The study drew on the National Health and Nutrition Examination Survey, or NHANES, covering survey cycles from 2007 to 2018, with mortality outcomes linked to the National Death Index through December 31, 2019. After applying survey weights, the analytic cohort represented approximately 106.9 million US adults, with a mean age of 47.2 years. Rather than relying on body mass index alone, the investigators stratified participants into four distinct body composition phenotypes using two measurements: BMI, which captures overall mass relative to height, and the waist-to-height ratio, which serves as a practical proxy for central or abdominal adiposity. The four groups were obesity with central adiposity, obesity without central adiposity, normal weight with central adiposity, and normal weight without central adiposity.

The distribution of these phenotypes across the American population proved revealing in its own right. A slim majority, 53.3 percent of the weighted cohort, fell into the normal weight without central adiposity category, the presumed metabolically healthy baseline. Another 33.9 percent carried both a high BMI and a high waist-to-height ratio, the classic pattern of generalized obesity. But two smaller and often overlooked groups drew the researchers’ attention: 8.1 percent of adults had normal BMI values but prominent central fat stores, a phenomenon sometimes called normal weight central adiposity, while 4.7 percent were obese by BMI yet lacked significant abdominal fat accumulation. These last two groups complicate the simple arithmetic of conventional obesity screening.

The central outcome of the investigation was cardiovascular-kidney-metabolic multimorbidity, defined as the coexistence of two or more of the following conditions: hypertension, hyperlipidemia, diabetes, chronic kidney disease, or established cardiovascular disease. This clustering of cardiometabolic disorders, increasingly framed under the umbrella of cardiovascular-kidney-metabolic syndrome, has been recognized by the American Heart Association as a major and growing driver of cardiovascular events and death. The syndrome reflects the intimate physiological coupling of the heart, kidneys, and metabolic organs: insulin resistance accelerates atherosclerosis, declining kidney function worsens volume overload and hypertension, and adipose tissue dysfunction amplifies inflammatory signaling that damages vascular beds throughout the body.

When the researchers tabulated multimorbidity prevalence across body composition phenotypes, a clear hierarchy emerged. Normal weight individuals with central adiposity had the highest rate of cardiovascular-kidney-metabolic multimorbidity at 46.5 percent, meaning nearly half of these apparently slim adults already carried at least two of the five defining conditions. This exceeded the multimorbidity burden observed in people with obesity with central adiposity, and it dwarfed the rates seen in the two phenotypes without abdominal fat excess. In other words, the single group that conventional BMI-based screening would most reliably classify as low risk was, by this metric, the sickest.

Mortality analyses sharpened the message considerably. Using survey-weighted Cox proportional hazards models, which allow researchers to estimate the association between a characteristic and the timing of death while adjusting for confounding factors and accounting for the complex sampling design of NHANES, the team found that normal weight adults with central adiposity faced an adjusted hazard ratio of 1.87 for all-cause mortality compared with the reference group, a statistically significant elevation with a 95 percent confidence interval of 1.08 to 3.25 and a p value of 0.025. Even more dramatic was the association with cardiovascular death: the adjusted hazard ratio reached 7.76, with a 95 percent confidence interval of 1.01 to 59.76 and a p value of 0.049. While the wide confidence interval reflects the relatively small number of events in this subgroup and should temper strong causal interpretation, the direction and magnitude of the association are consistent with a substantially elevated cardiovascular risk.

Kaplan-Meier survival curves, a standard technique for visualizing the probability of surviving over time across groups, reinforced the statistical models. Participants who combined cardiovascular-kidney-metabolic multimorbidity with the normal weight central adiposity phenotype demonstrated the poorest long-term survival of any group in the analysis, with the difference between curves reaching statistical significance at p less than 0.001. This convergence of evidence, spanning prevalence estimates, adjusted hazard modeling, and nonparametric survival analysis, points toward a coherent conclusion: the combination of a slim silhouette and a protruding waistline represents a particularly dangerous metabolic signature when it coexists with clustered cardiometabolic disease.

The biological plausibility behind these findings rests on the distinct behavior of visceral adipose tissue compared with subcutaneous fat. Fat deposited around internal organs is not an inert energy reservoir; it is a hormonally and immunologically active tissue that drains directly into the portal circulation, delivering free fatty acids and inflammatory cytokines to the liver and promoting insulin resistance, dyslipidemia, and hepatic steatosis. Visceral fat accumulation is also closely linked to ectopic fat deposition in the liver, pancreas, and heart itself, mechanisms that have been implicated in the progression of metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, and atherosclerotic cardiovascular disease. A person with a normal BMI but a high waist-to-height ratio may therefore harbor a metabolically hostile internal environment that is invisible to weight-based screening, while some individuals with obesity and preserved fat distribution may be relatively protected.

The study arrives at a moment when the scientific community is actively rethinking how obesity itself should be defined. A recent international commission has proposed diagnostic criteria for clinical obesity that move beyond BMI toward measures of fat distribution and organ dysfunction, and prior research has repeatedly shown that waist-to-height ratio outperforms BMI as a screening tool for cardiometabolic risk factors. The new findings extend this literature into the specific arena of cardiovascular-kidney-metabolic multimorbidity and long-term survival in a nationally representative population. The authors conclude that normal weight individuals with central adiposity bear the greatest CKM burden and mortality risk, a result that highlights the limitations of BMI-based risk assessment and argues for incorporating simple anthropometric measures of central fat, such as the waist-to-height ratio, into routine clinical screening. For clinicians, the practical implication is straightforward: a tape measure around the waist may identify high-risk patients that the scale alone would miss, and for the public, the reassuring sight of a normal number on the bathroom scale should not be mistaken for a clean bill of cardiometabolic health.

Subject of Research: The association of body composition phenotypes with cardiovascular-kidney-metabolic multimorbidity and long-term mortality in a US population-based cohort

Article Title: Body composition phenotypes are key predictors of cardiovascular-kidney-metabolic multimorbidity and long-term mortality: insights from a population-based cohort study

Article References: Kong, G., Intaran, M. A. U., Soh, E. S. W., Yazicioglu, Y., Goh, R., Nagarajan, S., Wang, J.-W., Zhou, X., Zhou, X.-D., Zheng, M.-H., Chan, M. Y., Mehta, A., le Roux, C. W., Mamas, M. A., Khan, M. S., & Chew, N. W. S. (2026). Body composition phenotypes are key predictors of cardiovascular-kidney-metabolic multimorbidity and long-term mortality: insights from a population-based cohort study. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-026-03010-5

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03010-5

Keywords: cardiovascular-kidney-metabolic syndrome, central adiposity, body mass index, waist-to-height ratio, obesity, NHANES, multimorbidity, mortality, visceral fat, cardiometabolic risk, population-based cohort study, risk screening

Traditionally, HFpEF was linked primarily to elevated blood pressure, which was thought to induce stiffness in the heart muscle. However, emerging data challenge this perspective, indicating that nearly all HFpEF patients harbor significant accumulations of internal fat surrounding vital organs, including the heart itself. Unlike subcutaneous fat, this visceral and pericardial adiposity engages in complex biochemical signaling that profoundly impacts cardiac structure and function. The Adipokine Hypothesis explicates these interactions and their pathophysiological consequences.

Adipokines are bioactive signaling molecules secreted by adipose tissue; in physiologic states, they maintain homeostasis by downregulating inflammation, supporting vascular and renal health, and modulating fluid balance. This harmonious crosstalk ensures cardiovascular resilience. In contrast, the presence of excessive internal fat tissue invokes a pathological transformation in adipokine secretion profiles. The altered adipokines potentiate inflammation, oxidative stress, and fibrotic remodeling within the myocardium, fostering the hallmark stiffness observed in HFpEF. Thus, the heart is not merely passively affected by extrinsic pressure but is actively injured via maladaptive molecular signals emanating from surrounding fat depots.

Experimental pharmacological studies corroborate this mechanistic framework. Therapeutic agents that target fat tissue biology—rather than the myocardium itself—have demonstrated efficacy in alleviating HFpEF phenotypes. These drugs modulate adipokine secretion, attenuate cardiac fibrosis, and improve diastolic function, thus validating the hypothesis that fat is a central driver rather than an innocent bystander. Notably, several such agents already bear FDA approval for HFpEF treatment but remain underutilized in clinical practice. Additionally, glucagon-like peptide 1 (GLP-1) receptor agonists, including semaglutide and tirzepatide, have shown promising adipokine-modulating effects, potentially offering another therapeutic avenue.

Measuring fat-related risk factors also demands refinement. Body mass index (BMI), a conventional indicator of obesity, fails to distinguish between adiposity and lean mass, leading to diagnostic ambiguity. Instead, waist-to-height ratio has emerged as a more reliable metric for identifying individuals with excessive internal fat accumulation. A ratio exceeding 0.5 signals heightened risk, and most patients with HFpEF have ratios surpassing 0.6. This simple anthropometric measure enables clinicians to screen more effectively for HFpEF risk and initiate timely evaluation for symptomatic patients frequently misattributing exertional breathlessness to mere obesity.

The clinical implications extend beyond diagnostics. Early recognition of aberrant adipokine signaling and its cardiac consequences enables targeted interventions. Patients with elevated waist-to-height ratios presenting with dyspnea on exertion should undergo thorough HFpEF assessment. This approach can prevent underdiagnosis and mismanagement, offering opportunities to deploy therapeutics that reverse fat-mediated cardiac injury and improve quality of life.

The Adipokine Hypothesis echoes the transformative impact of Packer’s earlier work on heart failure with reduced ejection fraction (HFrEF). Over three decades ago, he introduced the neurohormonal hypothesis, redefining heart failure pathophysiology and guiding new therapeutic developments. The current hypothesis similarly reshapes the conceptual landscape of HFpEF, a condition historically marked by limited therapeutic options and prognostic ambiguity.

To complement this foundational paper, two additional studies published concurrently in JACC: Heart Failure delve into related molecular mechanisms. One explores the influence of eicosanoid adipokines in orchestrating inflammation within the HFpEF milieu, while the other investigates adipoexosomal microRNAs as novel regulators of cardiac fibrosis and remodeling. Together, these investigations provide a multi-dimensional understanding of how fat tissue reprogramming disrupts cardiac homeostasis at both systemic and molecular levels.

The Adipokine Hypothesis galvanizes a shift toward precision cardiovascular medicine, where interventions focus on modulating the biochemistry of adipose tissue rather than solely attempting to palliate heart muscle dysfunction. This paradigm shift holds promise for addressing the vast and growing global burden of HFpEF, a syndrome presently impacting nearly 4 million Americans and over 32 million individuals worldwide. As obesity rates climb, untangling fat’s complex role in cardiovascular disease becomes increasingly vital.

In summary, the Adipokine Hypothesis elucidates a previously underappreciated etiological pathway in HFpEF: the transformation of internal fat tissue from a protective to a pathogenic entity. By secreting a deleterious array of adipokines, excess adiposity instigates cardiac inflammation and fibrosis, leading to impaired relaxation and heart failure symptoms. Importantly, targeted pharmacotherapy that restores adipose tissue homeostasis provides a compelling therapeutic strategy. This new model not only enhances diagnostic accuracy via waist-to-height ratio assessment but also empowers clinicians to apply existing and emerging therapies tailored to the root cause rather than just the cardiac consequence of HFpEF.

With HFpEF’s complexity unraveled through the prism of adipokine biology, this hypothesis opens avenues for innovative clinical trials, multidisciplinary research, and ultimately improved patient outcomes. The field now stands at the cusp of a transformative era that reconceptualizes fat as an active cardiac player rather than a passive risk factor—ushering in hope for millions awaiting effective treatments for this pervasive form of heart failure.

Subject of Research: Heart failure with preserved ejection fraction (HFpEF) and the role of internal fat tissue and adipokines.

Article Title: The Adipokine Hypothesis: A Novel Framework Explaining the Role of Internal Fat Tissue in HFpEF.

News Publication Date: Not explicitly stated; inferred from context as around ESC Congress 2025.

Web References:

• https://www.ACC.org
• https://www.jacc.org

Keywords: Cardiovascular disease, Heart failure with preserved ejection fraction, Adipokines, Internal fat tissue, Waist-to-height ratio, GLP-1 receptor agonists, Cardiac inflammation, Cardiac fibrosis, Obesity, Metabolic disorders