Most Prevalent Causes of Low Ejection Fraction
The most common causes of reduced left ventricular ejection fraction (LVEF <40%) are ischemic heart disease (coronary artery disease), hypertension, and dilated cardiomyopathy 1, 2. These three etiologies account for the substantial majority of heart failure with reduced ejection fraction (HFrEF) cases in Western populations 3.
Primary Etiologies
1. Ischemic Cardiomyopathy (Most Common)
Coronary artery disease represents the leading cause of reduced LVEF, particularly in men 4. The myocardial injury from acute or chronic ischemia leads to progressive ventricular remodeling and systolic dysfunction 1. Ischemic heart disease, peripheral arterial disease, and ventricular arrhythmias are strongly associated with presenting LVEF <40% 5.
2. Hypertension
Chronic hypertension is a major risk factor for both HFrEF and HFpEF 6. In women specifically, hypertensive heart disease is more likely than ischemic causes to lead to reduced ejection fraction 4. The pathophysiology involves inadequate hypertrophic response to pressure overload, leading to increased wall stress and declining ejection fraction 7.
3. Dilated Cardiomyopathy
Non-ischemic dilated cardiomyopathy accounts for a substantial proportion of HFrEF cases, with up to 30% having a genetic cause 3. This category encompasses idiopathic dilated cardiomyopathy and various secondary causes 1.
Important Secondary Causes
Valvular Heart Disease
Valvular disease remains a common cause of reduced LVEF 3:
- Aortic stenosis: When the hypertrophic response is inadequate, wall stress increases and afterload causes decreased ejection fraction 7. LVEF deterioration accelerates once aortic valve area reaches 1.2 cm² 8
- Mitral regurgitation: Chronic severe MR leads to LV dilation and eventual systolic dysfunction 9
- Aortic regurgitation: Progressive volume overload exhausts preload reserve, leading to reduced LVEF 7
Cardiotoxic Agents
Chemotherapy-induced cardiomyopathy has significant incidence rates 4:
- Anthracyclines (doxorubicin): 7-26% at 550 mg/m²
- Trastuzumab: 1.7-20.1%
- Tyrosine kinase inhibitors: 2.7-19%
- Cyclophosphamide: 7-28%
- Immune checkpoint inhibitors (increasingly recognized) 4
Tachycardia-Induced Cardiomyopathy
Persistently elevated ventricular rates ≥130 bpm during atrial fibrillation can produce dilated cardiomyopathy 10. This is critically important to recognize because rate control can reverse the process, with median LVEF increasing from 25% to 52% 10.
Demographic Considerations
Black and Hispanic patients are more likely to present with reduced LVEF compared to White patients 5. Women more commonly develop HF from hypertensive or valvular disease, while men more often have ischemic cardiomyopathy 4. Younger patients are more likely to present with LVEF <40% compared to older patients who more commonly have preserved ejection fraction 5.
Clinical Algorithm for Evaluation
When evaluating reduced LVEF, systematically assess:
- Ischemic vs. non-ischemic: History of coronary disease, risk factors, regional wall motion abnormalities
- Valvular disease: Murmurs, echocardiographic valve assessment
- Hypertension: Blood pressure history, LV hypertrophy patterns
- Tachycardia: Heart rate control, presence of atrial fibrillation
- Toxic exposures: Chemotherapy, alcohol, cocaine
- Genetic/familial: Family history of cardiomyopathy
Critical Pitfalls
Do not assume LVEF <50% is normal: In healthy adults, fewer than 1% of women and approximately 1% of men have LVEF below 50% 11. An LVEF <50% has less than 5% probability of being within normal range across all demographic groups 11.
Recognize reversible causes: Tachycardia-induced cardiomyopathy, severe aortic stenosis with excessive afterload, and acute ischemia may show significant LVEF improvement with appropriate intervention 10, 7.
Consider timing in valvular disease: In aortic stenosis, LVEF decline begins before stenosis becomes severe and accelerates after valve area reaches 1.2 cm² 8. LVEF <60% in moderate AS predicts further deterioration 8.