What is the differential diagnosis for a 41-year-old male with chest pain and dyspnea, who has a normal electrocardiogram (ECG) and stress test results, slightly elevated Hemoglobin A1c (HbA1c), and recent laboratory results showing normal alkaline phosphatase (ALK Phos), cholesterol (CHOL), high-density lipoprotein (HDL), triglycerides (Trig), low-density lipoprotein (LDL), C-reactive protein (CRP), and complete blood count (CBC) with a red blood cell (RBC) count, hemoglobin (Hgb), and hematocrit (Hct) within normal limits?

Differential Diagnosis for 41-Year-Old Male with Chest Pain, Dyspnea, and Elevated Hematocrit

The most critical finding in this patient is the significantly elevated hematocrit (52.0%) and hemoglobin (17.5 g/dL), which in combination with chest pain and dyspnea raises concern for polycythemia-related coronary complications, despite the negative stress test. 1

Primary Differential Diagnoses

1. Polycythemia Vera with Coronary Microvascular Dysfunction

• The elevated RBC count (6.07), hemoglobin (17.5), and hematocrit (52.0) are consistent with polycythemia, which creates a hypercoagulable state that can cause recurrent minor thrombotic coronary events even in the absence of obstructive coronary disease. 1
• The combination of chest pain, dyspnea, and polycythemia can lead to symptomatic coronary events through hemoconcentration and increased blood viscosity, particularly during physical exertion. 1
• Critical pitfall: A negative stress test does not exclude coronary microvascular dysfunction or vasospasm in polycythemia patients. 1
• The low HDL (38 mg/dL) further increases cardiovascular risk despite normal LDL. 2

2. Coronary Artery Vasospasm (Prinzmetal's Angina)

• Dyspnea during stress testing without ST-segment changes, combined with rare premature ventricular contractions, can indicate coronary vasospasm rather than fixed obstructive disease. 1
• Vasospasm can occur in patients with polycythemia due to increased vascular reactivity and is aggravated by physical stress. 1
• The normal resting ECG and absence of ST-segment deviation during stress do not exclude vasospastic angina, which typically occurs at rest or with variable exertion. 2

3. Coronary Microvascular Disease (Cardiac Syndrome X)

• Dyspnea as the presenting symptom carries significant prognostic importance and may indicate myocardial ischemia even with normal epicardial coronary arteries. 3
• Patients with dyspnea have four times the risk of sudden cardiac death compared to asymptomatic patients, even without obstructive coronary disease. 3
• The below-predicted exercise capacity (Peak METs 10.3 vs. Predicted 11.7) and dyspnea limiting the test suggest impaired myocardial oxygen delivery at the microvascular level. 2

4. Early Heart Failure with Preserved Ejection Fraction (HFpEF)

• The combination of dyspnea, fatigue, and below-predicted exercise capacity with normal ECG and stress test is consistent with early cardiovascular disease. 2
• The low HDL (38 mg/dL) and borderline HbA1c (5.7%) represent metabolic risk factors for diastolic dysfunction. 2
• Dyspnea preceding chest pain can indicate intermittent left ventricular failure coincident with myocardial ischemia. 4

5. Pulmonary Embolism (Must Be Excluded)

• Dyspnea and chest pain are present in >90% of pulmonary embolism cases, and polycythemia is a hypercoagulable state that increases PE risk. 2
• The rare premature ventricular contractions and dyspnea limiting exercise could represent right ventricular strain from chronic thromboembolic disease. 2
• Critical action: D-dimer and CT pulmonary angiography should be obtained if clinical suspicion exists, as silent recurrent PE can present as dyspnea and chronic right heart failure. 2

Recommended Diagnostic Algorithm

Immediate Next Steps:

1. Order JAK2-V617F mutation testing to evaluate for polycythemia vera, given the elevated hemoglobin (17.5), hematocrit (52.0), and RBC count (6.07). 1
2. Obtain coronary CT angiography (CCTA) to exclude non-obstructive coronary disease, plaque burden, and anatomic abnormalities not detected by stress testing. 2
3. Measure D-dimer and consider CT pulmonary angiography if elevated, given the hypercoagulable state and dyspnea. 2

Secondary Evaluation:

1. Perform transthoracic echocardiography to assess for diastolic dysfunction, valvular disease, and right ventricular function. 2
2. Consider cardiac MRI with stress perfusion imaging if CCTA shows intermediate stenosis (40-90%) or if microvascular disease is suspected. 2
3. Measure fasting lipid panel with apolipoprotein B, given the low HDL (38 mg/dL) which increases cardiovascular risk despite normal LDL. 2

If Polycythemia Confirmed:

1. Initiate antiplatelet therapy (aspirin 81-325 mg daily), statin therapy (atorvastatin), and consider phlebotomy to reduce hematocrit <45% to decrease thrombotic risk. 1
2. Add calcium channel blocker (amlodipine) for vasospasm prevention if coronary vasospasm is suspected. 1

Critical Red Flags Requiring Urgent Action

• Development of syncope, severe dyspnea at rest, or chest pain interrupting normal activity requires immediate emergency department evaluation. 2, 5
• Associated cold sweats, nausea, vomiting, or lightheadedness indicate possible acute coronary syndrome despite negative stress test. 2, 5
• Worsening dyspnea or new-onset orthopnea may indicate progression to heart failure or recurrent pulmonary embolism. 2

Key Clinical Pitfalls to Avoid

• Do not dismiss cardiac causes based solely on a negative stress test in a patient with polycythemia, as microvascular dysfunction and vasospasm are not reliably detected by standard stress testing. 1
• Do not attribute dyspnea to deconditioning in a patient with metabolic risk factors (low HDL, borderline HbA1c) and below-predicted exercise capacity, as dyspnea is an independent predictor of cardiac death. 3
• Do not overlook the prognostic significance of dyspnea—patients with dyspnea have more than twice the cardiac death risk compared to those with typical angina. 3