2026-04-30
Obesity and heart failure: weight loss may restore heart muscle contractility
Others
By Elodie Vaz | Published on April 30,
2026 | 4 min read
Long described as a disease of ventricular stiffness, heart failure with preserved ejection fraction (HFpEF) may, in patients with severe obesity, involve a distinct mechanism: an intrinsic impairment of heart muscle contraction. This is the finding of a study conducted by researchers at Johns Hopkins Medicine and published on April 23 in *Science*. The work shows that cardiac muscle cells in these patients develop marked contractile weakness, which is partially reversible after significant weight loss.
In the United States, about 6.6 million people
suffer from heart failure, and nearly half have HFpEF, according to the
American College of Cardiology. This form of heart failure is associated with a
one-year mortality rate of 20–29%.
In HFpEF, the heart’s main pumping chamber maintains a normal ejection fraction (around 65%) but becomes stiffer and relaxes more slowly, impairing its ability to fill properly. Historically, this condition mainly affected older patients with chronic hypertension, thickened and fibrotic heart walls, diabetes, or kidney disease.
However, more recent research shows that it also frequently affects obese patients, particularly those with severe obesity (BMI > 40 kg/m²), in whom the prognosis is poorer.
“This represents a major advance in understanding a common but puzzling form of heart failure that disproportionately affects people with severe obesity,” said Dr. David Kass, professor of cardiology at Johns Hopkins University School of Medicine and lead investigator of the study.
Ejection fraction measures the percentage of
blood pumped out with each heartbeat. While this indicator appears normal in
HFpEF, it does not necessarily reflect the function of cardiac muscle cells
(myocytes).
“This may underlie the fundamental paradox explaining how patients with heart failure can have different ejection fractions and responses to drugs while exhibiting similar symptoms,” explained Vivek Jani, first author of the study and MD-PhD candidate at Johns Hopkins.
The researchers therefore aimed to directly characterize the mechanical and molecular properties of cardiac muscle cells in this population.
They analyzed small samples of heart muscle taken from 80 patients with HFpEF, under the supervision of Kavita Sharma, director of the Johns Hopkins HFpEF Center. These samples were compared with heart tissue from organ donors without heart failure and from patients with advanced heart failure who had undergone transplantation.
A computational algorithm classified patients into two subgroups based on cellular properties and body mass index: one group with an average BMI of 43 kg/m² and another with an average BMI of 30 kg/m².
The researchers then measured the contractile response of myocytes to calcium and stretch—two key mechanisms of contraction. They also used X-ray analysis to study the crystalline structure of motor proteins, along with biochemical analysis of sarcomere proteins.
Cells from the more obese group showed a marked reduction in active force and slower relaxation. In contrast, resting stiffness—often considered a hallmark of HFpEF—was more prominent in the less obese group.
“Myocytes from people with HFpEF and severe obesity closely resembled those from patients with reduced ejection fraction heart failure undergoing heart transplantation,” explained Prof. Kass.
Structural analyses revealed abnormalities in motor proteins in the most obese group. These abnormalities were not observed in individuals with severe obesity but without heart failure.
The researchers also identified a molecular mechanism: increased phosphorylation of troponin I, a protein essential for muscle contraction and relaxation. This chemical modification alone appeared sufficient to weaken contraction.
In a subgroup of 16 patients with an initial average BMI of 39 kg/m², weight-loss treatment (mainly based on GLP-1 receptor agonists) was followed for a median duration of 1.5 years.
In patients who lost the most weight, cardiac muscle cells regained better contractile capacity. Those who lost at least 10% of their body weight showed near-normal maximal muscle force.
“HFpEF has long been viewed as a stiffness problem,” noted Prof. Kass. “Our study reveals a different picture in patients with severe obesity: the muscle itself may be weaker due to a specific chemical modification of a contractile protein, opening the door to targeted therapies.”
Toward new therapeutic approaches
In light of these findings, the authors urge caution in the use of certain treatments such as mavacamten or aficamten—used in hypertrophic cardiomyopathy—as they could worsen contractile weakness in these patients.
“This work opens the door to potential therapies,” concluded Vivek Jani. “These include promoting safe and sustained weight loss in patients and developing drugs capable of reversing the molecular modification we identified in sarcomere proteins.”
This study helps redefine obesity-related HFpEF as a distinct biological subtype, in which restoring myocardial contractility could become a central therapeutic goal.
Read next: Loneliness: an emerging factor in degenerative valvular heart disease
About the Author – Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on human life. A registered nurse since 2010, she spent twelve years at patients’ bedsides before exchanging her stethoscope for a notebook. She now investigates the links between environment and health, convinced that the vitality of life cannot be reduced to that of humans
Long described as a disease of ventricular stiffness, heart failure with preserved ejection fraction (HFpEF) may, in patients with severe obesity, involve a distinct mechanism: an intrinsic impairment of heart muscle contraction. This is the finding of a study conducted by researchers at Johns Hopkins Medicine and published on April 23 in *Science*. The work shows that cardiac muscle cells in these patients develop marked contractile weakness, which is partially reversible after significant weight loss.
A common and heterogeneous form of heart failure
In HFpEF, the heart’s main pumping chamber maintains a normal ejection fraction (around 65%) but becomes stiffer and relaxes more slowly, impairing its ability to fill properly. Historically, this condition mainly affected older patients with chronic hypertension, thickened and fibrotic heart walls, diabetes, or kidney disease.
However, more recent research shows that it also frequently affects obese patients, particularly those with severe obesity (BMI > 40 kg/m²), in whom the prognosis is poorer.
“This represents a major advance in understanding a common but puzzling form of heart failure that disproportionately affects people with severe obesity,” said Dr. David Kass, professor of cardiology at Johns Hopkins University School of Medicine and lead investigator of the study.
Exploring the paradox of a “preserved” ejection fraction
“This may underlie the fundamental paradox explaining how patients with heart failure can have different ejection fractions and responses to drugs while exhibiting similar symptoms,” explained Vivek Jani, first author of the study and MD-PhD candidate at Johns Hopkins.
The researchers therefore aimed to directly characterize the mechanical and molecular properties of cardiac muscle cells in this population.
They analyzed small samples of heart muscle taken from 80 patients with HFpEF, under the supervision of Kavita Sharma, director of the Johns Hopkins HFpEF Center. These samples were compared with heart tissue from organ donors without heart failure and from patients with advanced heart failure who had undergone transplantation.
A computational algorithm classified patients into two subgroups based on cellular properties and body mass index: one group with an average BMI of 43 kg/m² and another with an average BMI of 30 kg/m².
The researchers then measured the contractile response of myocytes to calcium and stretch—two key mechanisms of contraction. They also used X-ray analysis to study the crystalline structure of motor proteins, along with biochemical analysis of sarcomere proteins.
Contractile weakness specific to HFpEF associated with severe obesity
Cells from the more obese group showed a marked reduction in active force and slower relaxation. In contrast, resting stiffness—often considered a hallmark of HFpEF—was more prominent in the less obese group.
“Myocytes from people with HFpEF and severe obesity closely resembled those from patients with reduced ejection fraction heart failure undergoing heart transplantation,” explained Prof. Kass.
Structural analyses revealed abnormalities in motor proteins in the most obese group. These abnormalities were not observed in individuals with severe obesity but without heart failure.
The researchers also identified a molecular mechanism: increased phosphorylation of troponin I, a protein essential for muscle contraction and relaxation. This chemical modification alone appeared sufficient to weaken contraction.
Improvement after weight loss
In a subgroup of 16 patients with an initial average BMI of 39 kg/m², weight-loss treatment (mainly based on GLP-1 receptor agonists) was followed for a median duration of 1.5 years.
In patients who lost the most weight, cardiac muscle cells regained better contractile capacity. Those who lost at least 10% of their body weight showed near-normal maximal muscle force.
“HFpEF has long been viewed as a stiffness problem,” noted Prof. Kass. “Our study reveals a different picture in patients with severe obesity: the muscle itself may be weaker due to a specific chemical modification of a contractile protein, opening the door to targeted therapies.”
Toward new therapeutic approaches
In light of these findings, the authors urge caution in the use of certain treatments such as mavacamten or aficamten—used in hypertrophic cardiomyopathy—as they could worsen contractile weakness in these patients.
“This work opens the door to potential therapies,” concluded Vivek Jani. “These include promoting safe and sustained weight loss in patients and developing drugs capable of reversing the molecular modification we identified in sarcomere proteins.”
This study helps redefine obesity-related HFpEF as a distinct biological subtype, in which restoring myocardial contractility could become a central therapeutic goal.
Read next: Loneliness: an emerging factor in degenerative valvular heart disease
About the Author – Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on human life. A registered nurse since 2010, she spent twelve years at patients’ bedsides before exchanging her stethoscope for a notebook. She now investigates the links between environment and health, convinced that the vitality of life cannot be reduced to that of humans
Source(s) :
L’obésité sévère chez l’HFpEF humaine modifie la fonction et l’organisation des protéines contractiles ;
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