Metabolic Dysfunction: An Important Driver of Incident Heart Failure with Preserved and Reduced Ejection Fraction

This article refers to ‘Metabolic dysfunction and incidence of heart failure subtypes among Black individuals: The Jackson Heart Study’ by A.D. Kaze et al., published in this issue on pages xxx. Metabolic dysfunction is central to a wide spectrum of cardiovascular diseases. In particular, metabolic syndrome (MetS), characterized by the coexistence of interrelated metabolic risk factors in the same individual, was originally noted for its association with the onset and progression of atherosclerotic cardiovascular disease. However, it has since emerged as an important, and perhaps more powerful, risk factor for heart failure (HF). Indeed, MetS and many of its individual components (e.g. central obesity, hypertension, and dysglycaemia) have been associated with a substantially increased risk of incident HF.1, 2 However, whether MetS—as a single integrative measure of metabolic health status—is differentially associated with incident HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) has not been systematically evaluated. This important evidence gap is especially large in historically underrepresented racial and ethnic groups, including self-identified Black individuals, who are at particularly high risk of HF at younger ages.3 As the burden of HF and its upstream metabolic risk factors continue to expand worldwide,4, 5 studies examining the interplay between metabolic health and HF among Black adults are urgently needed to inform equitable healthcare delivery, research, and policy efforts targeting HF prevention. In this issue of the Journal, Kaze and colleagues evaluate the association between MetS, subclinical HF, and incident HFpEF and HFrEF in the Jackson Heart Study, a community-based (Jackson, MS, USA) prospective cohort study of African American adults.6 Overall, among 4069 participants (mean age, 54 years; 64% women), more than one in three had MetS at baseline. MetS and higher MetS severity were associated with subclinical myocardial injury and, despite lower B-type natriuretic peptide (BNP) levels, adverse cardiac remodelling, including higher left ventricular (LV) volume, LV mass, and left atrial volume, but not LV ejection fraction. Over 12 years, MetS was associated with a >2-fold higher rate of incident HF compared with individuals without MetS; higher MetS severity was additionally associated with an incrementally higher rate of incident HF. While MetS was associated with increased risk of HF irrespective of age, risk was enhanced among younger versus older individuals. Finally, MetS was associated with a higher rate of both HFpEF (hazard ratio [HR] 2.72; 95% confidence interval [CI] 1.93–3.84) and HFrEF (HR 1.61; 95% CI 1.15–2.25), but with a steeper gradient of risk with increasing MetS severity observed for HFpEF. This latter finding is consistent with the echocardiography data showing subclinical changes stereotypic of HFpEF with increasing MetS severity, providing important mechanistic insights. The authors should be congratulated for a rigorous analysis deepening understanding of the interplay between metabolic health and HF in a well-phenotyped cohort of Black adults, a historically understudied and underrepresented population. However, some limitations should be considered. First, only one definition of metabolic health—the National Cholesterol Education Program Adult Treatment Panel III criteria for MetS—was explored. Use of alternative or additional metrics, such as the homeostatic model assessment for insulin resistance or estimated glucose disposal rate, may have reclassified a higher proportion of study participants as having metabolic impairment and captured a wider spectrum of metabolic derangements, enhancing mechanistic insights.7 Second, inclusion of coronary heart disease, which may be along the causal pathway from metabolic dysfunction to incident HF, in the main statistical model may have attenuated the total effect of MetS on incident HF. However, the degree of attenuation was modest compared with models exclusive of coronary heart disease, emphasizing the importance of other pathophysiological pathways linking MetS and HF risk. Third, whether these data are generalizable to other communities or global populations is uncertain. For example, while MetS evaluates a clustering of risk factors, its individual components may vary considerably across different demographic profiles.8 Despite the above limitations, this analysis provides important insights relevant to clinical care and health policy. First, the high burden of MetS (37%) in this analysis, as well as the steep association between MetS severity and HF risk, underscores the need for systematic screening, prevention, and management of metabolic risk factors in all populations. Of note, the prevalence of MetS in the Jackson Heart Study was greater than nationwide estimates among Black adults over the enrolment period.4 This finding may be attributable, in part, to the high proportion of women (nearly two in three participants) in the study population. The prevalence of MetS in the US is higher among women versus men,4 which may reflect differences in social determinants of health and/or biological factors (e.g. body composition and/or sex-specific risk factors). This finding may additionally reflect the marked differences in health profiles and policy between individual states in the US. Indeed, the prevalence of obesity in Mississippi is among the highest in the US,9 emphasizing the need to tailor HF prevention efforts to local contexts. Second, while HFrEF and HFpEF have overlapping but unique mechanisms of onset, natural histories, and therapeutic considerations, this study extends prior research highlighting the key role of metabolic dysfunction in the pathogenesis of both (Figure 1).2 However, similar to prior analyses evaluating the gradient of HF risk according to body mass index (BMI),2 risk of incident HFpEF increased more steeply with higher MetS severity compared with HFrEF. This observation underscores the greater relevance of other factors in HFrEF pathogenesis. Moreover, while some metabolic traits (e.g. BMI) appear to be more strongly associated with incident HFpEF among women compared with men,2 MetS was similarly associated with incident HF in both men and women in this analysis. This finding aligns with a prior study in which the individual components of MetS were similarly predictive of incident HF in both women and men.2 Third, declines in global metabolic health5 amplify the urgent need for novel HF prevention approaches, the success of which may hinge on the ability to identify individuals at highest risk. As such, screening efforts to enhance identification of individuals with subclinical HF have been increasingly incorporated into guidelines, some of which recommend measurement of natriuretic peptides (NPs).10 However, the marked decline in BNP levels with increasing MetS severity in this analysis illustrates the potential for systematic underestimation of HF risk among those with worse metabolic impairments and more advanced cardiac remodelling, resulting in missed opportunities to avert preventable death and disability. These findings underscore the importance of tailoring interpretation of NP levels (and subsequent preventive interventions) to individual clinical profiles, suggesting providers participating in HF risk stratification and prevention efforts should be facile with the complex and bidirectional relationship between metabolic health and NPs. Indeed, higher NP levels among healthy individuals have been associated with more favourable adiposity profiles and less insulin resistance.11 Hence, lower BNP levels among those with higher MetS severity may reflect reverse causation (i.e. NP deficiency leading to metabolic dysfunction). Alternatively, mounting evidence suggests body composition, which is integral to metabolic health, plays a critical and nuanced role in NP metabolism. Namely, both adiposity profiles and skeletal muscle mass, which vary according to age, sex, and race and ethnicity,12 are each inversely related to NP levels.11, 13 While excess adiposity may directly suppress NP release (e.g. through excess pericardial restraint, among other mechanisms), skeletal muscle mass has been shown to participate in clearance of circulating NPs.14 Further, absolute skeletal muscle mass generally increases with higher adiposity (increasing NP clearance), but at a lower rate, resulting in lower relative muscle mass. As skeletal muscle is the primary site for insulin-mediated glucose disposal, reductions in relative muscle mass have been strongly linked with insulin resistance.15 Importantly, these processes may individually contribute to lower NP levels and worse metabolic health. Although NPs have been recommended to support HF prevention efforts—in addition to their well-established roles in HF diagnosis, risk stratification, and management—the complexities facing their interpretation among individuals at high risk for incident HF stress the need for additional or alternative approaches. Of note, high-sensitivity cardiac troponin I increased with greater cardiac remodelling and MetS severity in this analysis, suggesting it may be more readily interpretable if used to enhance identification of subclinical HF. More holistic screening pathways incorporating additional biomarkers [e.g. C-reactive protein, lipoprotein(a), fibrosis-4 index, and urine albumin-to-creatinine ratio] may also capture broader and complementary domains of cardiovascular-kidney-metabolic health, with relevance for risk stratification and prevention. Taken together, this analysis provides important insights into the association between MetS and incident HFrEF and HFpEF among Black individuals, further emphasizing (i) the utility of MetS as a clinically relevant, integrative, and continuous measure of metabolic health and HF risk; and (ii) the importance of metabolic health as a foundational priority of equitable and comprehensive HF prevention strategies. However, while overweight/obesity and its complications (e.g. hypertension and type 2 diabetes) are increasingly dominant upstream drivers of HF onset and progression in global populations, maintenance of optimal metabolic health across the lifespan is unlikely to eliminate HF risk. As such, efforts targeting metabolic health should be considered part of multifaceted strategies simultaneously addressing the numerous non-metabolic drivers of HF, such as cigarette smoking, substance use, genetic factors, and non-metabolic causes of ischaemic heart disease.