Introduction

Heart enlargement, medically referred to as cardiomegaly, is not a disease but a symptom of an underlying cardiac condition.¹ It is characterised by an increase in the size of the heart. This condition occurs when the heart muscle becomes enlarged, or the walls of the heart chambers thicken, often as a result of hypertension (high blood pressure), heart failure, or structural heart abnormalities. Over time, an enlarged heart loses efficiency, making it difficult to pump blood effectively, increasing the risk of heart failure, arrhythmias, and other complications.² 

This article compares the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)– the two drug classes that help to control heart enlargement caused by cardiomyopathies. Both target the renin-angiotensin-aldosterone (RAAS) system, but act differently and have unique effects on heart structure, side effects and outcomes. 

Mechanism of action

ACE inhibitors and ARBs are widely used for treating hypertension and related cardiovascular conditions. While both drug classes effectively lower blood pressure and reduce heart workload by targeting RAAS, their mode of action differs slightly.³ 

• ACE Inhibitors (captopril, enalapril and ramipril): These work by blocking the conversion of Angiotensin I to Angiotensin II, reducing vasoconstriction (narrowing of blood vessels) and decreasing aldosterone levels, thereby limiting sodium retention and cardiac remodelling.⁴ ACE inhibitors operate through various mechanisms and target multiple biological pathways, which modulate immune responses and inflammatory processes, which are significant in cardiovascular health. By influencing these pathways, ACE inhibitors help reduce inflammation, improve endothelial function, and limit cardiac remodelling (change in heart structure due to injury/illness). This enhances heart function and patient outcomes in individuals with heart failure and other cardiovascular conditions.⁵ ACE inhibitors, widely prescribed for hypertension and heart failure, can cause cough in 5-20% of patients and angioedema in 0.1-0.7%. Both side effects are believed to be primarily caused by bradykinin accumulation^{6 7}
• Angiotensin II Receptor Blockers (ARBs) (losartan, valsartan): Angiotensin receptor blockers (ARBs) are a class of medications that selectively block angiotensin II from binding to AT1 receptors, providing an alternative approach to inhibiting the renin-angiotensin system.⁸ Unlike ACE inhibitors, ARBs do not affect bradykinin breakdown, resulting in fewer side effects such as cough and angioedema (sudden swelling).⁹ This improved tolerability enhances patient compliance with long-term therapy

Effectiveness in treating heart enlargement

Effect on left ventricular hypertrophy (LVH)

• Several studies have shown that both ACE inhibitors and ARBs help reduce heart size by limiting ventricular hypertrophy (increase in the size of cells/tissues) and preventing further structural damage¹⁰ 
• ACE inhibitors are considered more effective in early-phase cardiac remodelling after a heart attack (myocardial infarction) or heart failure due to their reduction of heart muscle scarring (cardiac fibrosis)¹¹ 
• ARBs appeared to sensitise subjects to a hypertrophy response to Angiotensin II.¹² This was particularly noted when cardiac fibrosis is already advanced, as ACE inhibitors may be better at reducing matrix remodelling and accumulation of fibrosis (excess connective tissue)

Impact on heart failure with cardiomegaly

• In patients with heart failure and cardiomegaly, both drug classes help reduce cardiac remodelling and improve symptoms, however, ACE inhibitors offer a more significant mortality benefit
• Clinical trials such as SOLVD have shown that ACE inhibitors reduce all-cause mortality by 11% in patients with heart failure¹³ 
• In the VALIANT trial, ARBs were found to provide similar cardiovascular benefits without the robust mortality advantage, making them a second-line choice for heart failure patients who are unable to tolerate ACE inhibitors¹⁴ 

Side effects and patient tolerance

Common side effects of ACE inhibitors 

ACE inhibitors can cause several side effects, ranging from mild to severe.

Common side effects include:

• Persistent dry cough
• dizziness fatigue
• Headache
• Weakness

Less common side effects:

• Nausea
• Rashes 
• Taste disturbance, e.g. metallic taste. 

In rare cases, patients might develop jaundice (yellowing of skin or eyes ) due to liver dysfunction. It is therefore recommended to consult a physician /health care provider for any of these symptoms and monitor the signs that require urgent care. Severe reactions like angioedema– swelling of the face, lips or throat– require immediate medical attention as they can obstruct breathing.¹⁵ 

Common side effects of ARBs

Often prescribed as alternatives to ACE inhibitors, as they cause fewer side effects. The most common issue is dizziness, particularly when starting the treatment. In rare cases, ARBs may impair kidney function, especially in individuals with pre-existing renal artery disease, requiring regular blood tests. ARBs can also increase potassium levels, leading to hyperkalaemia, which may cause heart rhythm problems. Additionally, these medications are unsafe during pregnancy as they increase birth defects. Patients should avoid potassium supplements and consult doctors before combining ARBs with other medications.¹⁶ 

Patient adherence and long-term use

ACE inhibitors have shown side effects of angioedema (sudden swelling) and cough. Studies have shown that discontinuation of either ACE inhibitors or ARBs can lead to increased mortality compared to when not discontinued.¹⁷ Moreover, another study of hyperkalaemia related to discontinuation of ACE inhibitors/ARBs showed higher mortality rates. 

Clinical recommendations and guidelines

ACE inhibitors and ARBs are the main treatments for heart failure with reduced ejection fraction (HFrEF) (where the left ventricle does not eject enough blood), both reducing morbidity and mortality. However, ACE inhibitors have shown superior efficacy in lowering risks of myocardial infarction, cardiovascular death, and all-cause mortality, likely due to enhanced vasodilation (widening of blood vessels). In contrast, ARBs block AT1 but not AT2 receptors, which may have negative effects in certain conditions. As a result, guidelines recommend ACE inhibitors as first-line therapy, with ARBs reserved for patients who cannot tolerate ACE inhibitors. Combining ACE inhibitors with ARBs is generally avoided due to higher risks of hyperkalaemia and acute kidney injury, especially in diabetic kidney disease. 

Additional recommendations

Beta-blockers and mineralocorticoid receptor blockers (MRAs) can further reduce mortality when combined with ACE inhibitors or ARBs. MRAs block the hormone aldosterone, helping to eliminate excess salt and water. However, some patients may struggle with these combinations due to hypotension, hyperkalaemia, or kidney injury. MRAs are preferred with ACE inhibitors or ARBs for controlling proteinuria (elevated protein in urine, which may occur in kidney disease, hypotension and heart disease) and improving outcomes, though careful potassium monitoring is required. 

Direct renin inhibitors are not recommended with ACE inhibitors or ARBs due to increased risks without added benefit. 

Valsartan-sacubitril offers additional protection from mortality and hospitalisation, but cannot be used with ACE inhibitors due to the risk of angioedema. This regimen, when combined with MRAs and beta-blockers, offers the greatest reduction in mortality but carries increased risks of hypotension, hyperkalaemia, and kidney issues.¹⁸ 

Summary

ACE inhibitors and ARBs are both vital in managing cardiomegaly by limiting cardiac remodelling and reducing heart workload, with each class offering distinct advantages. ACE inhibitors are highly effective in preventing early cardiac fibrosis and improving survival rates in heart failure, but their side effects, such as dry cough and angioedema, can impact patient adherence. ARBs offer similar cardiovascular outcomes with fewer side effects, making them a preferred option for patients intolerant to ACE inhibitors. Ultimately, the choice between these therapies should be based on individual tolerance, comorbidities, and clinical guidelines to ensure optimal management and outcomes. Future research should continue exploring the long-term effects and potential combinations of these therapies, aiming to enhance patient outcomes and adherence.