ACE Inhibitors and ARBs

Introduction

Cardiac disease, particularly heart failure, hypertension, and ischemic cardiomyopathy, remains a leading cause of mortality worldwide. A common thread among these conditions is the overactivation of the renin–angiotensin–aldosterone system (RAAS), which promotes vasoconstriction, fluid retention, sympathetic activation, and structural remodeling of the myocardium.

Among the most important pharmacological breakthroughs in cardiovascular medicine has been the development of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). These drugs directly interfere with RAAS signaling, preventing the detrimental effects of angiotensin II and aldosterone. They not only reduce blood pressure but also improve survival in heart failure, prevent post-myocardial infarction remodeling, and reduce the risk of recurrent cardiovascular events.

This article explores the detailed mechanisms, clinical evidence, therapeutic benefits, and future perspectives of ACE inhibitors and ARBs in the context of cardiac disease.

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The Renin–Angiotensin–Aldosterone System (RAAS): Pathophysiological Background

To understand how ACE inhibitors and ARBs exert their effects, it is crucial to revisit the role of RAAS in cardiovascular physiology and pathology.

Normal Physiology of RAAS

1. Renin release: Produced by juxtaglomerular cells of the kidney in response to low blood pressure, low sodium, or sympathetic activation.
2. Angiotensinogen cleavage: Renin cleaves angiotensinogen (from the liver) into angiotensin I.
3. Conversion to Angiotensin II: Angiotensin-converting enzyme (ACE), mainly in pulmonary endothelial cells, converts angiotensin I → angiotensin II.
4. Actions of Angiotensin II:
   • Potent vasoconstrictor (via AT1 receptors).
   • Stimulates aldosterone release → sodium/water retention.
   • Enhances sympathetic neurotransmission.
   • Promotes myocardial hypertrophy and fibrosis.
   • Impairs endothelial function.

Pathological Overactivation of RAAS

In cardiac disease, particularly heart failure, hypertension, and ischemic heart disease, RAAS becomes chronically activated, leading to:

• Increased afterload (vasoconstriction).
• Increased preload (fluid retention).
• Ventricular hypertrophy and fibrosis.
• Vascular remodeling and endothelial dysfunction.

Thus, RAAS inhibition is both a hemodynamic and disease-modifying strategy in cardiac disease.

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ACE Inhibitors: Mechanism and Clinical Role

Mechanism of Action

ACE inhibitors block the conversion of angiotensin I to angiotensin II. Additionally, they prevent the breakdown of bradykinin, a vasodilator peptide.

Effects:

• ↓ Angiotensin II → reduced vasoconstriction and aldosterone secretion.
• ↑ Bradykinin → vasodilation, nitric oxide release, improved endothelial function.

Hemodynamic Benefits

• Reduced afterload (arterial vasodilation).
• Reduced preload (venodilation and natriuresis).
• Improved coronary perfusion.
• Enhanced cardiac output in heart failure.

Molecular and Structural Benefits

• Inhibit ventricular remodeling post-MI.
• Reduce fibrosis and hypertrophy.
• Improve endothelial function.

Major Clinical Applications

1. Heart Failure with Reduced Ejection Fraction (HFrEF):
   • Cornerstone therapy; improves survival and reduces hospitalizations.
   • Key trials: CONSENSUS, SOLVD.
2. Hypertension:
   • First-line agents, especially in diabetic and CKD patients.
3. Post-Myocardial Infarction:
   • Prevent remodeling and recurrent ischemic events.
   • Trial: SAVE study (captopril reduced mortality post-MI).
4. Diabetic Nephropathy:
   • Slow progression of kidney disease via glomerular pressure reduction.

Common ACE Inhibitors

• Captopril (first agent).
• Enalapril.
• Lisinopril.
• Ramipril (HOPE trial: reduced CV mortality and stroke).

Adverse Effects

• Cough (due to bradykinin accumulation).
• Angioedema (rare, but life-threatening).
• Hyperkalemia (due to reduced aldosterone).
• Renal dysfunction (especially in bilateral renal artery stenosis).
• Hypotension (particularly after first dose).

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ARBs: Mechanism and Clinical Role

Mechanism of Action

ARBs selectively block angiotensin II type 1 (AT1) receptors, preventing the effects of angiotensin II regardless of its source (ACE or alternative pathways).

Effects:

• Vasodilation and reduced aldosterone release.
• No effect on bradykinin metabolism → less cough/angioedema.
• Allow angiotensin II to stimulate AT2 receptors → vasodilatory and anti-proliferative effects.

Hemodynamic and Structural Benefits

• Similar to ACE inhibitors (reduce preload/afterload, improve remodeling).
• Particularly useful when ACEIs are not tolerated.

Major Clinical Applications

1. Heart Failure (HFrEF):
   • Alternative to ACEIs; reduce mortality and hospitalizations.
   • Trials: Val-HeFT (valsartan), CHARM (candesartan).
2. Hypertension:
   • Effective in lowering BP, especially in diabetics and patients with CKD.
3. Diabetic Nephropathy:
   • Prevent renal disease progression (losartan in RENAAL, irbesartan in IDNT).
4. Post-MI:
   • Reduce mortality (valsartan shown non-inferior to captopril in VALIANT trial).

Common ARBs

• Losartan.
• Valsartan.
• Candesartan.
• Irbesartan.
• Telmisartan.

Adverse Effects

• Less cough and angioedema than ACE inhibitors.
• Hyperkalemia and renal dysfunction still possible.
• Hypotension.

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ACE Inhibitors vs. ARBs: Comparative Insights

Feature	ACE Inhibitors	ARBs
Mechanism	Block ACE, reduce ang II, ↑ bradykinin	Block AT1 receptor, preserve AT2 stimulation
Benefits	Mortality reduction in HF, MI, HTN	Similar benefits, less bradykinin-related effects
Side Effects	Cough, angioedema, hyperkalemia, renal dysfunction	Hyperkalemia, renal dysfunction, rare angioedema
Clinical Preference	First-line in HF, post-MI	Used if ACEIs not tolerated
Key Trials	CONSENSUS, SOLVD, HOPE, SAVE	Val-HeFT, CHARM, VALIANT, RENAAL

Overall: ACEIs are usually first-line; ARBs are excellent alternatives.

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Landmark Clinical Trials

ACE Inhibitors

• CONSENSUS (1987): Enalapril reduced mortality in severe HF.
• SOLVD (1991): Enalapril reduced morbidity/mortality in HFrEF.
• HOPE (2000): Ramipril reduced CV death, MI, and stroke in high-risk patients.
• SAVE (1992): Captopril improved survival post-MI.

ARBs

• Val-HeFT (2001): Valsartan improved morbidity in HF.
• CHARM (2003): Candesartan reduced CV death and hospitalizations.
• VALIANT (2003): Valsartan non-inferior to captopril post-MI.
• RENAAL (2001): Losartan reduced progression of diabetic nephropathy.

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Special Considerations in Cardiac Disease

Heart Failure with Preserved Ejection Fraction (HFpEF)

• Evidence for ACEIs/ARBs is weaker; some benefit in reducing hospitalizations but not mortality.

Post-MI Patients

• Early initiation reduces remodeling and improves survival.

Hypertension with Comorbidities

• Diabetic nephropathy: ACEIs/ARBs prevent renal progression.
• CKD: reduce proteinuria.
• Stroke prevention: shown in HOPE and LIFE trials.

Combination Therapy?

• Dual blockade (ACEI + ARB) once thought promising.
• ONTARGET trial: no added benefit, but increased risk of adverse effects (hyperkalemia, renal dysfunction).
• Current consensus: avoid combination in most cases.

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Limitations and Challenges

• Cough and angioedema limit ACEI use.
• Renal dysfunction and hyperkalemia require close monitoring.
• Residual risk: Despite therapy, many patients progress to HF or recurrent MI → need for newer therapies like ARNIs and SGLT2 inhibitors.

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Future Perspectives

• ARNIs (Sacubitril/Valsartan): Combining neprilysin inhibition with ARB provides superior outcomes compared to ACEIs alone (PARADIGM-HF trial).
• Precision Medicine: Genetic profiling may help predict ACEI/ARB response.
• Combination with SGLT2 Inhibitors: Emerging standard in HF and diabetic patients.