Severe obesity in human HFpEF alters contractile protein function and organization.
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| Title: | Severe obesity in human HFpEF alters contractile protein function and organization. |
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| Authors: | Jani, Vivek P. (AUTHOR), Rhodehamel, Marcus (AUTHOR), Fenwick, Axel J. (AUTHOR), Ma, Weikang (AUTHOR), Fisher, Eli (AUTHOR), Giannakopoulos, Maria T. (AUTHOR), Moon, Sun (AUTHOR), Castillo, Romi L. (AUTHOR), Kennedy, Leslie M. (AUTHOR), Irving, Thomas C. (AUTHOR), Tardiff, Jil C. (AUTHOR), Murphy, Elizabeth (AUTHOR), Chaerkady, Raghothama (AUTHOR), Wang, Qing (AUTHOR), Barry, Meaghan E. (AUTHOR), Hahn, Virginia S. (AUTHOR), Sharma, Kavita (AUTHOR), Margulies, Kenneth B. (AUTHOR), Bedi Jr, Kenneth C. (AUTHOR), Cammarato, Anthony (AUTHOR) |
| Source: | Science. 6/4/2026, Vol. 392 Issue 6802, p1-17. 17p. |
| Subjects: | Heart failure, Contractile proteins, Myosin, Antiobesity agents, Cardiovascular system physiology, Phosphorylation, Heart cells, Obesity |
| Abstract: | Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality and has few effective therapies. Its phenotype has changed over time, with morbid obesity and metabolic defects supplanting hypertension and cardiac hypertrophy. We reveal that cardiomyocytes from patients with severe obesity and HFpEF have very depressed contractile reserve, including reduced calcium- and length-stimulated tension, power, and myosin activation compared with less-obese HFpEF and nonfailing (NF) controls with or without obesity but similar to those with advanced HF and reduced ejection fraction. Myocyte defects correlate with body mass index and exercise hemodynamics in patients with HFpEF but not NF and appear reversible upon weight loss. Increased troponin I phosphorylation at threonine 181 occurs only in heart failure with obesity, contributing to sarcomere dysfunction. Weight reduction and sarcomere enhancers may offer benefits in HFpEF with obesity. Editor's summary: Heart failure is classified into two main subtypes, with either reduced or preserved ejection fraction, depending on the heart's efficiency at pumping out blood. These subtypes are associated with different comorbidities, and heart failure with preserved ejection fraction (HFpEF) is particularly difficult to treat. Obesity generally increases the risk of heart failure, especially HFpEF, but not all patients with obesity and HFpEF are alike. Jani et al. discovered that HFpEF itself can cluster into two biological subgroups. Cardiomyocytes from the group with particularly severe obesity showed a characteristic pattern of functional impairment. However, weight loss improved both clinical parameters and cardiomyocyte function in these patients, suggesting a promising therapeutic approach for HFpEF in the setting of severe obesity. —Yevgeniya Nusinovich INTRODUCTION: More than half of heart failure patients have normal-appearing contraction as reflected by the percent of blood ejected with each heartbeat, the ejection fraction (EF). This syndrome, known as heart failure with preserved ejection fraction (HFpEF), confers substantial morbidity and mortality and has few effective treatments. It historically affected elderly individuals with hypertension and thickened hearts, but most HFpEF patients now have obesity, often severe, that is associated with worse clinical outcomes. Underlying cellular abnormalities in human HFpEF heart muscle and any potential impacts of coexisting severe obesity remain largely unknown. In addition, there are no data from human heart muscle of individuals without heart failure but with similarly severe obesity to determine whether and how this itself affects myocyte function. RATIONALE: We hypothesized that function and structure of the contractile apparatus (sarcomeres) in single cardiomyocytes from patients with HFpEF are adversely affected by the coexistence of severe obesity. We further proposed that such changes correlate with body mass index (BMI) and clinical exercise parameters, may be ameliorated after weight loss, and in part relate to sarcomere protein modifications. This study examined demembranated myocytes and myofibrils from small cardiac biopsies of patients with HFpEF and nonfailing (NF) controls with a broad BMI range. RESULTS: We measured ~30 different rest and reserve functional and structural parameters of cardiomyocytes-myofibrils from patients with HFpEF. Unsupervised machine learning identified two subgroups whose primary clinical difference was their BMI (31 kg/m2 in Group 1 (G1), 43 in G2, P < 10−12). Myocytes from more obese G2-HFpEF patients had markedly reduced calcium-stimulated and length-dependent tension and peak power like that in heart failure with reduced EF (such as from patients undergoing heart transplantation). G1-HFpEF data were similar to NF controls. Myosin crossbridge detachment was slowed and myofibrillar relaxation prolonged in both HFpEF groups, whereas resting stiffness was higher in less-obese G1 versus G2 or NF hearts. X-ray diffraction structural analysis revealed myosin deactivation in very obese G2-HFpEF patients. These abnormalities were not present in myocytes obtained from hearts of similarly obese but NF controls. Depressed myocyte contractility correlated with lower exercise work capacity that occurred with higher exercise-induced heart pressures. In patients with HFpEF treated with weight-loss therapy, the extent of BMI reduction correlated with enhanced myocyte contractility, suggesting that these abnormalities may be reversible. Finally, phosphorylation of sarcomere proteins increased in G2-HFpEF, and reducing it with phosphatase 2a (PP2a) improved contractility in this subgroup. Phosphorylation of cardiac troponin I at threonine 181 positively correlated with BMI in heart failure but was unchanged in NF myocardium. Mutating the threonine to mimic its phosphorylation depressed contractility in myocytes, as in G2-HFpEF patients. CONCLUSION: The combination of HFpEF and severe obesity reduces heart muscle cell contractile function and reserve and impairs myofilament structural activation in ways not found with severe obesity alone. These defects indicate that negative modulators of sarcomere function should be used cautiously or avoided in patients with severe obesity and in HFpEF patients, whereas weight loss and/or therapies targeting underlying sarcomere abnormalities may prove more effective. Cardiac myocytes from biopsies of human HFpEF and NF control hearts were subjected to an array of mechanical, structural, and molecular measurements.: Despite all patients having normal-range ejection fraction, active myocyte contractile function, reserve, and structural motor-protein activation were very reduced in severely obese HFpEF (G2), whereas diastolic abnormalities were somewhat greater in less-obese HFpEF patients (G1). Abnormal troponin I phosphorylation likely plays a role. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality and has few effective therapies. Its phenotype has changed over time, with morbid obesity and metabolic defects supplanting hypertension and cardiac hypertrophy. We reveal that cardiomyocytes from patients with severe obesity and HFpEF have very depressed contractile reserve, including reduced calcium- and length-stimulated tension, power, and myosin activation compared with less-obese HFpEF and nonfailing (NF) controls with or without obesity but similar to those with advanced HF and reduced ejection fraction. Myocyte defects correlate with body mass index and exercise hemodynamics in patients with HFpEF but not NF and appear reversible upon weight loss. Increased troponin I phosphorylation at threonine 181 occurs only in heart failure with obesity, contributing to sarcomere dysfunction. Weight reduction and sarcomere enhancers may offer benefits in HFpEF with obesity. Editor's summary: Heart failure is classified into two main subtypes, with either reduced or preserved ejection fraction, depending on the heart's efficiency at pumping out blood. These subtypes are associated with different comorbidities, and heart failure with preserved ejection fraction (HFpEF) is particularly difficult to treat. Obesity generally increases the risk of heart failure, especially HFpEF, but not all patients with obesity and HFpEF are alike. Jani et al. discovered that HFpEF itself can cluster into two biological subgroups. Cardiomyocytes from the group with particularly severe obesity showed a characteristic pattern of functional impairment. However, weight loss improved both clinical parameters and cardiomyocyte function in these patients, suggesting a promising therapeutic approach for HFpEF in the setting of severe obesity. —Yevgeniya Nusinovich INTRODUCTION: More than half of heart failure patients have normal-appearing contraction as reflected by the percent of blood ejected with each heartbeat, the ejection fraction (EF). This syndrome, known as heart failure with preserved ejection fraction (HFpEF), confers substantial morbidity and mortality and has few effective treatments. It historically affected elderly individuals with hypertension and thickened hearts, but most HFpEF patients now have obesity, often severe, that is associated with worse clinical outcomes. Underlying cellular abnormalities in human HFpEF heart muscle and any potential impacts of coexisting severe obesity remain largely unknown. In addition, there are no data from human heart muscle of individuals without heart failure but with similarly severe obesity to determine whether and how this itself affects myocyte function. RATIONALE: We hypothesized that function and structure of the contractile apparatus (sarcomeres) in single cardiomyocytes from patients with HFpEF are adversely affected by the coexistence of severe obesity. We further proposed that such changes correlate with body mass index (BMI) and clinical exercise parameters, may be ameliorated after weight loss, and in part relate to sarcomere protein modifications. This study examined demembranated myocytes and myofibrils from small cardiac biopsies of patients with HFpEF and nonfailing (NF) controls with a broad BMI range. RESULTS: We measured ~30 different rest and reserve functional and structural parameters of cardiomyocytes-myofibrils from patients with HFpEF. Unsupervised machine learning identified two subgroups whose primary clinical difference was their BMI (31 kg/m2 in Group 1 (G1), 43 in G2, P < 10−12). Myocytes from more obese G2-HFpEF patients had markedly reduced calcium-stimulated and length-dependent tension and peak power like that in heart failure with reduced EF (such as from patients undergoing heart transplantation). G1-HFpEF data were similar to NF controls. Myosin crossbridge detachment was slowed and myofibrillar relaxation prolonged in both HFpEF groups, whereas resting stiffness was higher in less-obese G1 versus G2 or NF hearts. X-ray diffraction structural analysis revealed myosin deactivation in very obese G2-HFpEF patients. These abnormalities were not present in myocytes obtained from hearts of similarly obese but NF controls. Depressed myocyte contractility correlated with lower exercise work capacity that occurred with higher exercise-induced heart pressures. In patients with HFpEF treated with weight-loss therapy, the extent of BMI reduction correlated with enhanced myocyte contractility, suggesting that these abnormalities may be reversible. Finally, phosphorylation of sarcomere proteins increased in G2-HFpEF, and reducing it with phosphatase 2a (PP2a) improved contractility in this subgroup. Phosphorylation of cardiac troponin I at threonine 181 positively correlated with BMI in heart failure but was unchanged in NF myocardium. Mutating the threonine to mimic its phosphorylation depressed contractility in myocytes, as in G2-HFpEF patients. CONCLUSION: The combination of HFpEF and severe obesity reduces heart muscle cell contractile function and reserve and impairs myofilament structural activation in ways not found with severe obesity alone. These defects indicate that negative modulators of sarcomere function should be used cautiously or avoided in patients with severe obesity and in HFpEF patients, whereas weight loss and/or therapies targeting underlying sarcomere abnormalities may prove more effective. Cardiac myocytes from biopsies of human HFpEF and NF control hearts were subjected to an array of mechanical, structural, and molecular measurements.: Despite all patients having normal-range ejection fraction, active myocyte contractile function, reserve, and structural motor-protein activation were very reduced in severely obese HFpEF (G2), whereas diastolic abnormalities were somewhat greater in less-obese HFpEF patients (G1). Abnormal troponin I phosphorylation likely plays a role. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adz7118 |
