Ejection Fraction (EF) measures the percentage of blood the heart’s main pumping chamber, the left ventricle, pushes out with each beat. A normal EF typically ranges from 55% to 70%. Heart failure is classified based on this measurement. Heart Failure with Preserved Ejection Fraction (HFpEF) occurs when the EF is 50% or higher, indicating a problem with the heart’s ability to relax and fill. The focus of drug therapy intended to increase pumping capacity centers on Heart Failure with Reduced Ejection Fraction (HFrEF), diagnosed when the EF is 40% or lower. In HFrEF, the weakened muscle cannot contract forcefully enough, and the goal of medical intervention is to reverse the damage and raise the EF percentage.
Modulating the Renin-Angiotensin System
When the heart begins to fail, the body activates the Renin-Angiotensin-Aldosterone System (RAAS), a powerful neurohormonal pathway intended to manage blood pressure. Angiotensin-Converting Enzyme Inhibitors (ACEi) were developed to block this compensatory mechanism. They prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, which reduces the resistance the heart must pump against. This systemic unloading decreases strain on the weakened left ventricle, initiating reverse remodeling and leading to a gradual increase in EF over time.
For patients who cannot tolerate the persistent dry cough caused by ACEi, Angiotensin Receptor Blockers (ARBs) offer a similar therapeutic benefit. ARBs block the binding of Angiotensin II to its receptor site, achieving the same goal of reducing vasoconstriction and aldosterone release. Both ACEi and ARBs interrupt the cycle of chronic strain that damages the heart muscle.
The most contemporary approach utilizes Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), which combine an ARB with a neprilysin inhibitor like sacubitril. While the ARB component blocks the RAAS, sacubitril prevents the breakdown of beneficial natriuretic peptides (NPs). These NPs are naturally released by the heart and promote vasodilation and sodium excretion. This dual action of blocking the RAAS while enhancing the protective NP system leads to superior reverse remodeling and a more significant improvement in LVEF compared to ACEi alone.
Protecting the Heart Muscle
A foundational category of therapy focuses on counteracting the persistent overstimulation of the sympathetic nervous system in heart failure. Beta-Blockers accomplish this by blocking the effects of stress hormones like adrenaline and norepinephrine on the heart muscle. Chronic high levels of these hormones are toxic, leading to cell death and further damage. By inhibiting these effects, beta-blockers slow the heart rate and reduce oxygen demand, allowing the muscle to rest and recover. This protection is a prerequisite for reverse remodeling, leading to sustained increases in EF over many months. Specific beta-blockers like carvedilol and metoprolol succinate are used to improve survival and heart function in HFrEF.
Mineralocorticoid Receptor Antagonists (MRAs), such as spironolactone and eplerenone, contribute to heart muscle protection by targeting aldosterone. Chronically elevated aldosterone promotes fluid retention and causes fibrosis, or scarring, of the heart muscle tissue. MRAs block the mineralocorticoid receptor, inhibiting this action. This reduction in scarring allows the left ventricle to become less stiff and more compliant, aiding in the improvement of the heart’s structure and pumping function.
New Metabolic and Renal Approaches
Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors are a newer class of drugs originally developed for type 2 diabetes, but they show powerful benefits for increasing EF. Their mechanism in heart failure is complex, involving both renal and metabolic effects. They work in the kidney to block the reabsorption of glucose and sodium, promoting their excretion in the urine. This results in mild osmotic diuresis, which reduces fluid volume and pressure within the circulatory system, easing the heart’s workload.
Beyond the renal effect, SGLT2 inhibitors induce a beneficial metabolic shift in the failing heart. The heart muscle in HFrEF often suffers from energy deprivation, struggling to use fatty acids as fuel. These drugs promote the production of ketone bodies, which the heart uses as a more energy-efficient “super-fuel.” This improved cardiac energetics enhances contractile function and contributes significantly to increases in LVEF.
This medication class has rapidly become a standard component of HFrEF treatment, improving outcomes regardless of whether a patient has diabetes. Their unique metabolic and volume-regulating actions complement the neurohormonal blockade provided by other foundational drug classes. The combination of these distinct actions helps stabilize the damaged heart muscle and drives structural improvement.
Adjunct Therapies for Severe Conditions
When standard foundational therapies are insufficient, adjunct medications are used for specific populations or advanced disease. The combination of Hydralazine and Isosorbide Dinitrate is often recommended for African American patients with HFrEF who remain symptomatic despite optimal conventional treatment. Hydralazine acts as an arterial vasodilator, reducing afterload, while Isosorbide dinitrate acts as a venous vasodilator, reducing preload. This dual vasodilating effect significantly reduces cardiac workload, promoting improved forward flow and a measurable increase in EF. The combination is also an option for patients unable to tolerate primary neurohormonal agents like ACEi or ARNIs.
Digoxin is reserved for symptom management in advanced HFrEF, particularly when symptoms persist despite other guideline-directed therapies. Digoxin works as a mild positive inotrope, increasing the force of the heart muscle contraction by inhibiting the sodium-potassium pump. While its effect on long-term survival is neutral, it can improve symptoms and quality of life by providing a modest boost to the pumping action of the weakened ventricle.