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.
A common and heterogeneous form of heart
failure
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.
Exploring the paradox of a “preserved”
ejection fraction
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.
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.
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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
