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Differential Regulation of Muscarinic Cholinergic Receptors in Human Heart Failure and Reverse Remodelling
S8 Journal of Cardiac Failure Vol. 19 No. 8S August 2013 Conclusions: In HFPEF patients with treated hypertension, the DASH/SRD was associated with favorable changes in diastolic function, global contractility, and V-A coupling.
018 Right Ventricular Sarcomeric Myofilament Dysfunction Is Present in Patients with Biventricular Heart Failure of Idiopathic but Not Ischemic Etiology Amrut V. Ambardekar, Rebecca L. Shtofman, Peter M. Buttrick; University of Colorado, Aurora, CO Introduction: Right ventricular (RV) dysfunction is associated with worse outcomes in patients with heart failure (HF). However, the underlying pathology of RV dysfunction is poorly understood, and targeted treatments to improve RV function are not available. Sarcomeric myofilament dysfunction is present in left ventricular myocytes isolated from patients with end-stage idiopathic cardiomyopathy (CM), but less is known about RV myofilament function. We postulated that RV myocyte sarcomeric contractility would be diminished in patients with biventricular end-stage HF. Methods: RV free wall tissue samples were collected and flash frozen from 8 patients with biventricular HF at the time of cardiac transplantation. Four patients had ischemic CM, and 4 patients had ischemic CM. RV free wall tissue from 4 non-failing donor hearts harvested but not used for cardiac transplantation was used for comparison. Myocytes were isolated from the frozen RV samples by mechanical homogenization and chemical permeabilization in order to remove the cell membrane and calcium handling apparatus and allow for direct assessment of myofilament interactions. The isolated skinned myocytes were attached to an ultrasensitive force transducer and motor on the stage of an inverted microscope, and myocyte dimensions were recorded. The maximal calcium saturated force (Fmax) and passive tension (Fpass) were recorded as the myocyte was exposed to solutions containing ATP and varying concentrations of calcium. Results: Force recordings and myocyte dimensions were measured from 22 nonfailing, 13 idiopathic CM, and 16 ischemic CM myocytes (Table). Compared to myocytes from nonfailing donors, myocytes from patients with idiopathic CM had a lower mean Fmax and Fpass, but had a larger cross-sectional area and volume. There were no differences between force measurements or size for myocytes from nonfailing donors versus from patients with ischemic CM. Fmax, Fpass, and cross-sectional area were all significantly different in myocytes from patients with idiopathic versus ischemic CM. Conclusions: RV sarcomeric myofilament dysfunction and myocyte hypertrophy is present in idiopathic but not ischemic CM. This suggests that the underlying pathology of RV dysfunction is different depending on the etiology of heart failure. Treatments that address sarcomeric myofilament biology are needed to address RV dysfunction in patients with idiopathic CM. Table.
Fmax (mN/mm2) Fpass (mN/mm2) Cross-Sectional Area (mm2) Volume (mm3)
Nonfailing
Idiopathic CM
Ischemic CMz
20.363.4 5.861.3 491680
13.261.1* 2.560.3* 680674*
20.262.8 5.461.5 486661
63636613610
100690613549y
76063610036
*P value!0.05 for T tests between Nonfailing vs Idiopathic CM and Idiopathic vs Ischemic CM. y P value!0.05 for T test between Nonfailing vs Idiopathic CM, P50.08 for T test between Idiopathic vs Ischemic CM. z P values not significant for comparisons between Nonfailing vs Ischemic CM.
019
significantly elevated in membrane preparations from F as compared to NF. With two different thereapeutic approaches, muscarinic receptors were regulated in opposite directions. Support of the failing heart prior to transplant with a left ventricular assist device (LVAD) resulted in further increases in total receptors, above the level measured in F. In contrast, patients who had been trained with a self-regulation method known as biofeedback (BF), designed to optimize autonomic balance by teaching the patient to control activation of the sympathetic and parasympathetic branches through breathing and relaxation, showed a reduction in total muscarinic receptor density, to the levels measured in NF. Although further data are needed to substantiate our model, we hypothesize that the initial up-regulation of muscarinic receptors in failing human hearts represents a counter-regulatory mechanism designed to compensate for the down-regulation of beta adrenergic receptors. It is unclear whether the further up-regulation in patients supported by LVAD and/or the recovery in patients trained with BF represent beneficial adaptations or limitations to recovery.
020 Carvedilol Versus Metoprolol Succinate Do Not Differ in Determining Improvement in Myocardial Performance, Reverse Remodeling, and LongTerm Outcomes in Chronic Systolic Heart Failure Kevin Shrestha1, Richard W. Troughton2, Allen G. Borowski1, Randall C. Starling1, Allan L. Klein1, W.H. Wilson Tang1; 1Cleveland Clinic, Cleveland, OH; 2 Christchurch Heart Institute, Christchurch, New Zealand Introduction: Carvedilol and metoprolol succinate are commonly used beta-blockers in the management of heart failure (HF) patients. Hypothesis: In beta-blocker na€ıve chronic systolic HF patients, we hypothesized that carvedilol versus metoprolol succinate would not differ significantly in determining improvement in myocardial structure, performance, or long-term clinical outcomes. Methods: In 78 beta-blocker na€ıve chronic systolic HF patients (LVEF!40%, NYHA I-IV), we initiated carvedilol versus metoprolol succinate therapy and performed comprehensive echocardiographic assessment of cardiac structure and performance at baseline and 6 months. Adverse long-term events (death, transplant, HF hospitalization) were tracked for 5 years. Results: In our study cohort (age 58614 years; LVEF 2666%, median NT-
Differential Regulation of Muscarinic Cholinergic Receptors in Human Heart Failure and Reverse Remodelling Christine S. Moravec1, Wendy E. Sweet1, Jessica A. French1, Dana L. Schneeberger1, Michael G. McKee2, W.H. Wilson Tang3, Randall C. Starling1; 1Cleveland Clinic, Cleveland, OH; 2Cleveland Clinic, Cleveland, OH; 3Cleveland Clinic, Cleveland, OH
Autonomic dysregulation is a key feature of human heart failure. For many years, research and therapeutic strategies have focused on the overactive sympathetic branch, while insufficient attention has been given to the parasympathetic arm. More recently, with the demonstration that stimulation of parasympathetic activity can have potent anti-inflammatory effects, along with the advent of vagal nerve stimulation as new therapy for end-stage heart failure, attention has focused on parasympathetic innervation of the heart and its alterations in cardiovascular disease. While it has been established beyond a reasonable doubt that the beta-adrenergic receptor system, responsible for sympathetic stimulation of cardiac myocytes and the conduction system, is altered in heart failure, the cholinergic effectors are less well understood. At the level of cardiac muscle, muscarinic cholinergic receptors are responsible for signal transduction. We tested the hypothesis that muscarinic cholinergic receptors are regulated in human heart failure, and asked whether two different therapeutic approaches alter receptor density. Total muscarinic receptors were measured in a population of failing human hearts (F), as compared to a population of non-failing human hearts (NF), by radioligand binding and Scatchard analysis. Data revealed that muscarinic receptors are
D Heart rate (bpm) D Mean arterial pressure (mmHg) D LV end-systolic volume index (mL/m2) D LV end-diastolic volume index (mL/m2) D LV ejection fraction (%) D Pulmonary vein S/D ratio D Miltral E/septale’ ratio D LA volume index (mL/m2) D RV s’ (cm/s) D Tricuspid E/e’ ratio D Hepatic vein S/D ratio D RA volume index (mL/m2)
Carvedilol (n547)
Metoprolol (n531)
p-value
-19610 -1.266.7 -19643
-16617 -1.0610.4 -18630
0.79 0.73 0.75
-19648
-19638
0.87
4611 0.260.6 -4611 4619 0.162.9 2.062.3 -0.360.9 -4615
268 0.060.6 -2615 -7617 0.263.9 -2.264.0 0.260.3 -3612
0.68 0.25 0.12 0.05 0.80 0.01 0.50 0.79
Abbreviations: LV, left ventricular; LA, left atrial; RV, right ventricular; RA, right atrial.
018 Right Ventricular Sarcomeric Myofilament Dysfunction Is Present in Patients with Biventricular Heart Failure of Idiopathic but Not Ischemic Etiology Amrut V. Ambardekar, Rebecca L. Shtofman, Peter M. Buttrick; University of Colorado, Aurora, CO Introduction: Right ventricular (RV) dysfunction is associated with worse outcomes in patients with heart failure (HF). However, the underlying pathology of RV dysfunction is poorly understood, and targeted treatments to improve RV function are not available. Sarcomeric myofilament dysfunction is present in left ventricular myocytes isolated from patients with end-stage idiopathic cardiomyopathy (CM), but less is known about RV myofilament function. We postulated that RV myocyte sarcomeric contractility would be diminished in patients with biventricular end-stage HF. Methods: RV free wall tissue samples were collected and flash frozen from 8 patients with biventricular HF at the time of cardiac transplantation. Four patients had ischemic CM, and 4 patients had ischemic CM. RV free wall tissue from 4 non-failing donor hearts harvested but not used for cardiac transplantation was used for comparison. Myocytes were isolated from the frozen RV samples by mechanical homogenization and chemical permeabilization in order to remove the cell membrane and calcium handling apparatus and allow for direct assessment of myofilament interactions. The isolated skinned myocytes were attached to an ultrasensitive force transducer and motor on the stage of an inverted microscope, and myocyte dimensions were recorded. The maximal calcium saturated force (Fmax) and passive tension (Fpass) were recorded as the myocyte was exposed to solutions containing ATP and varying concentrations of calcium. Results: Force recordings and myocyte dimensions were measured from 22 nonfailing, 13 idiopathic CM, and 16 ischemic CM myocytes (Table). Compared to myocytes from nonfailing donors, myocytes from patients with idiopathic CM had a lower mean Fmax and Fpass, but had a larger cross-sectional area and volume. There were no differences between force measurements or size for myocytes from nonfailing donors versus from patients with ischemic CM. Fmax, Fpass, and cross-sectional area were all significantly different in myocytes from patients with idiopathic versus ischemic CM. Conclusions: RV sarcomeric myofilament dysfunction and myocyte hypertrophy is present in idiopathic but not ischemic CM. This suggests that the underlying pathology of RV dysfunction is different depending on the etiology of heart failure. Treatments that address sarcomeric myofilament biology are needed to address RV dysfunction in patients with idiopathic CM. Table.
Fmax (mN/mm2) Fpass (mN/mm2) Cross-Sectional Area (mm2) Volume (mm3)
Nonfailing
Idiopathic CM
Ischemic CMz
20.363.4 5.861.3 491680
13.261.1* 2.560.3* 680674*
20.262.8 5.461.5 486661
63636613610
100690613549y
76063610036
*P value!0.05 for T tests between Nonfailing vs Idiopathic CM and Idiopathic vs Ischemic CM. y P value!0.05 for T test between Nonfailing vs Idiopathic CM, P50.08 for T test between Idiopathic vs Ischemic CM. z P values not significant for comparisons between Nonfailing vs Ischemic CM.
019
significantly elevated in membrane preparations from F as compared to NF. With two different thereapeutic approaches, muscarinic receptors were regulated in opposite directions. Support of the failing heart prior to transplant with a left ventricular assist device (LVAD) resulted in further increases in total receptors, above the level measured in F. In contrast, patients who had been trained with a self-regulation method known as biofeedback (BF), designed to optimize autonomic balance by teaching the patient to control activation of the sympathetic and parasympathetic branches through breathing and relaxation, showed a reduction in total muscarinic receptor density, to the levels measured in NF. Although further data are needed to substantiate our model, we hypothesize that the initial up-regulation of muscarinic receptors in failing human hearts represents a counter-regulatory mechanism designed to compensate for the down-regulation of beta adrenergic receptors. It is unclear whether the further up-regulation in patients supported by LVAD and/or the recovery in patients trained with BF represent beneficial adaptations or limitations to recovery.
020 Carvedilol Versus Metoprolol Succinate Do Not Differ in Determining Improvement in Myocardial Performance, Reverse Remodeling, and LongTerm Outcomes in Chronic Systolic Heart Failure Kevin Shrestha1, Richard W. Troughton2, Allen G. Borowski1, Randall C. Starling1, Allan L. Klein1, W.H. Wilson Tang1; 1Cleveland Clinic, Cleveland, OH; 2 Christchurch Heart Institute, Christchurch, New Zealand Introduction: Carvedilol and metoprolol succinate are commonly used beta-blockers in the management of heart failure (HF) patients. Hypothesis: In beta-blocker na€ıve chronic systolic HF patients, we hypothesized that carvedilol versus metoprolol succinate would not differ significantly in determining improvement in myocardial structure, performance, or long-term clinical outcomes. Methods: In 78 beta-blocker na€ıve chronic systolic HF patients (LVEF!40%, NYHA I-IV), we initiated carvedilol versus metoprolol succinate therapy and performed comprehensive echocardiographic assessment of cardiac structure and performance at baseline and 6 months. Adverse long-term events (death, transplant, HF hospitalization) were tracked for 5 years. Results: In our study cohort (age 58614 years; LVEF 2666%, median NT-
Differential Regulation of Muscarinic Cholinergic Receptors in Human Heart Failure and Reverse Remodelling Christine S. Moravec1, Wendy E. Sweet1, Jessica A. French1, Dana L. Schneeberger1, Michael G. McKee2, W.H. Wilson Tang3, Randall C. Starling1; 1Cleveland Clinic, Cleveland, OH; 2Cleveland Clinic, Cleveland, OH; 3Cleveland Clinic, Cleveland, OH
Autonomic dysregulation is a key feature of human heart failure. For many years, research and therapeutic strategies have focused on the overactive sympathetic branch, while insufficient attention has been given to the parasympathetic arm. More recently, with the demonstration that stimulation of parasympathetic activity can have potent anti-inflammatory effects, along with the advent of vagal nerve stimulation as new therapy for end-stage heart failure, attention has focused on parasympathetic innervation of the heart and its alterations in cardiovascular disease. While it has been established beyond a reasonable doubt that the beta-adrenergic receptor system, responsible for sympathetic stimulation of cardiac myocytes and the conduction system, is altered in heart failure, the cholinergic effectors are less well understood. At the level of cardiac muscle, muscarinic cholinergic receptors are responsible for signal transduction. We tested the hypothesis that muscarinic cholinergic receptors are regulated in human heart failure, and asked whether two different therapeutic approaches alter receptor density. Total muscarinic receptors were measured in a population of failing human hearts (F), as compared to a population of non-failing human hearts (NF), by radioligand binding and Scatchard analysis. Data revealed that muscarinic receptors are
D Heart rate (bpm) D Mean arterial pressure (mmHg) D LV end-systolic volume index (mL/m2) D LV end-diastolic volume index (mL/m2) D LV ejection fraction (%) D Pulmonary vein S/D ratio D Miltral E/septale’ ratio D LA volume index (mL/m2) D RV s’ (cm/s) D Tricuspid E/e’ ratio D Hepatic vein S/D ratio D RA volume index (mL/m2)
Carvedilol (n547)
Metoprolol (n531)
p-value
-19610 -1.266.7 -19643
-16617 -1.0610.4 -18630
0.79 0.73 0.75
-19648
-19638
0.87
4611 0.260.6 -4611 4619 0.162.9 2.062.3 -0.360.9 -4615
268 0.060.6 -2615 -7617 0.263.9 -2.264.0 0.260.3 -3612
0.68 0.25 0.12 0.05 0.80 0.01 0.50 0.79
Abbreviations: LV, left ventricular; LA, left atrial; RV, right ventricular; RA, right atrial.