The pathophysiology of wild-type transthyretin amyloidosis: implications for exercise intolerance

Wild-type transthyretin amyloidosis (ATTRwt) is an age-associated protein misfolding disorder marked by extracellular deposition of transthyretin fibrils within the myocardium, peripheral nerves, lungs, blood vessels, and musculoskeletal tissues. ATTRwt typically presents as a restrictive cardiomyopathy with preserved left ventricular ejection fraction that contributes to the development of hallmark symptoms such as exercise intolerance. Amyloid infiltration severely impairs ventricular compliance and diastolic reserve, limiting stroke volume and cardiac output augmentation during exercise, and is frequently accompanied by coronary microvascular dysfunction. These central limitations are compounded by autonomic dysfunction, including chronotropic incompetence and impaired sympathetic vasomotor control, which blunt heart rate responses and disrupt appropriate blood flow responses. Pulmonary hypertension, right ventricular-pulmonary artery uncoupling, and ventilatory inefficiency further constrain oxygen transport and contribute to exertional dyspnea and early fatigue. Other peripheral factors such as amyloid-related derangements in vascular endothelial function and musculoskeletal pathologies likely result in impaired hyperemic responses to exercise and accelerated cardiovascular deconditioning, further limiting physical capacity. Together, these integrated cardiac, pulmonary, autonomic, and peripheral abnormalities convergently impair exercise performance in ATTRwt. Considering the universal presentation of exercise intolerance in ATTRwt, therapies that may have favorable effects on physical capacity are of great interest to patients, physicians, and scientists alike. This review seeks to synthesize current evidence describing the central and peripheral pathophysiological mechanisms underlying exercise intolerance in ATTRwt and discuss the potential of pharmacologic and exercise-based interventions that may improve physical capacity in this population.