What is the appropriate management for a patient presenting with pre-systolic accentuation, potentially indicative of hypertrophic cardiomyopathy?

Pre-Systolic Accentuation in Hypertrophic Cardiomyopathy

Pre-systolic accentuation (a prominent fourth heart sound/S4) in the context of hypertrophic cardiomyopathy reflects severe diastolic dysfunction with increased reliance on atrial contraction for ventricular filling, and management should focus on optimizing diastolic function with non-vasodilating beta-blockers as first-line therapy, titrated to maximum tolerated dose. 1

Understanding the Pathophysiology

Pre-systolic accentuation manifests as a prominent S4 gallop, which occurs when:

• Impaired ventricular myocardial relaxation creates greater dependency on atrial systole for ventricular filling, making the atrial contribution audible as a fourth heart sound 1
• Altered ventricular load with high intracavitary pressures, impaired LV compliance from hypertrophy and fibrosis, altered energetics, microvascular ischemia, and delayed inactivation from abnormal intracellular calcium reuptake all contribute to this diastolic dysfunction 1
• Increased stiffness and severe hypertrophy significantly compromise ventricular cavity size and stroke volume, potentially resulting in restrictive physiology 1

This finding is particularly important because diastolic dysfunction can contribute to decreased exercise capacity and adverse prognosis independent of left ventricular outflow tract obstruction 1

Initial Diagnostic Evaluation

Perform transthoracic echocardiography to confirm HCM diagnosis, assess the degree of myocardial hypertrophy, evaluate for dynamic LVOTO, assess mitral regurgitation, and comprehensively evaluate diastolic function 1

The echocardiographic assessment should include:

• Doppler myocardial imaging, pulmonary vein flow velocities, pulmonary artery systolic pressure, and left atrial size to comprehensively evaluate diastolic function 1
• Assessment for restrictive LV filling pattern (E/A ratio ≥2; E-wave deceleration time ≤150 ms), which may indicate higher risk for adverse outcome even with preserved ejection fraction 1
• Provocative maneuvers (standing, Valsalva strain, or exercise) if resting peak LVOT gradient is <50 mm Hg, as gradients vary with heart rate, blood pressure, volume status, and activity 1

Examine for the classic physical examination findings: harsh crescendo-decrescendo systolic murmur, prominent apical point of maximal impulse, abnormal carotid pulse, and the fourth heart sound itself 1

First-Line Medical Management

Initiate non-vasodilating beta-blockers (metoprolol or propranolol) titrated to maximum tolerated dose 2, 3, 4

This approach is prioritized because:

• Beta-blockers reduce symptoms and suppress ventricular ectopy in HCM patients 2
• They improve diastolic filling by prolonging diastole and reducing heart rate, which is particularly beneficial when atrial contribution is critical 5
• Non-vasodilating agents avoid worsening outflow tract obstruction 2

If beta-blockers are contraindicated or not tolerated, use non-dihydropyridine calcium channel blockers (verapamil 240-480 mg/day or diltiazem) 2, 3, 4

• Verapamil predominantly improves diastolic filling characteristics and has demonstrated objective improvement in HCM patients 5
• In a long-term study of 61 HCM patients treated with verapamil (average dose 530 mg/day), 85% achieved subjective improvement with significant reduction in heart volume, QRS amplitude, and left atrial diameter 5
• The annual mortality rate was only 1.3% over 256 patient-treatment-years, considerably lower than reported for patients receiving no treatment or beta-blockade 5

Critical Safety Considerations

Avoid verapamil in patients with severe left ventricular dysfunction (ejection fraction <30%) or moderate to severe symptoms of cardiac failure 6

In patients with severe left ventricular outflow obstruction and past history of left ventricular dysfunction, verapamil carries risk of pulmonary edema and severe hypotension 6

• In a study of 120 HCM patients, three died in pulmonary edema—all had severe LVOT obstruction and past history of LV dysfunction 6
• Eight other patients developed pulmonary edema and/or severe hypotension, with abnormally high pulmonary wedge pressure (>20 mmHg) and marked LVOT obstruction 6

Use diuretics cautiously, as excessive preload reduction can cause symptomatic hypotension in HCM patients 2, 4

Vasodilators should be avoided entirely, as they worsen outflow tract obstruction 2

Management of Poor Atrial Fibrillation Tolerance

Recognize that patients with prominent S4 and diastolic dysfunction have poor tolerance of atrial fibrillation due to greater dependency on atrial systole for ventricular filling 1

Prompt restoration of sinus rhythm or appropriate rate control is essential in patients with new-onset or poorly controlled atrial fibrillation 3, 4

Advanced Therapy Considerations

If beta-blockers alone are ineffective and LVOT gradient ≥50 mm Hg persists with refractory symptoms, add disopyramide to beta-blocker therapy 4

For patients with LVOT gradient ≥50 mm Hg and symptoms refractory to maximum medical therapy, consider septal reduction therapy (surgical myectomy or alcohol septal ablation) 4

• Extended septal myectomy via transaortic approach is the standard surgical procedure 3, 4
• Intraoperative transesophageal echocardiogram is mandatory to assess mitral valve anatomy and adequacy of septal myectomy 1

Determining if Diastolic Dysfunction is the Primary Problem

If exercise intolerance or symptoms persist despite optimal medical management and absence of significant LVOTO, invasive testing may be required to determine if diastolic dysfunction is the primary cause 1

Follow-up transthoracic echocardiography every 1-2 years is recommended in patients with no change in clinical status, but repeat immediately if clinical status changes 1