What is the most likely cause of symptoms in a patient with hypertension, fatigue, shortness of breath, and bilateral ankle edema, with an S4 gallop on cardiac exam?

Heart Failure with Preserved Ejection Fraction (HFpEF)

The most likely cause of this patient's symptoms is heart failure with preserved ejection fraction (HFpEF), given the constellation of chronic dyspnea, fatigue, bilateral ankle edema, elevated jugular venous pressure, S4 gallop, and multiple risk factors including hypertension, obesity, and rheumatoid arthritis. 1

Clinical Reasoning

This patient meets the Universal Definition of Heart Failure based on classic symptoms (dyspnea, fatigue) and signs (elevated JVP, bilateral ankle edema, S4 gallop) caused by structural/functional cardiac abnormalities. 1 The S4 gallop specifically indicates impaired ventricular compliance and diastolic dysfunction, which is the hallmark of HFpEF. 2

Why HFpEF is Most Likely:

Major Criteria Present:

• Elevated jugular venous pressure (objective sign of congestion) 1
• Bilateral ankle edema (systemic congestion) 1
• S4 gallop (indicates diastolic dysfunction) 2

Minor Criteria Present:

• Dyspnea on exertion 1
• Fatigue 1
• Ankle edema 1

Risk Factor Profile Strongly Supports HFpEF:

• Hypertension (most important risk factor for HFpEF) 3, 2
• Obesity (BMI elevated, highly prevalent in HFpEF) 1, 3
• Female sex (HFpEF more common in women) 3, 2
• Rheumatoid arthritis (chronic inflammatory condition associated with HFpEF) 1
• Methotrexate use (can contribute to cardiac dysfunction) 1

Why Other Diagnoses Are Less Likely:

Interstitial Lung Disease (Option A):

• Would present with dry cough, crackles on pulmonary exam, and hypoxemia 1
• This patient has normal pulmonary exam and normal oxygen saturation 1
• No history of wheezing, cough, or phlegm 1

Pulmonary Embolism (Option B):

• Typically presents acutely, not with 6 months of progressive symptoms 1
• Would not explain chronic bilateral ankle edema or elevated JVP 1
• The unilateral leg asymmetry (right > left by measurement) raises concern for chronic venous insufficiency, not acute PE 4

Obesity Hypoventilation Syndrome (Option D):

• Would present with daytime hypercapnia, hypoxemia, and sleep-disordered breathing 1
• This patient has normal oxygen saturation (adequate) 1
• Does not explain elevated JVP or S4 gallop 1

Diagnostic Confirmation Needed

Essential Next Steps:

• Echocardiogram to assess ejection fraction (expect ≥50%), left ventricular wall thickness, diastolic function parameters (E/e' ratio), and estimated pulmonary artery pressures 1
• BNP or NT-proBNP measurement (expect elevation >35 pg/mL for BNP or >125 pg/mL for NT-proBNP in ambulatory setting, though levels may be lower in HFpEF compared to HFrEF, especially with obesity) 1, 3
• H2FPEF score calculation incorporating age, hypertension, obesity, atrial fibrillation status, and echocardiographic parameters (score >5 indicates >95% probability of HFpEF) 3

Critical Pitfalls to Avoid

Do not dismiss HFpEF based on:

• Normal pulmonary exam (65% of HFpEF patients present with overt congestion, but 35% have "unexplained" dyspnea without clear physical signs at rest) 3
• Lower natriuretic peptide levels compared to HFrEF (obesity suppresses BNP levels) 1
• Absence of orthopnea or paroxysmal nocturnal dyspnea (not required for diagnosis) 1, 2

Consider HFpEF mimics requiring specific workup:

• The parasternal lift suggests possible right ventricular involvement or pulmonary hypertension, which warrants echocardiographic assessment 1
• Rheumatoid arthritis raises consideration for infiltrative cardiomyopathy or pericardial disease, though less likely given the clinical presentation 1

Management Implications

Once HFpEF is confirmed:

• First-line pharmacologic therapy: SGLT2 inhibitors (dapagliflozin or empagliflozin) reduce HF hospitalization and cardiovascular death by approximately 20% 3
• Diuretics: Loop diuretics (furosemide or torsemide) for symptomatic relief of congestion 4, 3, 2
• Optimize blood pressure control: Continue lisinopril and amlodipine, targeting SBP <130 mmHg 5, 6
• Lifestyle modifications: Exercise training, dietary sodium restriction, and weight loss produce clinically meaningful improvements in functional capacity and quality of life 3
• Heart failure self-care education: Adherence to medications, daily weight monitoring, dietary restrictions 3

The soft parasternal lift and elevated JVP suggest right-sided involvement, making aggressive decongestion with diuretics particularly important while monitoring renal function and electrolytes closely. 4, 7