What are the potential causes of persistent shortness of breath with activity, requiring oxygen to maintain saturation, in a patient with a history of asthma and ejection fraction (EF) preserved heart failure?

Potential Causes of Exertional Desaturation in an 82-Year-Old Female with Asthma and HFpEF

In this patient with preserved oxygen saturation at rest but desaturation with activity, the most likely causes are decompensated HFpEF with exertional elevation of left atrial pressures, poorly controlled asthma, pulmonary hypertension secondary to HFpEF, or deconditioning from prolonged immobility. 1

Primary Differential Diagnoses

Cardiac Causes

• HFpEF exacerbation with exertional elevation of filling pressures: Approximately 35% of HFpEF patients present with "unexplained" dyspnea on exertion without overt congestion at rest, but develop elevated atrial pressures with exercise 2
• Pulmonary hypertension secondary to HFpEF: Postcapillary pulmonary hypertension from elevated left ventricular filling pressures is common in HFpEF and manifests primarily with exertional symptoms 3
• Valvular heart disease: Particularly aortic stenosis or mitral regurgitation that may worsen with increased cardiac output during activity 1
• Atrial fibrillation with inadequate rate control: Loss of atrial kick and rapid ventricular rates during exertion can precipitate symptoms 1
• Infiltrative cardiomyopathy: Consider cardiac amyloidosis, especially if there is increased LV wall thickness on echocardiography 1

Pulmonary Causes

• Asthma exacerbation or poor control: Exertional bronchoconstriction may not manifest at rest 1
• Pulmonary embolism: Should be considered in any patient with new or worsening dyspnea, though most minor PEs don't cause hypoxemia 1
• Pleural effusion: Common in HFpEF and may accumulate during rehabilitation 1
• Pneumonia or other acute pulmonary infection: May present subtly in elderly patients 1
• Interstitial lung disease or pulmonary fibrosis: Can coexist with HFpEF and cause exertional desaturation 1

Non-Cardiopulmonary Causes

• Severe deconditioning: Prolonged immobility and ICU stays lead to reaching physiological limits at low activity levels 4
• Severe anemia: Though most anemic patients don't require oxygen, severe anemia can contribute to exertional symptoms 1
• Chronic kidney disease: Can cause fluid overload and contribute to pulmonary congestion 1
• Obesity (if BMI >40): Severe obesity is a risk factor for hypercapnic respiratory failure and restrictive physiology 1
• Dysfunctional breathing pattern disorder: Functional alteration in breathing mechanics causing symptoms without organic pathology 4

Recommended Workup

Immediate Assessment

• Vital signs with orthostatic measurements: Measure respiratory rate, heart rate, blood pressure, and temperature; tachypnea and tachycardia are more sensitive than cyanosis for detecting hypoxemia 1
• Pulse oximetry at rest and with ambulation: Document oxygen saturation during 6-minute walk test or standardized activity 1
• Arterial blood gas: Essential to exclude hypercapnia and assess acid-base status, particularly in patients with potential respiratory failure 1

Laboratory Studies

• BNP or NT-proBNP: Elevated natriuretic peptides support HFpEF diagnosis and indicate cardiac congestion 3, 5, 2
• Complete blood count: Assess for anemia as a contributing factor 1
• Comprehensive metabolic panel: Evaluate renal function and electrolytes, particularly if on diuretics or considering MRA therapy 3
• Troponin: If acute coronary syndrome is suspected 1
• D-dimer: If pulmonary embolism is in the differential (age-adjusted cutoff) 1

Imaging Studies

• Chest radiograph: Evaluate for pneumonia, pleural effusion, pulmonary edema, or pneumothorax 1
• Echocardiography with Doppler: Assess for valvular disease, right ventricular function, estimated pulmonary artery systolic pressure (PASP), E/e' ratio, and signs of infiltrative disease 1, 3
• CT pulmonary angiography: If pulmonary embolism is suspected based on clinical probability 1

Functional Assessment

• Spirometry with bronchodilator response: Evaluate for asthma control and exclude COPD (if patient can perform test) 1
• Six-minute walk test with continuous oximetry: Quantify functional capacity and document desaturation pattern 4
• Cardiopulmonary exercise testing: Consider if diagnosis remains unclear; can differentiate cardiac vs. pulmonary vs. deconditioning causes 4, 2
• Doppler echocardiography stress testing: Can estimate left atrial pressures with exercise in patients with unexplained exertional dyspnea 2

Specialized Testing (If Indicated)

• Invasive hemodynamic assessment: Consider if HFpEF diagnosis uncertain or if pulmonary hypertension needs characterization (precapillary vs. postcapillary) 3, 2
• Cardiac MRI: If infiltrative cardiomyopathy (amyloidosis), hypertrophic cardiomyopathy, or pericardial disease suspected 1
• Monoclonal protein screen: If cardiac amyloidosis suspected (serum/urine immunofixation electrophoresis and serum free light chains) 1
• Technetium pyrophosphate scan: If transthyretin cardiac amyloidosis suspected 1

Critical Clinical Pearls

Common pitfalls to avoid: Do not assume shortness of breath is always due to HFpEF decompensation—consider pulmonary, renal, or other cardiac causes 6. The 2023 ACC guidelines emphasize that not all patients with dyspnea and preserved EF have HFpEF; systematic evaluation for noncardiac mimics (kidney disease, liver disease, chronic venous insufficiency) and cardiac mimics (infiltrative cardiomyopathy, valvular disease, pericardial disease) is essential 1.

Target oxygen saturation: Aim for 94-98% unless the patient has risk factors for hypercapnic respiratory failure (severe COPD, severe obesity with BMI >40, neuromuscular disease), in which case target 88-92% 1. Never discontinue oxygen therapy to obtain room air measurements in patients who clearly require supplemental oxygen 1.

H2FPEF score utility: In patients with unexplained dyspnea, the H2FPEF score (incorporating age, hypertension, obesity, atrial fibrillation, estimated PASP, and E/e' ratio) can assist diagnosis; scores >5 indicate >95% probability of HFpEF 2.