Heart Failure and Ischemic

Introduction

Heart failure (HF) and ischemic heart disease (IHD) remain the leading causes of morbidity and mortality worldwide. Despite advances in interventional cardiology and surgical strategies, pharmacological management continues to be the cornerstone of therapy for both conditions. Modern drug therapy for HF and IHD is not limited to symptom control—it is aimed at modifying disease progression, improving survival, reducing hospitalizations, and enhancing quality of life.

This section explores the major drug classes and strategies used in HF and IHD management, beginning with traditional approaches and culminating in the new generation of targeted therapies. The focus will be on:

Pharmacological management of heart failure: old and new strategies.
ACE inhibitors and ARBs: renin–angiotensin system modulation.
ARNIs (sacubitril/valsartan): the revolution in HF treatment.
Diuretics in cardiology: loop, thiazide, and potassium-sparing agents.
Pharmacotherapy of myocardial ischemia: nitrates, beta-blockers, and ranolazine.

1. Pharmacological Management of Heart Failure: Old and New Strategies

Pathophysiological Basis of HF Therapy

Heart failure is characterized by impaired ventricular filling or ejection of blood. Compensatory mechanisms—activation of the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous system (SNS), and natriuretic peptide pathways—temporarily maintain cardiac output but eventually cause remodeling, fibrosis, and worsening dysfunction.

Pharmacological therapy aims to:

Reduce preload and afterload → improve hemodynamics.
Inhibit maladaptive neurohormonal activation.
Promote reverse remodeling.
Relieve symptoms and prolong survival.

Traditional Strategies (“Old” Approaches)

Cardiac glycosides (Digoxin):
- Increase inotropy by inhibiting Na⁺/K⁺-ATPase.
- Improve symptoms, reduce hospitalization but no survival benefit.
- Limited by narrow therapeutic index and toxicity risk.
Diuretics:
- Symptomatic relief of congestion.
- Do not alter disease progression.
Vasodilators (Hydralazine + isosorbide dinitrate):
- Reduce preload/afterload.
- Shown to improve outcomes in African American patients.

Modern Evidence-Based Therapy (“New” Approaches)

ACE inhibitors / ARBs / ARNIs → inhibit RAAS, improve survival.
Beta-blockers (carvedilol, bisoprolol, metoprolol succinate):
- Reduce SNS overdrive.
- Improve EF, survival, and prevent arrhythmias.
Mineralocorticoid receptor antagonists (spironolactone, eplerenone):
- Block aldosterone-mediated fibrosis and sodium retention.
- Mortality reduction in HFrEF.
ARNIs (sacubitril/valsartan):
- Enhance natriuretic peptides while blocking RAAS.
- Markedly improve outcomes compared to ACE inhibitors.
SGLT2 inhibitors (dapagliflozin, empagliflozin):
- Initially anti-diabetic drugs, now proven to reduce HF mortality and hospitalization regardless of diabetes status.
Ivabradine:
- Selective sinus node inhibitor.
- For patients with HR >70 bpm despite beta-blocker therapy.
Vericiguat (soluble guanylate cyclase stimulator):
- Enhances nitric oxide signaling.
- For patients with worsening HF despite standard therapy.

➡️ The evolution from symptomatic relief to disease-modifying, molecularly targeted therapies has revolutionized HF management.

2. ACE Inhibitors and ARBs: Renin–Angiotensin System Modulation in Cardiac Disease

Role of RAAS in Heart Failure and Ischemia

Angiotensin II → vasoconstriction, sodium retention, sympathetic activation, aldosterone release, and fibrosis.
Chronic activation → ventricular hypertrophy and remodeling.

ACE Inhibitors (Enalapril, Lisinopril, Ramipril)

Inhibit conversion of angiotensin I → II.
Increase bradykinin levels (vasodilation, but also cough/angioedema).
Clinical benefits:
- Improve survival in HFrEF (CONSENSUS, SOLVD trials).
- Reduce post-MI mortality (HOPE trial with ramipril).

ARBs (Losartan, Valsartan, Candesartan)

Block AT1 receptors → prevent angiotensin II effects without affecting bradykinin.
Alternative for ACEI-intolerant patients.
Effective in reducing morbidity and mortality in HF and post-MI.

Key Differences

ACE inhibitors: first-line in HFrEF and ischemic cardiomyopathy.
ARBs: reserved for ACEI intolerance.
Both improve remodeling, reduce afterload, and slow HF progression.

3. ARNIs (Sacubitril/Valsartan): Revolution in Heart Failure Treatment

Mechanism of Action

Sacubitril: neprilysin inhibitor → prevents degradation of natriuretic peptides → enhanced vasodilation, natriuresis, anti-fibrotic effects.
Valsartan: ARB component → blocks RAAS.

➡️ Dual mechanism = RAAS suppression + NP enhancement → synergistic benefit.

Clinical Evidence

PARADIGM-HF trial:
- Compared sacubitril/valsartan vs. enalapril in HFrEF.
- Result: 20% reduction in cardiovascular death, 21% reduction in HF hospitalizations.
Improved quality of life scores and reduced sudden cardiac death.

Clinical Use

Indicated in symptomatic HFrEF (NYHA II–III) despite standard therapy.
Now recommended as first-line therapy instead of ACEIs in many guidelines.

Limitations

Risk of hypotension, renal dysfunction, and hyperkalemia.
Avoid with concomitant ACE inhibitors or neprilysin inhibitors (risk of angioedema).

Future Perspectives

ARNIs mark the beginning of neprilysin-based therapies, with ongoing studies in HFpEF and post-MI remodeling.

4. Diuretics in Cardiology: Loop, Thiazide, and Potassium-Sparing Agents

Diuretics are essential for symptom relief in heart failure and fluid overload states. They do not improve survival but provide rapid relief of congestion.

Loop Diuretics (Furosemide, Bumetanide, Torsemide)

Site of action: thick ascending limb of Henle’s loop.
Potent natriuresis and diuresis.
Used in acute decompensated HF for pulmonary edema and volume overload.
Adverse effects: hypokalemia, hypomagnesemia, metabolic alkalosis, ototoxicity.

Thiazide Diuretics (Hydrochlorothiazide, Metolazone)

Site: distal convoluted tubule.
Mild diuretic effect; often combined with loop diuretics for synergy in diuretic resistance.
Used in hypertension with HF.
Risks: hypokalemia, hyponatremia, hyperuricemia (gout).

Potassium-Sparing Diuretics

Aldosterone antagonists (Spironolactone, Eplerenone):
- Reduce remodeling and fibrosis.
- Improve survival in HFrEF (RALES, EMPHASIS-HF trials).
Amiloride, Triamterene:
- Block epithelial sodium channels.
- Mainly prevent potassium loss with other diuretics.

Clinical Strategy

Loop diuretics: cornerstone for congestion.
Thiazides: add-on in resistant edema.
Spironolactone/eplerenone: dual role as diuretic + disease-modifying agent.

5. Pharmacotherapy of Myocardial Ischemia: Nitrates, Beta-Blockers, and Ranolazine

Pathophysiological Basis

Myocardial ischemia results from imbalance between oxygen supply and demand. Pharmacotherapy targets:

Increasing oxygen supply (coronary vasodilation).
Reducing oxygen demand (lower HR, BP, contractility).

Nitrates (Nitroglycerin, Isosorbide Dinitrate/Mononitrate)

Mechanism: release NO → ↑ cGMP → venodilation → ↓ preload.
Benefits: rapid angina relief, reduced wall stress, improved coronary perfusion.
Uses:
- Stable angina (symptomatic relief).
- Acute coronary syndromes (with beta-blockers/antiplatelets).
- Acute HF with pulmonary edema.
Limitations: tolerance with continuous use, headache, hypotension.

Beta-Blockers (Metoprolol, Atenolol, Carvedilol)

Reduce HR, contractility, and BP → ↓ myocardial oxygen demand.
Improve survival post-MI and in HFrEF.
Prevent arrhythmias and reduce ischemic burden.
Contraindicated in severe bradycardia, asthma, acute decompensated HF.

Ranolazine

Novel anti-anginal agent.
Mechanism: inhibits late sodium current (INa), reducing intracellular calcium overload.
Improves diastolic relaxation, reduces wall tension.
Advantages:
- Relieves angina without affecting HR or BP.
- Useful in patients intolerant to beta-blockers.
Side effects: dizziness, constipation, QT prolongation.