Current Management of Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) encompasses nearly half of heart failure (HF) worldwide, and still remains a poor prognostic indicator. It commonly coexists in patients with vascular disease and needs to be recognized and managed appropriately to reduce morbidity and mortality. Due to the heterogeneity of HFpEF as a disease process, targeted pharmacotherapy to this date has not shown a survival benefit among this population. This article serves as a comprehensive historical review focusing on the management of HFpEF by reviewing past, present, and future randomized controlled trials that attempt to uncover a therapeutic value. With a paradigm shift in the pathophysiology of HFpEF as an inflammatory, neurohormonal, and interstitial process, a phenotypic approach has increased in popularity focusing on the treatment of HFpEF as a systemic disease. This article also addresses common comorbidities associated with HFpEF as well as current and ongoing clinical trials looking to further elucidate such links.

Keywords: BNP; HFpEF; diastolic dysfunction; heart failure; pathophysiology; preserved ejection fraction; treatment of HFpEF.

Fig. 1

“Central Illustration”: This image illustrates the treatment rationale for drug therapies among heart failure with preserved ejection fraction (HFpEF) patients. Elevated left ventricular filling pressures (LVFP) are characteristic of diastolic dysfunction. Medications like diuretics, nitrates, phosphodiesterase 5 (PDE5) inhibitors, and Angiotensin Receptor Neprilysin Inhibitor (ARNIs) are thought to mitigate LVFPs and provide possible therapeutic benefit among HFpEF patients. Systemic inflammatory responses often driven by comorbidities leads to sympathetic hyperstimulation, myocardial fibrosis/interstitial remodeling, endothelial and mitochondrial dysfunction that can serve as major proposed pathophysiological targets. Renin-angiotensin-aldosterone system (RAAS) induced interstitial remodeling and myocardial fibrosis have both been implicated in structural changes seen within the myocardium of HFpEF patients. Medications like Angiotensin-converting enzyme (ACE) inhibitors, Angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRA), ARNIs, and even loop diuretics may provide benefit to HFpEF patients by inhibiting the RAAS pathway from various points and deterring fibroblast proliferation. Endothelial dysfunction, microvascular inflammation, and arterial stiffening are also thought perpetuate imbalances in myocardial supply and demand, leading to chronic ischemia, increased angiogenesis, and fibrosis. Therapy thought to target this pathway include nitrates, PD5E inhibitors, Sodium-glucose co-transporter 2 (SGLT2) inhibitors, ARNI, and calcium channel blockers (CCB). Sympathetic hyperstimulation is also seen among HFpEF patients. Drugs like beta blockers, and digoxin are thought to augment adrenergic activation in hopes to decreased rates of hospitalization and mortality within this population. Mitochondrial dysfunction, decreased Adenosine Triphosphatase (ATP) production, and increased reactive oxygen species (ROS) has also been recently implicated in HFpEF perpetuating the inflammatory cascade. Targeted therapies like potassium nitrate, Coenzyme Q10 (CoQ10), Neladenoson, and D-Ribose are currently being researched to combat this phenomenon.

Fig. 2

The timeline of key clinical trials and future trials that are currently being conducted among patients with HFpEF. Each trial is shown along with the medical therapy below. The clinical trial from 1993-2002 were RCTs looking at the utility of betablocker therapy among both HFpEF and HFrEF patients. The metanalysis by Cleland et al, extrapolated data from each of these trials to understand the role of beta blocker therapy among HFpEF patients. More details about this article are written within the body of the article. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; CoQ10, CoEnzyme Q10; ARB, angiotensin receptor blocker; PDE5, phosphodiesterase 5 inhibitor; SGLT2, sodium glucose transporter 2 inhibitor.