What is the recommended evaluation and management approach for a patient presenting with exertional shortness of breath, including history, physical examination, initial investigations, and treatment of cardiac, pulmonary, hematologic, and deconditioning causes?

Approach to Exertional Shortness of Breath

Begin with BNP or NT-proBNP measurement as the single most important initial test when basic cardiac and pulmonary workup is unrevealing, as a BNP <100 pg/mL has 96-99% sensitivity for ruling out heart failure. 1

Initial History and Physical Examination

Key Historical Elements to Elicit:

• Duration and progression of symptoms (acute vs. chronic onset) 2
• Number of pillows required for sleep and presence of paroxysmal nocturnal dyspnea 3
• Recent weight gain, leg swelling, or abdominal distension 3
• Smoking history and occupational exposures 2
• Medication use, particularly beta-blockers which can mask cardiac limitation 2
• Level of physical activity and recent deconditioning 2

Critical Physical Examination Findings:

• Peripheral edema, elevated jugular venous pressure, and pulmonary rales suggesting heart failure 3
• Cardiac auscultation for murmurs, gallops, and arrhythmias 3
• Signs of obesity or skeletal deformities causing restrictive physiology 4
• Wheezing or prolonged expiratory phase suggesting airway disease 2

Initial Diagnostic Testing

First-Line Laboratory and Imaging:

• BNP or NT-proBNP: Order this first if initial workup is unrevealing; BNP ≥100 pg/mL warrants echocardiography 1
• Complete blood count: To identify anemia as a contributing factor 1
• Chest radiography: To evaluate for cardiomegaly, pulmonary edema, pleural effusions, or parenchymal disease 3
• Electrocardiogram: To detect arrhythmias, ischemic changes, or conduction abnormalities 3
• Spirometry with bronchodilator: To rule out obstructive or restrictive lung disease 4

Algorithmic Approach Based on Initial Results

If BNP is Elevated (≥100 pg/mL):

• Proceed to echocardiography to assess for heart failure with preserved ejection fraction (HFpEF), systolic dysfunction, valvular disease, pulmonary hypertension, or pericardial disease 1
• Critical pitfall: A negative cardiac stress test does NOT exclude HFpEF, which is particularly common in middle-aged women and presents with normal systolic function but diastolic dysfunction 1
• Refer to cardiology if echocardiography reveals valvular disease requiring intervention or confirmed HFpEF 1

If BNP is Normal (<100 pg/mL) and Spirometry is Normal:

• Consider cardiopulmonary exercise testing (CPET) to distinguish between cardiac limitation, pulmonary limitation, deconditioning, or exercise-induced bronchoconstriction 1, 4
• CPET is the gold standard for identifying the cause of dyspnea when resting tests are inconclusive 5

Cardiopulmonary Exercise Testing Interpretation

CPET Patterns and Their Diagnostic Implications:

Low Peak VO₂ with Normal Peak Heart Rate:

• Suggests early/mild cardiovascular disease, pulmonary vascular disease, deconditioning, obesity, anemia, or mitochondrial myopathy 2
• Distinguishing features:
  • Low anaerobic threshold (AT) and low O₂ pulse favor cardiac disease over deconditioning 2
  • Abnormal VE/VCO₂, increased dead space (VD/VT), and desaturation suggest pulmonary vascular disease 2
  • Normal VE/MVV ratio helps exclude ventilatory limitation 2

Low Peak VO₂ with Low Peak Heart Rate:

• Indicates chronotropic dysfunction, beta-blocker use, coronary artery disease, poor effort, or peripheral factors (musculoskeletal, neuromuscular) 2

Normal Peak VO₂ with Symptoms:

• Consider dysfunctional breathing patterns, hyperventilation, or psychogenic dyspnea 6
• May require continuous laryngoscopy during exercise to diagnose paradoxical vocal fold motion disorder 6

Exercise-Induced Bronchoconstriction Evaluation

If spirometry is normal but symptoms suggest airway disease:

• Perform exercise challenge testing using treadmill or cycle ergometry, as indirect challenges are more sensitive than methacholine for diagnosing exercise-induced bronchoconstriction 4
• Patient must achieve and sustain heart rate ≥85% of maximum for 6 minutes 4
• Measure spirometry at baseline, immediately post-exercise, and at 5,10, and 15 minutes to detect delayed bronchoconstriction 4
• Critical pitfall: Exercise-induced bronchoconstriction may not be detected on resting pulmonary function tests 1

Differential Diagnosis by System

Cardiac Causes:

• Heart failure with preserved ejection fraction (HFpEF) 1
• Coronary artery disease (may present with dyspnea without angina) 2
• Valvular disease (mitral or aortic stenosis/regurgitation) 2
• Pulmonary hypertension 2
• Cardiac dysrhythmias including supraventricular tachycardia 2
• Hypertrophic cardiomyopathy 2

Pulmonary Causes:

• Exercise-induced bronchoconstriction (most common pathologic cause in young adults) 4
• Early COPD with ventilatory inefficiency and increased dead space ventilation 7
• Interstitial lung disease (may require CT chest for diagnosis) 1
• Pulmonary vascular disease 2
• Exercise-induced laryngeal dysfunction (inspiratory stridor during exercise) 4

Hematologic Causes:

• Anemia reducing oxygen-carrying capacity 1

Deconditioning and Other Causes:

• Physical deconditioning (common cause with normal resting cardiac and pulmonary function) 1
• Obesity causing increased oxygen cost of breathing 1
• Gastroesophageal reflux disease (exercise-onset GERD can mimic asthma) 2
• Mitochondrial myopathy (rare, presents with hyperdynamic hyperventilatory pattern) 2

Common Pitfalls to Avoid

• Do not assume a negative stress test excludes all cardiac causes—it primarily rules out obstructive coronary disease but not HFpEF, valvular disease, or pulmonary hypertension 1
• Do not diagnose based on self-reported symptoms alone—objective testing with bronchoprovocation or CPET is required for accurate diagnosis 4
• Do not initiate therapeutic trials without establishing a diagnosis—this leads to unnecessary medication use and missed alternative diagnoses 4
• Do not delay evaluation of unexplained dyspnea—it is associated with increased all-cause mortality and may represent early manifestations of serious disease 1
• Do not assume orthopnea is always cardiac—COPD patients also develop orthopnea through different mechanisms 3

Specialist Referral Indications

• Cardiology referral: If echocardiography reveals valvular disease requiring intervention, confirmed HFpEF, or cardiac etiology remains suspected despite negative initial testing 1
• Pulmonology referral: For consideration of interstitial lung disease, pulmonary vascular disease, or if CPET suggests pulmonary limitation 1
• Right heart catheterization: May be required for definitive diagnosis of pulmonary hypertension, particularly when exercise-induced 8, 5