Diastolic Heart Failure: What Is It?

Congestive Heart Failure: 5 Warning Signs One's Heart Is Failing Without Even Knowing It

A persistent cough that produces white or pink-tinged mucus, may indicate heart failure as its underlying cause. The buildup of fluid in lung tissue known as pulmonary congestion, creates airway irritation which results in this condition. Wheezing together with a rattling sound during breathing, occurs frequently in patients. This coughing symptom differs from typical cold-related coughs, because it worsens when you rest, and does not respond to standard treatment methods. A doctor needs to evaluate you when you experience a chronic cough that differs from your previous symptoms.

Internal Fat May Be The Leading Cause Of Heart Failure, Study Finds

A new theory suggests signals from fat tissue, not just the heart, may drive a common type of heart failure. (CREDIT: Shutterstock)

Heart failure with preserved ejection fraction, or HFpEF, has puzzled doctors for years. Nearly four million Americans and more than 30 million people worldwide live with this condition, yet treatment options remain limited.

Unlike traditional heart failure, where the heart muscle weakens and struggles to pump, HFpEF looks normal on scans. The heart still pushes blood forward, but it cannot relax and fill properly between beats. That stiffness makes you feel short of breath, drained of energy, and sometimes swollen in the legs, belly, or lungs.

For decades, high blood pressure was thought to be the primary culprit. But a new idea challenges that view. According to Milton Packer, MD, Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center and Visiting Professor at Imperial College London, the real driver may not be the heart at all.

His team suggests that signals coming from fat tissue could be behind much of the disease. Their theory, called the Adipokine Hypothesis, was published in JACC and presented at the 2025 European Society of Cardiology Congress.

Central illustration: Lines of evidence supporting the Adipokine Hypothesis of HFpEF. (CREDIT: Packer M, JACC 2025)

Fat as a Messenger, Not Just Storage

Many people picture fat as little more than stored calories. In reality, fat is a living organ that sends out chemical messages across the body. These messengers, called adipokines, are proteins and hormones that can influence your heart, blood vessels, metabolism, and immune system.

When fat is healthy, adipokines protect organs, reduce inflammation, and help control fluid balance. But when fat becomes excessive and unhealthy, the signals change. Harmful adipokines are released in higher amounts while the protective ones decline.

This shift in fat biology, Packer explains, transforms fat into an organ that drives stress, inflammation, and scarring inside the heart. "Up to now, there has been no unifying hypothesis to explain HFpEF. That has resulted in significant misunderstanding and a lack of direction in both diagnosis and therapy," he said. "This bold new framework helps to identify the true cause of HFpEF in most people. That should make an enormous difference in guiding effective treatments."

Related Stories How Fat Signals Disrupt the Heart

The new framework outlines several ways that adipokines from unhealthy fat might set HFpEF in motion. One route is inflammation. When fat tissue becomes stressed, it attracts immune cells that release even more inflammatory chemicals.

These molecules damage blood vessel linings and heart muscle cells. Another pathway is vascular stiffness. Arteries lose flexibility, making it harder for blood to move and raising pressure inside the heart. Over time, scarring—or fibrosis—sets in. That scar-like tissue prevents the heart from relaxing and filling properly. Add in metabolic stress from conditions like diabetes or high blood pressure, and the cycle accelerates.

The result is a heart that seems to pump normally but fails to deliver enough blood to meet the body's needs during exertion. Climbing a flight of stairs may suddenly feel exhausting, not because the heart cannot squeeze, but because it cannot fill.

The Adipokine Hypothesis: Secretion of Adipokines From Biologically Transformed Visceral Adipose Tissue Leads to HFpEF. (CREDIT: JACC)

Strong Evidence Builds the Case

The Adipokine Hypothesis pulls together findings from many different fields. Patients with HFpEF almost always show extra fat stored deep inside the body, often wrapping around organs like the heart. Laboratory experiments in animals and cells demonstrate that adipokines can directly impair relaxation of heart muscle.

Blood vessel studies confirm that harmful adipokines limit dilation, which forces blood pressure up. And clinical data reveal that HFpEF commonly strikes those with metabolic syndrome—a cluster of obesity, high blood sugar, and high blood pressure—pointing again to fat's central role.

What makes this idea powerful is that it unites these scattered observations under one roof. Instead of viewing obesity, diabetes, and hypertension as separate risks, it links them through the signals fat tissue sends.

Shifting the Way Doctors Think

If Packer is correct, HFpEF is not only a heart problem but a systemic disease. The heart shows the symptoms, but the roots spread across the body, starting with fat. This perspective changes how doctors might diagnose and treat patients. Rather than focusing only on cardiac function, physicians could measure inflammation markers, study fat distribution, and check waist-to-height ratios.

Mediators of Adipocyte Dysfunction to the Heart. Adipose tissue can secrete a broad array of molecules and cellular constituents that can act in an endocrine or paracrine manner to exert favorable or deleterious effects on the heart. (CREDIT: JACC)

Packer stresses that body mass index, or BMI, is a poor guide because it is influenced by muscle and bone. Instead, the waist-to-height ratio is more telling. A healthy ratio is less than 0.5, meaning your waist is less than half your height.

Most HFpEF patients have a ratio above 0.5, and often above 0.6, even if they do not meet obesity criteria by BMI. "In patients with an elevated waist-to-height ratio, clinicians should be very vigilant to ask about potential symptoms of HFpEF," he noted. Shortness of breath, often blamed on weight alone, may signal a treatable heart problem.

Treatments May Already Be Here

One striking implication of the hypothesis is that drugs may help by changing fat biology rather than directly targeting the heart. Several medications already approved for other uses appear to reshape adipokine profiles. GLP-1 receptor agonists such as semaglutide and tirzepatide, originally designed for diabetes and weight loss, have shown encouraging effects.

By shrinking unhealthy fat and restoring healthier signaling, these drugs may reduce inflammation and scarring that drive HFpEF. Experimental studies support the idea, and more clinical trials are underway.

Lifestyle measures that reduce harmful fat—like diet, exercise, or surgery—could also prove essential. If confirmed, this approach would offer a range of new strategies for the millions struggling with the disease.

Characterization of Adipokine Domains. In healthy people, adipocytes primarily secrete Domain I adipokines, with minimal secretion of Domain II adipokines and with suppression of Domain III adipokines. In people with visceral adiposity or obesity, adipose tissue secretes primarily Domain III adipokines, with suppression of Domain I adipokines. (CREDIT: JACC)

Looking Ahead

The Adipokine Hypothesis is still a theory, not a proven fact. Much of the current evidence comes from models and associations. Scientists need more large-scale clinical studies to pinpoint which adipokines matter most, how they interact with other risk factors, and whether altering them truly improves outcomes. Still, experts see promise. Packer himself notes that 33 years ago he proposed the neurohormonal hypothesis for another type of heart failure, and that theory transformed treatment. The hope is that this new one could spark a similar revolution for HFpEF.

If confirmed, the Adipokine Hypothesis could shift both prevention and treatment of heart failure. Doctors may screen patients using waist-to-height ratios, giving earlier warning of risk. Patients with high ratios could receive therapies aimed at reducing harmful fat signals.

Already approved drugs like semaglutide may gain new roles in managing HFpEF. For patients, this means that shortness of breath and fatigue often brushed aside as "just weight issues" might be recognized as treatable heart symptoms.

At a public health level, the findings highlight the urgent need to address rising obesity rates, since HFpEF cases are expected to rise sharply in coming decades. By tackling fat as an active organ, science may open new doors for prevention and care.

Note: The article above provided above by The Brighter Side of News.

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GLP-1s Reduced Adverse Heart Failure Events By 40% In Patients With HFpEF

A new study evaluated real-world data on the efficacy of GLP-1s in patients with obesity and heart failure with preserved ejection fraction (HFpEF), confirming findings from prior research.

Patients with heart failure with preserved ejection fraction (HFpEF) who initiated semaglutide or tirzepatide saw a 40% risk reduction in combined hospitalization for HF or all-cause mortality, a new study published in JAMA reported.1

HFpEF is increasingly prevalent among individuals with obesity, and recent clinical trials like the Emulation of the STEP-HFpEF DM Heart Failure Trial in Healthcare Claims Data (STEP-HFpEF; NCT06914102) and the Emulation of the SUMMIT Heart Failure Trial in Healthcare Claims Data (DUP-SUMMIT; NCT06914154) provide evidence supporting the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in improving some of the functional capacity and symptoms among patients with obesity. However, these randomized trials were limited in study population size, thus encouraging researchers to collect and evaluate real-world evidence to complement previous findings on the effectiveness and safety of GLP-1 RAs in patients with HFpEF.1,2

GLP-1 usages reduced adverse heart failure by 40% in patients with heart failure with preserved ejection fraction and obesity.Image Credit: @muhamed-adobestock.Com

The new study published in JAMA used 3 US claims data sources, all of which contained longitudinal patient-level information, including demographics, diagnoses, procedures, and outpatient prescription medications.1 The eligibility criteria required patients to have at least 12 months of continuous enrollment in addition to other criteria emulating the STEP-HFpEF and SUMMIT clinical trials and created 5 active-comparator, new-user cohort studies. The cohorts were semaglutide vs sitagliptin, tirzepatide vs sitagliptin, tirzepatide vs semaglutide, and 2 additional cohorts based on data and eligibility expansion to reflect routine clinical populations. Sitagliptin served as a placebo proxy in the study, and its effect was similar to that seen in previous research, in which it had no effect on HF events.

"Because regulatory agencies and guideline committees have emphasized the need for further evidence for major clinical outcomes in heart failure, these findings were first benchmarked against results from the STEP-HFpEF DM and SUMMIT trials," the study authors explained.

The study population consisted of 1,670,792 individuals who had initiated semaglutide, tirzepatide, or sitagliptin, of whom only 21,151 met the trial eligibility criteria emulating that of the STEP-HFpEF trial. Moreover, 58,333 were included in the semaglutide vs sitagliptin cohort under the expanded eligibility criteria. For the tirzepatide vs sitagliptin cohort, 3173 patients met the trial criteria emulating that of the SUMMIT trial, and 11,257 were included under expanded eligibility. The semaglutide vs tirzepatide cohort consisted of 28,000 patients. The mean age across all of the cohorts ranged from 66.7 to 70.8 years; 53.3% to 54.7% were female; the mean body mass index ranged from 36.6 to 40.2 among patients with available data, and a history of HF hospitalization in the past 12 months was present in 4.1% to 5.8% of patients.

GLP-1 RA Efficacy in Patients with HFpEF

Researchers found that initiation of semaglutide or tirzepatide was associated with a significantly lower risk of the composite outcome of hospitalization for heart failure or all-cause mortality compared with sitagliptin. Specifically, patients starting semaglutide had a 42% reduction (HR, 0.58; 95% CI, 0.51-0.65), and those starting tirzepatide had a 58% reduction (HR, 0.42; 95% CI, 0.31-0.57) in the primary composite end point. In a direct head-to-head comparison, tirzepatide showed no meaningful benefit over semaglutide (HR, 0.86; 95% CI, 0.70-1.06), indicating similar effectiveness between these drugs. Both treatments also reduced broader secondary endpoints, including urgent visits and additional HF-related events, with no significant safety concerns identified.

"These observations suggest semaglutide may rapidly improve disease trajectory through cardiometabolic mechanisms independent of weight loss, although the underlying pathophysiology requires further investigation," the study authors wrote. "While tirzepatide has demonstrated greater benefits than semaglutide in other indications, in this study, only modest differences were observed for hospitalization for heart failure and mortality, which supports the use of either agent as an effective option."

The study was limited by its nonrandomized design, leaving potential for unmeasured confounding despite propensity score adjustment. Medication use was inferred from dispensing records rather than adherence data, and HF symptoms and EF were assessed using claims-based algorithms rather than standardized clinical measures. Finally, the use of sitagliptin as a placebo proxy relies on prior evidence but still represents an assumption that could influence the interpretation of results.

"This stepwise approach anchored in trial evidence strengthens confidence in the validity and applicability of the current results, reinforcing the role of GLP-1–based therapies beyond previously established benefits in the evolving management of cardiometabolic HFpEF," the study authors concluded.

References

1. Krüger N, Schneeweiss S, Fuse K, et al. Semaglutide and tirzepatide in patients with heart failure with preserved ejection fraction. JAMA. Published online August 31, 2025. Doi:10.1001/jama.2025.14092

2. Patel R, Kokori E, Olatunji G, et al. Therapeutic potential of GLP-1 receptor agonists in heart failure with preserved ejection fraction (HFpEF) in obese patients. Curr Heart Fail Rep. 2025;22(1):17. Doi:10.1007/s11897-025-00704-1

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