Jason G E Zelt1,2,3, Sarah Schock4, Robert A deKemp5, Duncan J Stewart6,7,8, William A Staines4, Ali Ahmadi5, Rob Beanlands5,6,7, Lisa M Mielniczuk5,6,7. 1. Molecular Function and Imaging Program, The National Cardiac PET Centre, Division of Cardiology, Department of Medicine and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada. jzelt@ottawaheart.ca. 2. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada. jzelt@ottawaheart.ca. 3. Division of Cardiology, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Canada. jzelt@ottawaheart.ca. 4. Department of Biochemistry Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada. 5. Molecular Function and Imaging Program, The National Cardiac PET Centre, Division of Cardiology, Department of Medicine and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada. 6. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada. 7. Division of Cardiology, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Canada. 8. Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Canada.
Abstract
BACKGROUND: Little is known about the sequelae of chronic sympathetic nervous system (SNS) activation in patients with pulmonary arterial hypertension (PAH) and right heart failure (RHF). We aimed to, (1) validate the use of [11C]-meta-hydroxyephedrine (HED) for assessing right ventricular (RV) SNS integrity, and (2) determine the effects of β-receptor blockade on ventricular function and myocardial SNS activity in a PAH rat model. METHODS: PAH was induced in male Sprague-Dawley rats (N = 36) using the Sugen+chronic hypoxia model. At week 5 post-injection, PAH rats were randomized to carvedilol (15 mg·kg-1·day-1 oral; N = 16) or vehicle (N = 16) for 4 weeks. Myocardial SNS function was assessed with HED positron emission tomography(PET). RESULTS: With increasing PAH disease severity, immunohistochemistry confirmed selective sympathetic denervation within the RV and sparing of parasympathetic nerves. These findings were confirmed on PET with a significant negative relationship between HED volume of distribution(DV) and right ventricular systolic pressure (RVSP) in the RV (r = -0.90, p = 0.0003). Carvedilol did not reduce hemodynamic severity compared to vehicle. RV ejection fraction (EF) was lower in both PAH groups compared to control (p < 0.05), and was not further reduced by carvedilol. Carvedilol improved SNS function in the LV with significant increases in the HED DV, and decreased tracer washout in the LV (p < 0.05) but not RV. CONCLUSIONS: PAH disease severity correlated with a reduction in HED DV in the RV. This was associated with selective sympathetic denervation. Late carvedilol treatment did not lead to recovery of RV function. These results support the role of HED imaging in assessing SNS innervation in a failing right ventricle.
BACKGROUND: Little is known about the sequelae of chronic sympathetic nervous system (SNS) activation in patients with pulmonary arterial hypertension (PAH) and right heart failure (RHF). We aimed to, (1) validate the use of [11C]-meta-hydroxyephedrine (HED) for assessing right ventricular (RV) SNS integrity, and (2) determine the effects of β-receptor blockade on ventricular function and myocardial SNS activity in a PAH rat model. METHODS: PAH was induced in male Sprague-Dawley rats (N = 36) using the Sugen+chronic hypoxia model. At week 5 post-injection, PAH rats were randomized to carvedilol (15 mg·kg-1·day-1 oral; N = 16) or vehicle (N = 16) for 4 weeks. Myocardial SNS function was assessed with HED positron emission tomography(PET). RESULTS: With increasing PAH disease severity, immunohistochemistry confirmed selective sympathetic denervation within the RV and sparing of parasympathetic nerves. These findings were confirmed on PET with a significant negative relationship between HED volume of distribution(DV) and right ventricular systolic pressure (RVSP) in the RV (r = -0.90, p = 0.0003). Carvedilol did not reduce hemodynamic severity compared to vehicle. RV ejection fraction (EF) was lower in both PAH groups compared to control (p < 0.05), and was not further reduced by carvedilol. Carvedilol improved SNS function in the LV with significant increases in the HED DV, and decreased tracer washout in the LV (p < 0.05) but not RV. CONCLUSIONS: PAH disease severity correlated with a reduction in HED DV in the RV. This was associated with selective sympathetic denervation. Late carvedilol treatment did not lead to recovery of RV function. These results support the role of HED imaging in assessing SNS innervation in a failing right ventricle.
Entities:
Keywords:
Beta adrenergic blockade; Positron emissions tomography; Pulmonary arterial hypertension; Right heart failure; Sympathetic nervous system
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