Wild-Type Transthyretin Cardiac Amyloidosis Is Associated with Increased Antecedent Physical Activity

Excerpt

Cardiac amyloidosis is characterized by deposition of misfolded proteins, such as immunoglobulin light chains (AL) or transthyretin (ATTR). Transthyretin circulates in the blood as a homotetramer. Misfolded TTR infiltrates the heart, causing heart failure. ATTR is subdivided into hereditary (ATTRv) and wild-type (ATTRwt) forms. An autopsy series of patients with HFpEF without known cardiac amyloidosis reported that 5% had moderate or severe ATTRwt deposits in the heart, while 12% had mild ATTR deposition [1]. Pathogenic variants destabilize the TTR tetramer, either thermodynamically or kinetically, causing misfolding, aggregation, and fibril formation. However, little is known about the pathogenesis of ATTRwt. ATTRwt occurs predominantly in men who are in their seventh decade or older. Fibrillogenesis in ATTR includes amyloidogenic TTR cleavage fragments arising from biomechanical forces combined with specific proteolytic cleavage enzymes, including plasmin which is increased in response to exercise [2]. People with cardiac amyloidosis have lower BMI than those with heart failure and without amyloid [3]. Intensive physical activity (PA) lowers BMI and increases oxidative stress, which may contribute to TTR destabilization. We designed a pilot study to explore whether a history of increased PA is associated with ATTRwt. …