Targeting Obesity and Diabetes to Treat Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need that is characterized by the presence of multiple cardiovascular and non-cardiovascular comorbidities. Foremost among these comorbidities are obesity and diabetes, which are not only risk factors for the development of HFpEF, but worsen symptoms and outcome. Coronary microvascular inflammation with endothelial dysfunction is a common denominator among HFpEF, obesity, and diabetes that likely explains at least in part the etiology of HFpEF and its synergistic relationship with obesity and diabetes. Thus, pharmacological strategies to supplement nitric oxide and subsequent cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling may have therapeutic promise. Other potential approaches include exercise and lifestyle modifications, as well as targeting endothelial cell mineralocorticoid receptors, non-coding RNAs, sodium glucose transporter 2 inhibitors, and enhancers of natriuretic peptide protective NO-independent cGMP-initiated and alternative signaling, such as LCZ696 and phosphodiesterase-9 inhibitors. Additionally, understanding the role of adipokines in HFpEF may lead to new treatments. Identifying novel drug targets based on the shared underlying microvascular disease process may improve the quality of life and lifespan of those afflicted with both HFpEF and obesity or diabetes, or even prevent its occurrence.

Keywords: diastolic dysfunction; endothelial and microvascular dysfunction; heart function; hypertension; inflammation; metabolic disease.

Figures

Figure 1

Major comorbidities that negatively affect prognosis in patients with HFpEF. The graph shows the prevalence of comorbidities (in percent) in HFpEF patients enrolled in different clinical studies as summarized by Triposkiadis et al. (35): hypertension (HTN), atrial fibrillation (AF), anemia, diabetes mellitus or type II diabetes (DM), chronic kidney disease (CKD), obesity.

Figure 2

Scheme for the proposed etiology of heart failure with preserved ejection fraction (HFpEF) relevant to obesity and type 2 diabetes. Left side: at the organ level, HFpEF is characterized by cardiac hypertrophy and a marked increase in the left ventricular mass/volume ratio (concentric remodeling), as well as increased stiffness and often enlargement of the left atrium. Right panel: coronary microvascular inflammation is postulated to play a key role in HFpEF progression, encompassing endothelial dysfunction and reduced nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)—protein kinase G (PKG) signaling. Increased stiffness of both myofilaments and the extracellular matrix is thought to impair diastolic function of the heart. The former is postulated to result in part from reduced PKG-mediated phosphorylation of titin, the protein that determines passive elasticity of cardiomyocytes. The later would result from increased collagen deposition and cross-linking (fibrosis), due to loss of cGMP/PKG anti-fibrotic signaling and increased inflammatory endothelium-mediated recruitment of immune cells that activate resident cardiac fibroblasts. Diastolic dysfunction is likely an antecedent event that interacts synergistically with other remodeling events at the cellular level to foster development of HFpEF (images adapted and reproduced with permission from the copyright holder http://servier.com/Powerpoint-image-bank).