What is the best course of action for a 36-year-old patient with a history of fen-phen (phentermine and fenfluramine) use, presenting with increasing shortness of breath and fatigue, a grade 2/6 systolic murmur, and a history of a walking exercise program for weight loss?

Immediate Echocardiographic Evaluation is Mandatory

This patient requires urgent transthoracic echocardiography to assess for valvular heart disease and pulmonary hypertension given the history of fen-phen exposure, even if discontinued years ago, combined with new cardiopulmonary symptoms and a cardiac murmur. 1, 2

Clinical Context and Risk Assessment

This presentation is highly concerning for fenfluramine-associated valvulopathy, which can manifest years after drug discontinuation:

• The combination of fen-phen was directly associated with valvular heart disease and pulmonary hypertension, with the first reports published in 1997 showing unusual valvular morphology affecting both right-sided and left-sided heart valves 2
• Fenfluramine (not phentermine) was the causative agent through its metabolites directly activating serotonin receptors (5-hydroxytryptamine type 2B) in cardiac tissue, causing plaque-like encasement of valve leaflets and chordal structures 1, 3
• The patient's progressive dyspnea, fatigue, and new systolic murmur at the apex strongly suggest mitral regurgitation, which occurred in fenfluramine-exposed patients 2, 4

Immediate Diagnostic Workup

Order the following tests urgently:

• Transthoracic echocardiography with Doppler to assess:

  • Mitral and aortic valve morphology and regurgitation severity 2, 4
  • Tricuspid and pulmonic valve function 2
  • Right ventricular size and function 5
  • Estimated pulmonary artery systolic pressure 5, 2
  • Left ventricular ejection fraction 4

• ECG to evaluate for right ventricular strain or arrhythmias 5

• Chest X-ray to assess cardiac silhouette and pulmonary vasculature 5

• BNP or NT-proBNP if heart failure is suspected based on clinical presentation 1

Evidence Supporting This Approach

The landmark 1997 New England Journal of Medicine case series identified 24 women with valvular heart disease after fen-phen exposure, with echocardiography demonstrating unusual valvular morphology and regurgitation in all patients, and 8 also had newly documented pulmonary hypertension 2. A subsequent controlled study of 1,473 subjects found significantly increased prevalence of aortic regurgitation in fen-phen treated patients (13.7%) compared to untreated controls (4.1%), with relative risk of 3.34 4.

Critical autopsy findings from a 36-year-old woman who received fen-phen for 7 months and developed pulmonary hypertension (PA pressure 56 mmHg) showed right ventricular dilatation with fibroproliferative tricuspid valve and severe fibroproliferative plaque in pulmonary arteries 5. This demonstrates the serious morbidity and mortality risk.

If Echocardiography Confirms Valvular Disease

Refer immediately to cardiology for:

• Determination of regurgitation severity and hemodynamic significance 2
• Assessment for surgical intervention if severe regurgitation or heart failure is present (5 of 24 patients in the original series required cardiac surgery) 2
• Evaluation for pulmonary hypertension with possible right heart catheterization 5, 2
• Endocarditis prophylaxis recommendations 6
• Serial echocardiographic monitoring every 6-12 months, as valvular disease may stabilize or progress slowly after drug discontinuation 6

If Echocardiography is Normal

Still refer to cardiology because:

• The systolic murmur requires explanation 2
• Cardiopulmonary exercise testing may be warranted to evaluate for exercise-induced pulmonary hypertension or other causes of dyspnea and fatigue 1
• Alternative diagnoses such as cardiomyopathy, coronary disease, or primary pulmonary hypertension must be excluded 1

Common Pitfalls to Avoid

• Do not dismiss the fen-phen history because it was "many years ago" - valvular disease can persist or progress after drug discontinuation, and patients require long-term monitoring 6, 2
• Do not attribute symptoms solely to deconditioning or obesity without cardiac evaluation - this patient has a known cardiotoxic drug exposure and objective findings (murmur) 2
• Do not confuse phentermine monotherapy safety with fen-phen combination safety - phentermine alone has not been associated with valvular disease; fenfluramine was the culprit 1, 3
• Do not delay echocardiography - early detection allows for appropriate monitoring and timely surgical intervention if needed 2