The Anrep Effect: Mechanism and Clinical Management
The Anrep effect is a homeometric autoregulation mechanism of the heart that increases left ventricular contractility in response to acute afterload elevation, helping preserve stroke volume without changes in preload, and is clinically managed through appropriate vasodilator therapy while avoiding beta blockers when possible.
Mechanism of the Anrep Effect
The Anrep effect represents an intrinsic cardiac adaptation that occurs in response to sudden increases in afterload. This phenomenon has two distinct phases:
Initial Phase:
- Sudden increased afterload is momentarily equilibrated by enhanced left ventricular contractility
- Results from higher power strokes of strongly-bound myosin cross-bridges 1
Secondary Phase:
- Delayed recovery of stroke volume
- Dependent on Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activation
- Involves oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2)
- Maximizes recruitment of available strongly-bound myosin cross-bridges 1
Recent research has identified that CaMKII activation through S-nitrosylation at the Cys290 site is essential for mediating this intrinsic afterload-induced enhancement of myocyte sarcoplasmic reticulum Ca²⁺ uptake, release, and Ca²⁺ transient amplitude 2.
Clinical Significance
The Anrep effect is physiologically important because:
- It helps maintain cardiac output when facing increased afterload
- Preserves stroke volume at constant preload
- Provides an intrinsic compensatory mechanism for acute pressure changes
- May be dysregulated in pathological states like hypertrophic cardiomyopathy 3
Clinical Management Approach
1. Pharmacological Management
Vasodilator Therapy:
- Vasodilators are recommended for patients with increased afterload conditions, particularly in hypertensive patients 4
- Agents that do not slow heart rate are preferred in conditions where the Anrep effect is activated 4
Avoid Beta Blockers:
- Beta blockers may worsen the situation by increasing diastolic filling period 4
- Beta blockers should be avoided as first-line agents except in specific situations like aortic root disease 4
2. Blood Pressure Management
- For patients with hypertension (a common cause of increased afterload):
3. Combination Therapy
For patients with resistant hypertension or severe afterload conditions:
- Combination of a renin-angiotensin system blocker, calcium antagonist, and diuretic at effective doses is recommended 5
- Fixed-dose combinations can simplify treatment and improve patient compliance 5
4. Special Considerations
Heart Failure:
- In heart failure with preserved ejection fraction (HFpEF), where the Anrep effect may be impaired:
Aortic Insufficiency:
- In patients with aortic insufficiency, where afterload mismatch is common:
- Vasodilator therapy is recommended for hypertensive patients
- Agents that do not slow heart rate are preferred 4
Monitoring and Follow-up
- Regular assessment of blood pressure control
- Echocardiographic evaluation to assess ventricular function and adaptation
- Monitoring for signs of heart failure or maladaptive cardiac remodeling
Potential Complications
- Persistent activation of the Anrep effect may contribute to pathological cardiac hypertrophy
- In hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect 3
Conclusion
Understanding the Anrep effect provides important insights into cardiac adaptation to increased afterload. Clinical management focuses on appropriate vasodilator therapy while avoiding agents that may interfere with this compensatory mechanism. Proper blood pressure control and tailored pharmacological therapy are essential for managing conditions where the Anrep effect is activated.