td /F1 9.8 Tf [(The R6/2 Huntington disease mouse model, which display a more rapid disease progression, develop serious cardiac )] TJ ET BT 26.250 367.119 Td /F1 9.8 Tf [(dysfunction suggesting a cardiotoxic effect of )] TJ ET BT 222.976 367.119 Td /F5 9.8 Tf [(htt)] TJ ET BT 233.818 367.119 Td /F1 9.8 Tf [( deposits in the heart)] TJ ET 0.267 0.267 0.267 rg BT 324.327 367.119 Td /F1 9.8 Tf [( [15])] TJ ET 0.271 0.267 0.267 rg BT 343.300 367.119 Td /F1 9.8 Tf [( , and we speculate that BACHD mice may develop )] TJ ET BT 26.250 355.215 Td /F1 9.8 Tf [(cardiac dysfunction at an older age. Future work can be directed to study the susceptibility of this BACHD model to )] TJ ET BT 26.250 343.310 Td /F1 9.8 Tf [(cardiovascular stresses as well as design management strategies focused on cardiovascular health to offset and reduce the )] TJ ET BT 26.250 331.405 Td /F1 9.8 Tf [(chances of serious cardiovascular events in HD patients.)] TJ ET BT 26.250 294.803 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 274.848 Td /F1 9.8 Tf [(Work supported by NRSA award F31NS070529 to AMS as well as CHDI Foundation Grant A-4339 and a Stein Oppenheimer )] TJ ET BT 26.250 262.944 Td /F1 9.8 Tf [(award to CSC.)] TJ ET BT 26.250 226.341 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 206.387 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 169.784 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 142.330 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 142.330 Td /F1 9.8 Tf [(Margolis RL, Ross CA. Diagnosis of Huntington disease. Clin Chem. 2003 Oct;49\(10\):1726-32. Review. PubMed PMID: )] TJ ET BT 26.250 130.425 Td /F1 9.8 Tf [(14500613.)] TJ ET BT 26.250 111.021 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 111.021 Td /F1 9.8 Tf [(Chiu E, Alexander L. Causes of death in Huntington's disease. Med J Aust. 1982 Feb 20;1\(4\):153. PubMed PMID: 6210834.)] TJ ET BT 26.250 91.616 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 91.616 Td /F1 9.8 Tf [(Lanska DJ, Lavine L, Lanska MJ, Schoenberg BS. Huntington's disease mortality in the United States. Neurology. 1988 )] TJ ET BT 26.250 79.711 Td /F1 9.8 Tf [(May;38\(5\):769-72. PubMed PMID: 2966305.)] TJ ET BT 26.250 60.306 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 60.306 Td /F1 9.8 Tf [(Sharma KR, Romano JG, Ayyar DR, Rotta FT, Facca A, Sanchez-Ramos J. Sympathetic skin response and heart rate )] TJ ET BT 26.250 48.402 Td /F1 9.8 Tf [(variability in patients with Huntington disease. Arch Neurol. 1999 Oct;56\(10\):1248-52. PubMed PMID: 10520941.)] TJ ET Q q 15.000 38.521 577.500 738.479 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(The BACHD mice showed deficits in the baroreceptor reflex, whereby the response in HR to the transient hyper- and )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(hypotension induced by ATII and NP, respectively, is blunted compared to WTs. This blunted response in both directions of the )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(reflex suggests that both branches of the ANS may be affected. The primary deficit in the baroreceptor reflex in BACHD mice is )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(unknown, as this process is mediated by various regions of the brain that include the brainstem and hypothalamus, along with )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(possible deficits in the outputs from the central autonomic nervous system)] TJ ET 0.267 0.267 0.267 rg BT 345.426 719.857 Td /F1 9.8 Tf [( [6])] TJ ET BT 358.978 719.857 Td /F1 9.8 Tf [([18])] TJ ET BT 375.241 719.857 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 391.504 719.857 Td /F1 9.8 Tf [( . )] TJ ET BT 399.636 719.857 Td /F5 9.8 Tf [(Htt)] TJ ET BT 412.096 719.857 Td /F1 9.8 Tf [( deposits are found globally in BACHD )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(mice, which could disrupt function among cells in the baroreceptor pathway, even without evidence for gross degeneration of )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(these brain regions )] TJ ET 0.267 0.267 0.267 rg BT 111.874 696.048 Td /F1 9.8 Tf [([17] )] TJ ET 0.271 0.267 0.267 rg BT 130.848 696.048 Td /F1 9.8 Tf [(. In HD patients, the detection of alterations in the baroreceptor pathway, such as the vagal nuclei and )] TJ ET BT 26.250 684.143 Td /F1 9.8 Tf [(cerebral cortex, are establishing structural cause for the dysfunction)] TJ ET 0.267 0.267 0.267 rg BT 318.331 684.143 Td /F1 9.8 Tf [( [5])] TJ ET BT 331.883 684.143 Td /F1 9.8 Tf [( [6])] TJ ET BT 345.436 684.143 Td /F1 9.8 Tf [([27])] TJ ET BT 361.699 684.143 Td /F1 9.8 Tf [( [28])] TJ ET BT 380.672 684.143 Td /F1 9.8 Tf [([29])] TJ ET 0.271 0.267 0.267 rg BT 396.935 684.143 Td /F1 9.8 Tf [( . Ideally, identification of the site of )] TJ ET BT 26.250 672.238 Td /F1 9.8 Tf [(dysfunction could be used to devise an appropriate therapeutic approach to manage symptomatic HD patients)] TJ ET 0.267 0.267 0.267 rg BT 500.441 672.238 Td /F1 9.8 Tf [( [30])] TJ ET 0.271 0.267 0.267 rg BT 519.415 672.238 Td /F1 9.8 Tf [( . In humans, )] TJ ET BT 26.250 660.333 Td /F1 9.8 Tf [(similar studies have been conducted to test the response of the baroreceptor reflex. Results have been mixed, however recent )] TJ ET BT 26.250 648.429 Td /F1 9.8 Tf [(studies report deficits during the Valsalva maneuver, hand-grip test, and the head up tilt test)] TJ ET 0.267 0.267 0.267 rg BT 421.866 648.429 Td /F1 9.8 Tf [( [4] [7])] TJ ET BT 448.971 648.429 Td /F1 9.8 Tf [([31])] TJ ET BT 465.234 648.429 Td /F1 9.8 Tf [([32])] TJ ET 0.271 0.267 0.267 rg BT 481.497 648.429 Td /F1 9.8 Tf [(. Furthermore, )] TJ ET BT 26.250 636.524 Td /F1 9.8 Tf [(patients complain of dizziness and light-headedness upon standing, which are symptoms of baroreceptor dysregulation )] TJ ET BT 26.250 624.619 Td /F1 9.8 Tf [(resulting in orthostatic hypotension )] TJ ET 0.267 0.267 0.267 rg BT 179.071 624.619 Td /F1 9.8 Tf [([6])] TJ ET BT 189.913 624.619 Td /F1 9.8 Tf [( [8])] TJ ET 0.271 0.267 0.267 rg BT 203.466 624.619 Td /F1 9.8 Tf [(. Other measurements such as Heart Rate Variability and sympathetic skin response )] TJ ET BT 26.250 612.714 Td /F1 9.8 Tf [(suggest that both branches of the ANS are disrupted in HD patients)] TJ ET 0.267 0.267 0.267 rg BT 317.278 612.714 Td /F1 9.8 Tf [( [4])] TJ ET BT 330.830 612.714 Td /F1 9.8 Tf [( [5])] TJ ET BT 344.383 612.714 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 355.225 612.714 Td /F1 9.8 Tf [(. During the very early stages of HD, the )] TJ ET BT 26.250 600.810 Td /F1 9.8 Tf [(sympathetic nervous system appears to be hyperactive )] TJ ET 0.267 0.267 0.267 rg BT 266.851 600.810 Td /F1 9.8 Tf [([6] [7] [9] )] TJ ET 0.271 0.267 0.267 rg BT 307.508 600.810 Td /F1 9.8 Tf [(. As the disease advances, parasympathetic activity )] TJ ET BT 26.250 588.905 Td /F1 9.8 Tf [(progressively decreases )] TJ ET 0.267 0.267 0.267 rg BT 134.075 588.905 Td /F1 9.8 Tf [([4] [5] )] TJ ET BT 161.180 588.905 Td /F1 9.8 Tf [([7] )] TJ ET 0.271 0.267 0.267 rg BT 174.733 588.905 Td /F1 9.8 Tf [(. In our experiments, the blunted increase in HR after NP administration in BACHD mice may )] TJ ET BT 26.250 577.000 Td /F1 9.8 Tf [(be a result of a ceiling effect for sympathetic activity, in that the range for further activation is limited due to an already )] TJ ET BT 26.250 565.095 Td /F1 9.8 Tf [(hyperactive sympathetic nervous system. The blunted decrease in HR after ATII administration may be a result of the )] TJ ET BT 26.250 553.191 Td /F1 9.8 Tf [(dysfunction of both branches of the autonomic nervous system. The hyperactivity of the sympathetic nervous system may not )] TJ ET BT 26.250 541.286 Td /F1 9.8 Tf [(allow the HR to fully depress and in addition, the progressive dysfunction of the parasympathetic nervous system may be )] TJ ET BT 26.250 529.381 Td /F1 9.8 Tf [(inadequate to slow HR. Tests to measure both the sympathetic and parasympathetic nervous system activity in BACHD mice )] TJ ET BT 26.250 517.476 Td /F1 9.8 Tf [(would be able to determine the extent of the dysfunction of each of the branches.)] TJ ET BT 26.250 498.072 Td /F1 9.8 Tf [(There is a high prevalence of autonomic dysfunction in Huntingtons disease patients that manifest as various clinical symptoms )] TJ ET BT 26.250 486.167 Td /F1 9.8 Tf [(and signs such as gastrointestinal complaints, urinary difficulties and postural dizziness )] TJ ET 0.267 0.267 0.267 rg BT 404.482 486.167 Td /F1 9.8 Tf [([8] )] TJ ET 0.271 0.267 0.267 rg BT 418.034 486.167 Td /F1 9.8 Tf [(. More profound may be the )] TJ ET BT 26.250 474.262 Td /F1 9.8 Tf [(increased risk of cardiac arrhythmias, and the development of coronary heart disease, that result in a significant number of )] TJ ET BT 26.250 462.357 Td /F1 9.8 Tf [(deaths within the Huntingtons disease population )] TJ ET 0.267 0.267 0.267 rg BT 243.031 462.357 Td /F1 9.8 Tf [([2] [3] [5] [33])] TJ ET 0.271 0.267 0.267 rg BT 299.952 462.357 Td /F1 9.8 Tf [( . Importantly, these autonomic symptoms occur before any )] TJ ET BT 26.250 450.453 Td /F1 9.8 Tf [(motor deficits, therefore measures of autonomic dysfunction could be a valuable tool in Huntingtons disease diagnosis and )] TJ ET BT 26.250 438.548 Td /F1 9.8 Tf [(staging)] TJ ET 0.267 0.267 0.267 rg BT 57.684 438.548 Td /F1 9.8 Tf [( [8] [9] )] TJ ET 0.271 0.267 0.267 rg BT 87.499 438.548 Td /F1 9.8 Tf [(. Upon diagnosis, vigilant monitoring of the cardiovascular system may help deter the incidence of fatal events. )] TJ ET BT 26.250 426.643 Td /F1 9.8 Tf [(We were able to measure changes in the morphometry of the heart in BACHD mice relative to body frame size \(TL\), which )] TJ ET BT 26.250 414.738 Td /F1 9.8 Tf [(could indicate the start of cardiac remodeling in response to the increased BP and aberrant autonomic signaling. )] TJ ET BT 26.250 402.834 Td /F1 9.8 Tf [(Echocardiogram results do not show functional changes in the hearts of BACHD mice, suggesting that the hearts at this stage )] TJ ET BT 26.250 390.929 Td /F1 9.8 Tf [(of the disease are still able to compensate despite the morphological and physiological changes in the cardiovascular system. )] TJ ET BT 26.250 379.024 Td /F1 9.8 Tf [(The R6/2 Huntington disease mouse model, which display a more rapid disease progression, develop serious cardiac )] TJ ET BT 26.250 367.119 Td /F1 9.8 Tf [(dysfunction suggesting a cardiotoxic effect of )] TJ ET BT 222.976 367.119 Td /F5 9.8 Tf [(htt)] TJ ET BT 233.818 367.119 Td /F1 9.8 Tf [( deposits in the heart)] TJ ET 0.267 0.267 0.267 rg BT 324.327 367.119 Td /F1 9.8 Tf [( [15])] TJ ET 0.271 0.267 0.267 rg BT 343.300 367.119 Td /F1 9.8 Tf [( , and we speculate that BACHD mice may develop )] TJ ET BT 26.250 355.215 Td /F1 9.8 Tf [(cardiac dysfunction at an older age. Future work can be directed to study the susceptibility of this BACHD model to )] TJ ET BT 26.250 343.310 Td /F1 9.8 Tf [(cardiovascular stresses as well as design management strategies focused on cardiovascular health to offset and reduce the )] TJ ET BT 26.250 331.405 Td /F1 9.8 Tf [(chances of serious cardiovascular events in HD patients.)] TJ ET BT 26.250 294.803 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 274.848 Td /F1 9.8 Tf [(Work supported by NRSA award F31NS070529 to AMS as well as CHDI Foundation Grant A-4339 and a Stein Oppenheimer )] TJ ET BT 26.250 262.944 Td /F1 9.8 Tf [(award to CSC.)] TJ ET BT 26.250 226.341 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 206.387 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 169.784 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 142.330 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 142.330 Td /F1 9.8 Tf [(Margolis RL, Ross CA. Diagnosis of Huntington disease. Clin Chem. 2003 Oct;49\(10\):1726-32. Review. PubMed PMID: )] TJ ET BT 26.250 130.425 Td /F1 9.8 Tf [(14500613.)] TJ ET BT 26.250 111.021 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 111.021 Td /F1 9.8 Tf [(Chiu E, Alexander L. Causes of death in Huntington's disease. Med J Aust. 1982 Feb 20;1\(4\):153. PubMed PMID: 6210834.)] TJ ET BT 26.250 91.616 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 91.616 Td /F1 9.8 Tf [(Lanska DJ, Lavine L, Lanska MJ, Schoenberg BS. Huntington's disease mortality in the United States. Neurology. 1988 )] TJ ET BT 26.250 79.711 Td /F1 9.8 Tf [(May;38\(5\):769-72. PubMed PMID: 2966305.)] TJ ET BT 26.250 60.306 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 60.306 Td /F1 9.8 Tf [(Sharma KR, Romano JG, Ayyar DR, Rotta FT, Facca A, Sanchez-Ramos J. Sympathetic skin response and heart rate )] TJ ET BT 26.250 48.402 Td /F1 9.8 Tf [(variability in patients with Huntington disease. Arch Neurol. 1999 Oct;56\(10\):1248-52. PubMed PMID: 10520941.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(6)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 318 0 obj << /Type /Annot /Subtype /Link /A 319 0 R /Border [0 0 0] /H /I /Rect [ 345.4260 718.9553 358.9785 728.8759 ] >> endobj 319 0 obj << /Type /Action >> endobj 320 0 obj << /Type /Annot /Subtype /Link /A 321 0 R /Border [0 0 0] /H /I /Rect [ 358.9785 718.9553 375.2415 728.8759 ] >> endobj 321 0 obj << /Type /Action >> endobj 322 0 obj << /Type /Annot /Subtype /Link /A 323 0 R /Border [0 0 0] /H /I /Rect [ 375.2415 718.9553 391.5045 728.8759 ] >> endobj 323 0 obj << /Type /Action >> endobj 324 0 obj << /Type /Annot /Subtype /Link /A 325 0 R /Border [0 0 0] /H /I /Rect [ 111.8745 695.1458 130.8480 705.0665 ] >> endobj 325 0 obj << /Type /Action >> endobj 326 0 obj << /Type /Annot /Subtype /Link /A 327 0 R /Border [0 0 0] /H /I /Rect [ 318.3308 683.2411 331.8833 693.1617 ] >> endobj 327 0 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Td /F1 9.8 Tf [(Andrich J, Schmitz T, Saft C, Postert T, Kraus P, Epplen JT, Przuntek H, Agelink MW. Autonomic nervous system function in )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Huntington's disease. J Neurol Neurosurg Psychiatry. 2002 Jun;72\(6\):726-31. PubMed PMID: 12023413; PubMed Central )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(PMCID: PMC1737927.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 716.762 Td /F1 9.8 Tf [(Kobal J, Meglic B, Mesec A, Peterlin B. Early sympathetic hyperactivity in Huntington's disease. Eur J Neurol. 2004 )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Dec;11\(12\):842-8. PubMed PMID: 15667417.)] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 685.452 Td /F1 9.8 Tf [(Br KJ, Boettger MK, Andrich J, Epplen JT, Fischer F, Cordes J, Koschke M, Agelink MW. Cardiovagal modulation upon )] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(postural change is altered in Huntington's disease. Eur J Neurol. 2008 Aug;15\(8\):869-71. Epub 2008 May 15. PubMed PMID: )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(18484985.)] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 642.238 Td /F1 9.8 Tf [(Aziz NA, Anguelova GV, Marinus J, van Dijk JG, Roos RA. Autonomic symptoms in patients and pre-manifest mutation )] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(carriers of Huntington's disease. Eur J Neurol. 2010 Aug;17\(8\):1068-74. Epub 2010 Feb 24. PubMed PMID: 20192977.)] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 610.929 Td /F1 9.8 Tf [(Kobal J, Melik Z, Cankar K, Bajrovic FF, Meglic B, Peterlin B, Zaletel M. Autonomic dysfunction in presymptomatic and early )] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(symptomatic Huntington's disease. Acta Neurol Scand. 2010 Jun;121\(6\):392-9. Epub 2009 Dec 28. PubMed PMID: 20047567.)] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 579.619 Td /F1 9.8 Tf [(Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. Heart rate variability from 24-hour electrocardiography and the 2-year )] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(risk for sudden death. Circulation. 1993 Jul;88\(1\):180-5. PubMed PMID: 8319331.)] TJ ET BT 26.250 548.310 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 548.310 Td /F1 9.8 Tf [(Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and )] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994 Aug;90\(2\):878-83. PubMed PMID: 8044959.)] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 517.000 Td /F1 9.8 Tf [(Dekker JM, Schouten EG, Klootwijk P, Pool J, Swenne CA, Kromhout D. Heart rate variability from short )] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study. Am J )] TJ ET BT 26.250 493.191 Td /F1 9.8 Tf [(Epidemiol. 1997 May 15;145\(10\):899-908. PubMed PMID: 9149661.)] TJ ET BT 26.250 473.786 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 473.786 Td /F1 9.8 Tf [(Mihm MJ, Amann DM, Schanbacher BL, Altschuld RA, Bauer JA, Hoyt KR. Cardiac dysfunction in the R6/2 mouse model of )] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(Huntington's disease. Neurobiol Dis. 2007 Feb;25\(2\):297-308. Epub 2006 Nov 27. PubMed PMID: 17126554; PubMed Central )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(PMCID: PMC1850107.)] TJ ET BT 26.250 430.572 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 430.572 Td /F1 9.8 Tf [(Pattison JS, Sanbe A, Maloyan A, Osinska H, Klevitsky R, Robbins J. Cardiomyocyte expression of a polyglutamine )] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(preamyloid oligomer causes heart failure. Circulation. 2008 May 27;117\(21\):2743-51. Epub 2008 May 19. PubMed PMID: )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(18490523; PubMed Central PMCID: PMC2413062.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Sassone J, Colciago C, Cislaghi G, Silani V, Ciammola A. Huntington's disease: the current state of research with )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(peripheral tissues. Exp Neurol. 2009 Oct;219\(2\):385-97. Epub 2009 May 19. Review. PubMed PMID: 19460373.)] TJ ET BT 26.250 356.048 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 356.048 Td /F1 9.8 Tf [(Kudo T, Schroeder A, Loh DH, Kuljis D, Jordan MC, Roos KP, Colwell CS. Dysfunctions in circadian behavior and )] TJ ET BT 26.250 344.143 Td /F1 9.8 Tf [(physiology in mouse models of Huntington's disease. Exp Neurol. 2011 Mar;228\(1\):80-90. Epub 2010 Dec 22. PubMed PMID: )] TJ ET BT 26.250 332.238 Td /F1 9.8 Tf [(21184755.)] TJ ET BT 26.250 312.834 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 312.834 Td /F1 9.8 Tf [(Gray M, Shirasaki DI, Cepeda C, Andr VM, Wilburn B, Lu XH, Tao J, Yamazaki I, Li SH, Sun YE, Li XJ, Levine MS, Yang )] TJ ET BT 26.250 300.929 Td /F1 9.8 Tf [(XW. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective )] TJ ET BT 26.250 289.024 Td /F1 9.8 Tf [(neuropathogenesis in BACHD mice. J Neurosci. 2008 Jun 11;28\(24\):6182-95. PubMed PMID: 18550760; PubMed Central )] TJ ET BT 26.250 277.119 Td /F1 9.8 Tf [(PMCID: PMC2630800.)] TJ ET BT 26.250 257.715 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 257.715 Td /F1 9.8 Tf [(Benarroch EE. The arterial baroreflex: functional organization and involvement in neurologic disease. Neurology. 2008 Nov )] TJ ET BT 26.250 245.810 Td /F1 9.8 Tf [(18;71\(21\):1733-8. Review. PubMed PMID: 19015490.)] TJ ET BT 26.250 226.405 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 226.405 Td /F1 9.8 Tf [(Pilowsky PM, Goodchild AK. Baroreceptor reflex pathways and neurotransmitters: 10 years on. J Hypertens. 2002 )] TJ ET BT 26.250 214.500 Td /F1 9.8 Tf [(Sep;20\(9\):1675-88. Review. PubMed PMID: 12195099.)] TJ ET BT 26.250 195.096 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 195.096 Td /F1 9.8 Tf [(Timmers HJ, Wieling W, Karemaker JM, Lenders JW. Denervation of carotid baro- and chemoreceptors in humans. J )] TJ ET BT 26.250 183.191 Td /F1 9.8 Tf [(Physiol. 2003 Nov 15;553\(Pt 1\):3-11. Epub 2003 Oct 3. Review. PubMed PMID: 14528027; PubMed Central PMCID: )] TJ ET BT 26.250 171.286 Td /F1 9.8 Tf [(PMC2343492.)] TJ ET BT 26.250 151.881 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 151.881 Td /F1 9.8 Tf [(Jordan MC, Henderson SA, Han T, Fishbein MC, Philipson KD, Roos KP. Myocardial function with reduced expression of )] TJ ET BT 26.250 139.977 Td /F1 9.8 Tf [(the sodium-calcium exchanger. J Card Fail. 2010 Sep;16\(9\):786-96. Epub 2010 May 14. PubMed PMID: 20797603; PubMed )] TJ ET BT 26.250 128.072 Td /F1 9.8 Tf [(Central PMCID: PMC2929393.)] TJ ET BT 26.250 108.667 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 108.667 Td /F1 9.8 Tf [(Myredal A, Friberg P, Johansson M. Elevated myocardial repolarization lability and arterial baroreflex dysfunction in healthy )] TJ ET BT 26.250 96.762 Td /F1 9.8 Tf [(individuals with nondipping blood pressure pattern. Am J Hypertens. 2010 Mar;23\(3\):255-9. Epub 2010 Jan 14. PubMed PMID: )] TJ ET BT 26.250 84.858 Td /F1 9.8 Tf [(20075850.)] TJ ET BT 26.250 65.453 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 65.453 Td /F1 9.8 Tf [(Kanbay M, Turgut F, Uyar ME, Akcay A, Covic A. Causes and mechanisms of nondipping hypertension. Clin Exp )] TJ ET BT 26.250 53.548 Td /F1 9.8 Tf [(Hypertens. 2008 Oct;30\(7\):585-97. Review. PubMed PMID: 18855262.)] TJ ET Q q 15.000 43.667 577.500 733.333 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Andrich J, Schmitz T, Saft C, Postert T, Kraus P, Epplen JT, Przuntek H, Agelink MW. Autonomic nervous system function in )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Huntington's disease. J Neurol Neurosurg Psychiatry. 2002 Jun;72\(6\):726-31. PubMed PMID: 12023413; PubMed Central )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(PMCID: PMC1737927.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 716.762 Td /F1 9.8 Tf [(Kobal J, Meglic B, Mesec A, Peterlin B. Early sympathetic hyperactivity in Huntington's disease. Eur J Neurol. 2004 )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Dec;11\(12\):842-8. PubMed PMID: 15667417.)] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 685.452 Td /F1 9.8 Tf [(Br KJ, Boettger MK, Andrich J, Epplen JT, Fischer F, Cordes J, Koschke M, Agelink MW. Cardiovagal modulation upon )] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(postural change is altered in Huntington's disease. Eur J Neurol. 2008 Aug;15\(8\):869-71. Epub 2008 May 15. PubMed PMID: )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(18484985.)] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 642.238 Td /F1 9.8 Tf [(Aziz NA, Anguelova GV, Marinus J, van Dijk JG, Roos RA. Autonomic symptoms in patients and pre-manifest mutation )] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(carriers of Huntington's disease. Eur J Neurol. 2010 Aug;17\(8\):1068-74. Epub 2010 Feb 24. PubMed PMID: 20192977.)] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 610.929 Td /F1 9.8 Tf [(Kobal J, Melik Z, Cankar K, Bajrovic FF, Meglic B, Peterlin B, Zaletel M. Autonomic dysfunction in presymptomatic and early )] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(symptomatic Huntington's disease. Acta Neurol Scand. 2010 Jun;121\(6\):392-9. Epub 2009 Dec 28. PubMed PMID: 20047567.)] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 579.619 Td /F1 9.8 Tf [(Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. Heart rate variability from 24-hour electrocardiography and the 2-year )] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(risk for sudden death. Circulation. 1993 Jul;88\(1\):180-5. PubMed PMID: 8319331.)] TJ ET BT 26.250 548.310 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 548.310 Td /F1 9.8 Tf [(Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and )] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994 Aug;90\(2\):878-83. PubMed PMID: 8044959.)] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 517.000 Td /F1 9.8 Tf [(Dekker JM, Schouten EG, Klootwijk P, Pool J, Swenne CA, Kromhout D. Heart rate variability from short )] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study. Am J )] TJ ET BT 26.250 493.191 Td /F1 9.8 Tf [(Epidemiol. 1997 May 15;145\(10\):899-908. PubMed PMID: 9149661.)] TJ ET BT 26.250 473.786 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 473.786 Td /F1 9.8 Tf [(Mihm MJ, Amann DM, Schanbacher BL, Altschuld RA, Bauer JA, Hoyt KR. Cardiac dysfunction in the R6/2 mouse model of )] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(Huntington's disease. Neurobiol Dis. 2007 Feb;25\(2\):297-308. Epub 2006 Nov 27. PubMed PMID: 17126554; PubMed Central )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(PMCID: PMC1850107.)] TJ ET BT 26.250 430.572 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 430.572 Td /F1 9.8 Tf [(Pattison JS, Sanbe A, Maloyan A, Osinska H, Klevitsky R, Robbins J. Cardiomyocyte expression of a polyglutamine )] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(preamyloid oligomer causes heart failure. Circulation. 2008 May 27;117\(21\):2743-51. Epub 2008 May 19. PubMed PMID: )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(18490523; PubMed Central PMCID: PMC2413062.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Sassone J, Colciago C, Cislaghi G, Silani V, Ciammola A. Huntington's disease: the current state of research with )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(peripheral tissues. Exp Neurol. 2009 Oct;219\(2\):385-97. Epub 2009 May 19. Review. PubMed PMID: 19460373.)] TJ ET BT 26.250 356.048 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 356.048 Td /F1 9.8 Tf [(Kudo T, Schroeder A, Loh DH, Kuljis D, Jordan MC, Roos KP, Colwell CS. Dysfunctions in circadian behavior and )] TJ ET BT 26.250 344.143 Td /F1 9.8 Tf [(physiology in mouse models of Huntington's disease. Exp Neurol. 2011 Mar;228\(1\):80-90. Epub 2010 Dec 22. PubMed PMID: )] TJ ET BT 26.250 332.238 Td /F1 9.8 Tf [(21184755.)] TJ ET BT 26.250 312.834 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 312.834 Td /F1 9.8 Tf [(Gray M, Shirasaki DI, Cepeda C, Andr VM, Wilburn B, Lu XH, Tao J, Yamazaki I, Li SH, Sun YE, Li XJ, Levine MS, Yang )] TJ ET BT 26.250 300.929 Td /F1 9.8 Tf [(XW. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective )] TJ ET BT 26.250 289.024 Td /F1 9.8 Tf [(neuropathogenesis in BACHD mice. J Neurosci. 2008 Jun 11;28\(24\):6182-95. PubMed PMID: 18550760; PubMed Central )] TJ ET BT 26.250 277.119 Td /F1 9.8 Tf [(PMCID: PMC2630800.)] TJ ET BT 26.250 257.715 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 257.715 Td /F1 9.8 Tf [(Benarroch EE. The arterial baroreflex: functional organization and involvement in neurologic disease. Neurology. 2008 Nov )] TJ ET BT 26.250 245.810 Td /F1 9.8 Tf [(18;71\(21\):1733-8. Review. PubMed PMID: 19015490.)] TJ ET BT 26.250 226.405 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 226.405 Td /F1 9.8 Tf [(Pilowsky PM, Goodchild AK. Baroreceptor reflex pathways and neurotransmitters: 10 years on. J Hypertens. 2002 )] TJ ET BT 26.250 214.500 Td /F1 9.8 Tf [(Sep;20\(9\):1675-88. Review. PubMed PMID: 12195099.)] TJ ET BT 26.250 195.096 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 195.096 Td /F1 9.8 Tf [(Timmers HJ, Wieling W, Karemaker JM, Lenders JW. Denervation of carotid baro- and chemoreceptors in humans. J )] TJ ET BT 26.250 183.191 Td /F1 9.8 Tf [(Physiol. 2003 Nov 15;553\(Pt 1\):3-11. Epub 2003 Oct 3. Review. PubMed PMID: 14528027; PubMed Central PMCID: )] TJ ET BT 26.250 171.286 Td /F1 9.8 Tf [(PMC2343492.)] TJ ET BT 26.250 151.881 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 151.881 Td /F1 9.8 Tf [(Jordan MC, Henderson SA, Han T, Fishbein MC, Philipson KD, Roos KP. Myocardial function with reduced expression of )] TJ ET BT 26.250 139.977 Td /F1 9.8 Tf [(the sodium-calcium exchanger. J Card Fail. 2010 Sep;16\(9\):786-96. Epub 2010 May 14. PubMed PMID: 20797603; PubMed )] TJ ET BT 26.250 128.072 Td /F1 9.8 Tf [(Central PMCID: PMC2929393.)] TJ ET BT 26.250 108.667 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 108.667 Td /F1 9.8 Tf [(Myredal A, Friberg P, Johansson M. Elevated myocardial repolarization lability and arterial baroreflex dysfunction in healthy )] TJ ET BT 26.250 96.762 Td /F1 9.8 Tf [(individuals with nondipping blood pressure pattern. Am J Hypertens. 2010 Mar;23\(3\):255-9. Epub 2010 Jan 14. PubMed PMID: )] TJ ET BT 26.250 84.858 Td /F1 9.8 Tf [(20075850.)] TJ ET BT 26.250 65.453 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 65.453 Td /F1 9.8 Tf [(Kanbay M, Turgut F, Uyar ME, Akcay A, Covic A. Causes and mechanisms of nondipping hypertension. Clin Exp )] TJ ET BT 26.250 53.548 Td /F1 9.8 Tf [(Hypertens. 2008 Oct;30\(7\):585-97. Review. PubMed PMID: 18855262.)] TJ ET Q q 15.000 43.667 577.500 733.333 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Andrich J, Schmitz T, Saft C, Postert T, Kraus P, Epplen JT, Przuntek H, Agelink MW. Autonomic nervous system function in )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Huntington's disease. J Neurol Neurosurg Psychiatry. 2002 Jun;72\(6\):726-31. PubMed PMID: 12023413; PubMed Central )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(PMCID: PMC1737927.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 716.762 Td /F1 9.8 Tf [(Kobal J, Meglic B, Mesec A, Peterlin B. Early sympathetic hyperactivity in Huntington's disease. Eur J Neurol. 2004 )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Dec;11\(12\):842-8. PubMed PMID: 15667417.)] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 685.452 Td /F1 9.8 Tf [(Br KJ, Boettger MK, Andrich J, Epplen JT, Fischer F, Cordes J, Koschke M, Agelink MW. Cardiovagal modulation upon )] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(postural change is altered in Huntington's disease. Eur J Neurol. 2008 Aug;15\(8\):869-71. Epub 2008 May 15. PubMed PMID: )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(18484985.)] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 642.238 Td /F1 9.8 Tf [(Aziz NA, Anguelova GV, Marinus J, van Dijk JG, Roos RA. Autonomic symptoms in patients and pre-manifest mutation )] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(carriers of Huntington's disease. Eur J Neurol. 2010 Aug;17\(8\):1068-74. Epub 2010 Feb 24. PubMed PMID: 20192977.)] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 610.929 Td /F1 9.8 Tf [(Kobal J, Melik Z, Cankar K, Bajrovic FF, Meglic B, Peterlin B, Zaletel M. Autonomic dysfunction in presymptomatic and early )] TJ ET BT 26.250 599.024 Td /F1 9.8 Tf [(symptomatic Huntington's disease. Acta Neurol Scand. 2010 Jun;121\(6\):392-9. Epub 2009 Dec 28. PubMed PMID: 20047567.)] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 579.619 Td /F1 9.8 Tf [(Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. Heart rate variability from 24-hour electrocardiography and the 2-year )] TJ ET BT 26.250 567.714 Td /F1 9.8 Tf [(risk for sudden death. Circulation. 1993 Jul;88\(1\):180-5. PubMed PMID: 8319331.)] TJ ET BT 26.250 548.310 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 548.310 Td /F1 9.8 Tf [(Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and )] TJ ET BT 26.250 536.405 Td /F1 9.8 Tf [(mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994 Aug;90\(2\):878-83. PubMed PMID: 8044959.)] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 517.000 Td /F1 9.8 Tf [(Dekker JM, Schouten EG, Klootwijk P, Pool J, Swenne CA, Kromhout D. Heart rate variability from short )] TJ ET BT 26.250 505.095 Td /F1 9.8 Tf [(electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study. Am J )] TJ ET BT 26.250 493.191 Td /F1 9.8 Tf [(Epidemiol. 1997 May 15;145\(10\):899-908. PubMed PMID: 9149661.)] TJ ET BT 26.250 473.786 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 473.786 Td /F1 9.8 Tf [(Mihm MJ, Amann DM, Schanbacher BL, Altschuld RA, Bauer JA, Hoyt KR. Cardiac dysfunction in the R6/2 mouse model of )] TJ ET BT 26.250 461.881 Td /F1 9.8 Tf [(Huntington's disease. Neurobiol Dis. 2007 Feb;25\(2\):297-308. Epub 2006 Nov 27. PubMed PMID: 17126554; PubMed Central )] TJ ET BT 26.250 449.976 Td /F1 9.8 Tf [(PMCID: PMC1850107.)] TJ ET BT 26.250 430.572 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 430.572 Td /F1 9.8 Tf [(Pattison JS, Sanbe A, Maloyan A, Osinska H, Klevitsky R, Robbins J. Cardiomyocyte expression of a polyglutamine )] TJ ET BT 26.250 418.667 Td /F1 9.8 Tf [(preamyloid oligomer causes heart failure. Circulation. 2008 May 27;117\(21\):2743-51. Epub 2008 May 19. PubMed PMID: )] TJ ET BT 26.250 406.762 Td /F1 9.8 Tf [(18490523; PubMed Central PMCID: PMC2413062.)] TJ ET BT 26.250 387.357 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 387.357 Td /F1 9.8 Tf [(Sassone J, Colciago C, Cislaghi G, Silani V, Ciammola A. Huntington's disease: the current state of research with )] TJ ET BT 26.250 375.453 Td /F1 9.8 Tf [(peripheral tissues. Exp Neurol. 2009 Oct;219\(2\):385-97. Epub 2009 May 19. Review. PubMed PMID: 19460373.)] TJ ET BT 26.250 356.048 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 356.048 Td /F1 9.8 Tf [(Kudo T, Schroeder A, Loh DH, Kuljis D, Jordan MC, Roos KP, Colwell CS. Dysfunctions in circadian behavior and )] TJ ET BT 26.250 344.143 Td /F1 9.8 Tf [(physiology in mouse models of Huntington's disease. Exp Neurol. 2011 Mar;228\(1\):80-90. Epub 2010 Dec 22. PubMed PMID: )] TJ ET BT 26.250 332.238 Td /F1 9.8 Tf [(21184755.)] TJ ET BT 26.250 312.834 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 312.834 Td /F1 9.8 Tf [(Gray M, Shirasaki DI, Cepeda C, Andr VM, Wilburn B, Lu XH, Tao J, Yamazaki I, Li SH, Sun YE, Li XJ, Levine MS, Yang )] TJ ET BT 26.250 300.929 Td /F1 9.8 Tf [(XW. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective )] TJ ET BT 26.250 289.024 Td /F1 9.8 Tf [(neuropathogenesis in BACHD mice. J Neurosci. 2008 Jun 11;28\(24\):6182-95. PubMed PMID: 18550760; PubMed Central )] TJ ET BT 26.250 277.119 Td /F1 9.8 Tf [(PMCID: PMC2630800.)] TJ ET BT 26.250 257.715 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 257.715 Td /F1 9.8 Tf [(Benarroch EE. The arterial baroreflex: functional organization and involvement in neurologic disease. Neurology. 2008 Nov )] TJ ET BT 26.250 245.810 Td /F1 9.8 Tf [(18;71\(21\):1733-8. Review. PubMed PMID: 19015490.)] TJ ET BT 26.250 226.405 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 226.405 Td /F1 9.8 Tf [(Pilowsky PM, Goodchild AK. Baroreceptor reflex pathways and neurotransmitters: 10 years on. J Hypertens. 2002 )] TJ ET BT 26.250 214.500 Td /F1 9.8 Tf [(Sep;20\(9\):1675-88. Review. PubMed PMID: 12195099.)] TJ ET BT 26.250 195.096 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 195.096 Td /F1 9.8 Tf [(Timmers HJ, Wieling W, Karemaker JM, Lenders JW. Denervation of carotid baro- and chemoreceptors in humans. J )] TJ ET BT 26.250 183.191 Td /F1 9.8 Tf [(Physiol. 2003 Nov 15;553\(Pt 1\):3-11. Epub 2003 Oct 3. Review. PubMed PMID: 14528027; PubMed Central PMCID: )] TJ ET BT 26.250 171.286 Td /F1 9.8 Tf [(PMC2343492.)] TJ ET BT 26.250 151.881 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 151.881 Td /F1 9.8 Tf [(Jordan MC, Henderson SA, Han T, Fishbein MC, Philipson KD, Roos KP. Myocardial function with reduced expression of )] TJ ET BT 26.250 139.977 Td /F1 9.8 Tf [(the sodium-calcium exchanger. J Card Fail. 2010 Sep;16\(9\):786-96. Epub 2010 May 14. PubMed PMID: 20797603; PubMed )] TJ ET BT 26.250 128.072 Td /F1 9.8 Tf [(Central PMCID: PMC2929393.)] TJ ET BT 26.250 108.667 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 108.667 Td /F1 9.8 Tf [(Myredal A, Friberg P, Johansson M. Elevated myocardial repolarization lability and arterial baroreflex dysfunction in healthy )] TJ ET BT 26.250 96.762 Td /F1 9.8 Tf [(individuals with nondipping blood pressure pattern. Am J Hypertens. 2010 Mar;23\(3\):255-9. Epub 2010 Jan 14. PubMed PMID: )] TJ ET BT 26.250 84.858 Td /F1 9.8 Tf [(20075850.)] TJ ET BT 26.250 65.453 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 65.453 Td /F1 9.8 Tf [(Kanbay M, Turgut F, Uyar ME, Akcay A, Covic A. Causes and mechanisms of nondipping hypertension. Clin Exp )] TJ ET BT 26.250 53.548 Td /F1 9.8 Tf [(Hypertens. 2008 Oct;30\(7\):585-97. Review. PubMed PMID: 18855262.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(7)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 470 0 obj << /Type /Page /Parent 3 0 R /Contents 471 0 R >> endobj 471 0 obj << /Length 10666 >> stream 0.271 0.267 0.267 rg q 15.000 437.000 577.500 340.000 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(White WB. Importance of blood pressure control over a 24-hour period. J Manag Care Pharm. 2007 Oct;13\(8 Suppl B\):34-9. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Review. PubMed PMID: 17970615.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Oakeshott S, Balci F, Filippov I, Murphy C, Port R, Connor D, Paintdakhi A, Lesauter J, Menalled L, Ramboz S, Kwak S, )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(Howland D, Silver R, Brunner D. Circadian Abnormalities in Motor Activity in a BAC Transgenic Mouse Model of Huntington's )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Disease. PLoS Curr. 2011 Apr 5;3:RRN1225. PubMed PMID: 21479110; PubMed Central PMCID: PMC3072044.)] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 685.452 Td /F1 9.8 Tf [(Ma X, Abboud FM, Chapleau MW. Analysis of afferent, central, and efferent components of the baroreceptor reflex in mice. )] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Am J Physiol Regul Integr Comp Physiol. 2002 Nov;283\(5\):R1033-40. PubMed PMID: 12376395.)] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 654.143 Td /F1 9.8 Tf [(Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993 )] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(Oct;68\(10\):988-1001. Review. PubMed PMID: 8412366.)] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 622.833 Td /F1 9.8 Tf [(Squitieri F, Cannella M, Giallonardo P, Maglione V, Mariotti C, Hayden MR. Onset and pre-onset studies to define the )] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(Huntington's disease natural history. Brain Res Bull. 2001 Oct-Nov 1;56\(3-4\):233-8. Review. PubMed PMID: 11719256.)] TJ ET BT 26.250 591.524 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 591.524 Td /F1 9.8 Tf [(Morota N. [Carcinoma of the esophagus associated with lung abscess and pyothorax seen in 18 year-old boy \(author's )] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(transl\)]. Nihon Kyobu Geka Gakkai Zasshi. 1977 Jun;25\(6\):791-7. Japanese. PubMed PMID: 915352.)] TJ ET BT 26.250 560.214 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 560.214 Td /F1 9.8 Tf [(Izzo JL Jr, Taylor AA. The sympathetic nervous system and baroreflexes in hypertension and hypotension. Curr Hypertens )] TJ ET BT 26.250 548.310 Td /F1 9.8 Tf [(Rep. 1999 Jun;1\(3\):254-63. Review. PubMed PMID: 10981075.)] TJ ET BT 26.250 528.905 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 528.905 Td /F1 9.8 Tf [(Den Heijer JC, Bollen WL, Reulen JP, van Dijk JG, Kramer CG, Roos RA, Buruma OJ. Autonomic nervous function in )] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(Huntington's disease. Arch Neurol. 1988 Mar;45\(3\):309-12. PubMed PMID: 2963605.)] TJ ET BT 26.250 497.595 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 497.595 Td /F1 9.8 Tf [(Aminoff MJ, Gross M. Vasoregulatory activity in patients with Huntington's chorea. J Neurol Sci. 1974 Jan;21\(1\):33-8. )] TJ ET BT 26.250 485.691 Td /F1 9.8 Tf [(PubMed PMID: 4280434.)] TJ ET BT 26.250 466.286 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 466.286 Td /F1 9.8 Tf [(Srensen SA, Fenger K. Causes of death in patients with Huntington's disease and in unaffected first degree relatives. J )] TJ ET BT 26.250 454.381 Td /F1 9.8 Tf [(Med Genet. 1992 Dec;29\(12\):911-4. PubMed PMID: 1479606; PubMed Central PMCID: PMC1016212.)] TJ ET Q q 15.000 437.000 577.500 340.000 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(White WB. Importance of blood pressure control over a 24-hour period. J Manag Care Pharm. 2007 Oct;13\(8 Suppl B\):34-9. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Review. PubMed PMID: 17970615.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Oakeshott S, Balci F, Filippov I, Murphy C, Port R, Connor D, Paintdakhi A, Lesauter J, Menalled L, Ramboz S, Kwak S, )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(Howland D, Silver R, Brunner D. Circadian Abnormalities in Motor Activity in a BAC Transgenic Mouse Model of Huntington's )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Disease. PLoS Curr. 2011 Apr 5;3:RRN1225. PubMed PMID: 21479110; PubMed Central PMCID: PMC3072044.)] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 685.452 Td /F1 9.8 Tf [(Ma X, Abboud FM, Chapleau MW. Analysis of afferent, central, and efferent components of the baroreceptor reflex in mice. )] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Am J Physiol Regul Integr Comp Physiol. 2002 Nov;283\(5\):R1033-40. PubMed PMID: 12376395.)] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 654.143 Td /F1 9.8 Tf [(Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993 )] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(Oct;68\(10\):988-1001. Review. PubMed PMID: 8412366.)] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 622.833 Td /F1 9.8 Tf [(Squitieri F, Cannella M, Giallonardo P, Maglione V, Mariotti C, Hayden MR. Onset and pre-onset studies to define the )] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(Huntington's disease natural history. Brain Res Bull. 2001 Oct-Nov 1;56\(3-4\):233-8. Review. PubMed PMID: 11719256.)] TJ ET BT 26.250 591.524 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 591.524 Td /F1 9.8 Tf [(Morota N. [Carcinoma of the esophagus associated with lung abscess and pyothorax seen in 18 year-old boy \(author's )] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(transl\)]. Nihon Kyobu Geka Gakkai Zasshi. 1977 Jun;25\(6\):791-7. Japanese. PubMed PMID: 915352.)] TJ ET BT 26.250 560.214 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 560.214 Td /F1 9.8 Tf [(Izzo JL Jr, Taylor AA. The sympathetic nervous system and baroreflexes in hypertension and hypotension. Curr Hypertens )] TJ ET BT 26.250 548.310 Td /F1 9.8 Tf [(Rep. 1999 Jun;1\(3\):254-63. Review. PubMed PMID: 10981075.)] TJ ET BT 26.250 528.905 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 528.905 Td /F1 9.8 Tf [(Den Heijer JC, Bollen WL, Reulen JP, van Dijk JG, Kramer CG, Roos RA, Buruma OJ. Autonomic nervous function in )] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(Huntington's disease. Arch Neurol. 1988 Mar;45\(3\):309-12. PubMed PMID: 2963605.)] TJ ET BT 26.250 497.595 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 497.595 Td /F1 9.8 Tf [(Aminoff MJ, Gross M. Vasoregulatory activity in patients with Huntington's chorea. J Neurol Sci. 1974 Jan;21\(1\):33-8. )] TJ ET BT 26.250 485.691 Td /F1 9.8 Tf [(PubMed PMID: 4280434.)] TJ ET BT 26.250 466.286 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 466.286 Td /F1 9.8 Tf [(Srensen SA, Fenger K. Causes of death in patients with Huntington's disease and in unaffected first degree relatives. J )] TJ ET BT 26.250 454.381 Td /F1 9.8 Tf [(Med Genet. 1992 Dec;29\(12\):911-4. PubMed PMID: 1479606; PubMed Central PMCID: PMC1016212.)] TJ ET Q q 15.000 437.000 577.500 340.000 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(White WB. Importance of blood pressure control over a 24-hour period. J Manag Care Pharm. 2007 Oct;13\(8 Suppl B\):34-9. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Review. PubMed PMID: 17970615.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Oakeshott S, Balci F, Filippov I, Murphy C, Port R, Connor D, Paintdakhi A, Lesauter J, Menalled L, Ramboz S, Kwak S, )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(Howland D, Silver R, Brunner D. Circadian Abnormalities in Motor Activity in a BAC Transgenic Mouse Model of Huntington's )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(Disease. PLoS Curr. 2011 Apr 5;3:RRN1225. PubMed PMID: 21479110; PubMed Central PMCID: PMC3072044.)] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 685.452 Td /F1 9.8 Tf [(Ma X, Abboud FM, Chapleau MW. Analysis of afferent, central, and efferent components of the baroreceptor reflex in mice. )] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Am J Physiol Regul Integr Comp Physiol. 2002 Nov;283\(5\):R1033-40. PubMed PMID: 12376395.)] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 654.143 Td /F1 9.8 Tf [(Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993 )] TJ ET BT 26.250 642.238 Td /F1 9.8 Tf [(Oct;68\(10\):988-1001. Review. PubMed PMID: 8412366.)] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 622.833 Td /F1 9.8 Tf [(Squitieri F, Cannella M, Giallonardo P, Maglione V, Mariotti C, Hayden MR. Onset and pre-onset studies to define the )] TJ ET BT 26.250 610.929 Td /F1 9.8 Tf [(Huntington's disease natural history. Brain Res Bull. 2001 Oct-Nov 1;56\(3-4\):233-8. Review. PubMed PMID: 11719256.)] TJ ET BT 26.250 591.524 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 591.524 Td /F1 9.8 Tf [(Morota N. [Carcinoma of the esophagus associated with lung abscess and pyothorax seen in 18 year-old boy \(author's )] TJ ET BT 26.250 579.619 Td /F1 9.8 Tf [(transl\)]. Nihon Kyobu Geka Gakkai Zasshi. 1977 Jun;25\(6\):791-7. Japanese. PubMed PMID: 915352.)] TJ ET BT 26.250 560.214 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 560.214 Td /F1 9.8 Tf [(Izzo JL Jr, Taylor AA. The sympathetic nervous system and baroreflexes in hypertension and hypotension. Curr Hypertens )] TJ ET BT 26.250 548.310 Td /F1 9.8 Tf [(Rep. 1999 Jun;1\(3\):254-63. Review. PubMed PMID: 10981075.)] TJ ET BT 26.250 528.905 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 528.905 Td /F1 9.8 Tf [(Den Heijer JC, Bollen WL, Reulen JP, van Dijk JG, Kramer CG, Roos RA, Buruma OJ. Autonomic nervous function in )] TJ ET BT 26.250 517.000 Td /F1 9.8 Tf [(Huntington's disease. Arch Neurol. 1988 Mar;45\(3\):309-12. PubMed PMID: 2963605.)] TJ ET BT 26.250 497.595 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 497.595 Td /F1 9.8 Tf [(Aminoff MJ, Gross M. Vasoregulatory activity in patients with Huntington's chorea. 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