What is the role of nitrates (e.g. isosorbide dinitrate) in the management of hypertrophic cardiomyopathy?

Nitrates in Hypertrophic Cardiomyopathy

Nitrates are contraindicated in hypertrophic cardiomyopathy (HCM) due to their potential to worsen left ventricular outflow tract obstruction (LVOTO) and cause clinical deterioration. 1

Mechanism and Risks

Nitrates are potent venodilators that reduce preload through venous pooling. In HCM, especially with obstructive physiology, this mechanism can be detrimental:

• Decreased preload leads to reduced ventricular volume
• Smaller ventricular cavity exacerbates systolic anterior motion of the mitral valve
• LVOTO worsens, potentially causing:
  • Increased pressure gradient
  • Worsened symptoms
  • Hemodynamic compromise

The 2024 ESC Guidelines explicitly state that "nitrates are not recommended in patients with hypertrophic cardiomyopathy" 1, placing this recommendation in their Class III (contraindicated) category.

Management Alternatives for HCM

Instead of nitrates, the following medications are recommended for symptom management in HCM:

1. First-line therapy:

   • Beta-blockers (non-vasodilating) 2
   • Target heart rate: 50-60 beats per minute
   • Mechanism: Reduce early LV ejection acceleration and systolic pushing force on mitral leaflet

2. Second-line therapy (if beta-blockers are ineffective or not tolerated):

   • Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) 2
   • Particularly effective for chest pain and improving exercise capacity
   • Caution: Potentially harmful in patients with severe dyspnea at rest, hypotension, or very high resting gradients (>100 mmHg)

3. Additional options for persistent symptoms:

   • Disopyramide (in combination with beta-blockers or calcium channel blockers) 2
   • Requires QTc interval monitoring during dose titration
   • Myosin inhibitors for selected patients 2

Special Considerations

1. For angina in HCM without LVOTO:

   • The 2014 ESC guidelines suggest that "in the absence of LVOTO, cautious use of oral nitrates may be considered" 1
   • This is a Class IIb recommendation (may be considered), indicating lower certainty of benefit
   • Even in this scenario, beta-blockers and calcium channel blockers should be tried first

2. Diagnostic use of nitrates:

   • Paradoxically, sublingual isosorbide dinitrate can be used as a provocative test to detect latent LVOTO in HCM patients 3, 4
   • This is specifically a diagnostic application, not a therapeutic one
   • The test is performed under controlled conditions with careful monitoring

Potential Complications

The FDA label for isosorbide dinitrate specifically warns: "Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy" 5. Additional risks include:

• Severe hypotension, especially with upright posture
• Paradoxical bradycardia
• Increased angina pectoris
• Hemodynamic compromise in obstructive HCM

Conclusion

Beta-blockers and calcium channel blockers remain the cornerstone of pharmacological management for HCM symptoms, with nitrates generally contraindicated due to their potential to worsen LVOTO. For patients with persistent symptoms despite optimal medical therapy, referral for consideration of septal reduction therapy (surgical myectomy or alcohol septal ablation) may be appropriate 6.