Obesity is the primary driver of heart failure (HF) with preserved ejection fraction (HFpEF), and weight loss should be a priority in patients with the condition, according to Aneesh Dhore-Patil, MD. Rising rates of HFpEF, and the dearth of guideline-directed therapy for the condition, has renewed interest in its pathophysiology. Specifically, the obese-diabetic phenotype of HFpEF is exceedingly common and is tied to worse outcomes.

For a paper published in Frontiers in Physiology, Dr. Dhore-Patil, and colleagues assessed multiple aspects of obesity’s impact on the heart, including obesity and sodium retention, obesity and low-grade systemic inflammation, and the role of chronic kidney disease in HFpEF. They specifically examined the obese-diabetic phenotype of HFpEF, underscoring the interaction between obesity, diabetes, and coronary microvascular dysfunction in left ventricular remodeling.

The review included a search of four databases for terms such as obesity, epicardial adipose tissue (EAT), and visceral adipose tissue (VAT), as well as HFpEF and type 2 diabetes (T2D). Results from four studies influenced the review (Table).

Impact of Obesity & Diabetes in HFpEF

The researchers noted that weight gain causes the build-up of adipose tissue through adipocyte hypertrophy or hyperplasia and that the increasing VAT becomes dysfunctional and inflamed, resulting in low-grade systemic inflammation. They also reported that approximately one-half of patients with HFpEF have chronic kidney disease and that treatment of the condition in patients with both HFpEF and obesity is difficult. While weight loss is beneficial for proteinuria and has a positive impact on estimated glomerular filtration rate, and bariatric surgery can markedly improve proteinuria, the latter strategy for weight loss has been tied to long-term renal complications, such as a nephrolithiasis and oxalate nephropathy.

Regarding the impact of T2D, Dr. Dhore-Patil and colleagues wrote that patients with HFpEF who have T2D frequently have higher BMI compared with patients with HFpEF who do not have T2D. Those with T2D-HFpEF also have more severe initial presentations and more frequent hospitalizations.

Furthermore, while exercise intolerance is common with both HFpEF and T2D, the cause is multifactorial. For patients with HFpEF, obesity and T2D significantly contribute to exercise intolerance, the researchers noted. As a result, they cited reversing exercise intolerance as important for patients with T2D-HFpEF.

The review also described therapeutic advances for patients, particularly those with the obese-T2D-HFpEF phenotype. Neutral results in several trials indicate that nitric oxide may not be optimal for alleviating endothelial dysfunction. Furthermore, while coronary microvascular dysfunction is widespread in patients with HFpEF, targeting this dysfunction does not appear to be therapeutically effective. Dr. Dhore-Patil and team noted that sodium retention secondary to increased aldosterone production is an important aspect of HFpEF with obesity, and that—in experimental models—mineralocorticoid receptor antagonists (MRAs) have been shown to decrease oxidative stress, cardiac inflammation, and fibrosis, as well as improve diastolic LV filling pressures. The impact of MRAs on diabetic nephropathy vary, with delayed progression in type 1 diabetes but not T2D. According to the authors, promising metabolic effects of MRAs seen in pre-clinical studies indicate that the antagonists may be effective for the obese-T2D-HFpEF phenotype.

Benefits of Lifestyle & Behavioral Modifications

While weight loss has yet to be a therapeutic target in managing HFpEF, and routine aerobic exercise can be difficult for those who are severely or morbidly obese, the Dr. Dhore-Patil, et al strongly support adherence to lifestyle and behavioral modifications for individuals with obesity, T2D, and HFpEF. They also noted that physicians should be proactive in helping patients lose weight effectively. Pharmacotherapy and bariatric surgery can be utilized after lifestyle and behavioral modifications, they explained, as recent advances in anti-diabetic therapies have enabled the targeting of obesity and HF in patients with T2D.

Looking ahead, Dr. Dhore-Patil and colleagues suggested that future research examine the role of VAT and EAT in risk-stratifying patients at the highest risk for HFpEF and the impact of VAT and EAT on the management of this condition.