The Pathophysiology and New Advancements in the Pharmacologic and Exercise-Based Management of Heart Failure With Reduced Ejection Fraction: A Narrative Review

Abstract

Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome whose management has significantly evolved based on the pathophysiology and disease process. It is widely prevalent, has a relatively high mortality rate, and is comparatively more common in men than women. In HFrEF, the series of maladaptive processes that occur lead to an inability of the muscle of the left ventricle to pump blood efficiently and effectively, causing cardiac dysfunction. The neurohormonal and hemodynamic adaptations play a significant role in the advancement of the disease and are critical to guiding the treatment and management of HFrEF. The first-line therapy, which includes loop diuretics, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, hydralazine/isosorbide-dinitrate, and mineralocorticoid receptor antagonists (MRAs), has been proven to provide symptomatic relief and decrease mortality and complications. The newly recommended drugs for guideline-based therapy, angiotensin receptor/neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors, soluble guanylate cyclase, and myosin activators and modulators have also been shown to improve cardiac function, reverse cardiac remodeling, and reduce mortality rates. Recent studies have demonstrated that exercise-based therapy has resulted in an improved quality of life, exercise capacity, cardiac function, and decreased hospital readmission rates, but it has not had a considerable reduction in mortality rates. Combining multiple therapies alongside holistic advances such as exercise therapy may provide synergistic benefits, ultimately leading to improved outcomes for patients with HFrEF. Although first-line treatment, novel pharmacologic management, and exercise-based therapy have been shown to improve prognosis, the existing literature suggests a need for further studies evaluating the long-term effects of MRA and ARNI.

Keywords: cardio-renal pathophysiology; exercise-based therapy; heart failure; pharmacologic therapy; reduced ejection fraction.

Figure 1. Schematic representation of the neurohormonal response to a reduction in cardiac output.

Baroreceptor dysfunction triggers the vasomotor center causing an increase in sympathetic nervous system (SNS) activity and arginine-vasopressin secretion. The increased SNS activity causes peripheral vasoconstriction which aids in maintaining blood pressure. Along with the increased vasopressin, it leads to a decrease in renal blood flow, increased aldosterone secretion, and sodium and water reabsorption. The renal system also triggers an increase in renin secretion, which leads to an increase in angiotensin II (renin-angiotensin-aldosterone system pathway). Created by BioRender.com.

Figure 2. Schematic representation of the renin-angiotensin-aldosterone system activation in response to a reduction in blood pressure.

The kidneys release renin, which converts angiotensinogen, released by the liver, to angiotensin I. The lungs release angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II. Angiotensin II, in turn, stimulates peripheral vasoconstriction, the posterior pituitary to release antidiuretic hormone (ADH), the adrenal cortex to release aldosterone, and the kidneys to increase water and sodium reabsorption. The result is a reactive increase in blood pressure. Created by BioRender.com.

Figure 3. Frank-Starling mechanism that displays the response of the heart to a reduction in venous return.

The Frank-Starling curve in heart failure exhibits a downward shift depicting that to increase contractility and stroke volume, there must be increased venous return and filling pressure. This explains the increase in fluid retention resulting from cardiac dysfunction. Created by BioRender.com.

Figure 4. Cardiac remodeling in heart failure: eccentric hypertrophy and concentric hypertrophy in patients with heart failure compared to a normal heart.

Eccentric and concentric hypertrophy are characterized by the arrangement of the sarcomeres. In heart failure with reduced ejection fraction, sarcomeres are added in a series rather than parallel as in concentric hypertrophy. Created by BioRender.com.