Exercise And The Development Of Transthyretin Amyloid Cardiomyopathy - Is There An Association?

Abstract

Introduction Cardiac amyloidosis is an infiltrative heart disease that is associated with multi-organ dysfunction as a result of systemic misfolded protein deposition. Transthyretin (ATTR) amyloidosis is a type of amyloidosis that is increasingly being recognized as a cause of heart failure. Novel pharmacologic treatments for ATTR amyloid cardiomyopathy (ATTR-CM) have recently become available sparking a renewed interest in the pathophysiology of this disease. Other than certain genetic mutations, risk factors for the development of ATTR-CM are largely unknown. In the experience of our heart failure clinic, we have empirically observed that ATTR-CM patients frequently have a substantial history of vigorous athletic activity. We sought to identify a novel association between exercise and ATTR-CM. Hypothesis Cumulative lifetime strenuous physical activity is a novel risk factor for the development of ATTR-CM. Methods In this single-center observational study, we recruited adults diagnosed with ATTR-CM and control subjects diagnosed with heart failure from non-amyloid cause. 50 ATTR-CM subjects and 22 controls were administered an in-depth lifetime physical activity survey. The survey identified type and quantity of physical activity from age 20 years until present day. Cumulative lifetime strenuous physical activity was quantified in metabolic equivalents of task (MET-minutes) of strenuous physical activity per active decade. Clinical and biochemical data were obtained retrospectively from the time of initial heart failure diagnosis. Results Wild-type ATTR amyloidosis was present in 82% (N=41) of ATTR-CM subjects, and 18% (N=9) of ATTR-CM subjects had genotype-confirmed hereditary ATTR amyloidosis. Both the ATTR-CM group and control group were male predominant (94% [N=47] vs 90.9% [N=20], p=0.63). ATTR-CM subjects were older at the time of diagnosis than controls (75.7 ±8.8 years vs. 63.6 ±9.4 years, p<0.0001). Left ventricular ejection fraction at the time of diagnosis was higher in ATTR-CM subjects than controls (49 ±14% vs. 32 ±15%, p<0.0001). Cumulative lifetime strenuous physical activity was higher in the ATTR-CM subjects than controls (1.44 × 106 MET-minutes per active decade vs. 0.751 × 106 MET-minutes per active decade, p=0.04). Conclusions Findings from this study suggest that increased cumulative lifetime strenuous physical activity per active decade is associated with ATTR-CM compared to other types of CM. Though larger prospective studies are needed to confirm this association, identifying strenuous exercise as a novel risk factor for ATTR-CM may offer new insight into the pathophysiology of this disease. Cardiac amyloidosis is an infiltrative heart disease that is associated with multi-organ dysfunction as a result of systemic misfolded protein deposition. Transthyretin (ATTR) amyloidosis is a type of amyloidosis that is increasingly being recognized as a cause of heart failure. Novel pharmacologic treatments for ATTR amyloid cardiomyopathy (ATTR-CM) have recently become available sparking a renewed interest in the pathophysiology of this disease. Other than certain genetic mutations, risk factors for the development of ATTR-CM are largely unknown. In the experience of our heart failure clinic, we have empirically observed that ATTR-CM patients frequently have a substantial history of vigorous athletic activity. We sought to identify a novel association between exercise and ATTR-CM. Cumulative lifetime strenuous physical activity is a novel risk factor for the development of ATTR-CM. In this single-center observational study, we recruited adults diagnosed with ATTR-CM and control subjects diagnosed with heart failure from non-amyloid cause. 50 ATTR-CM subjects and 22 controls were administered an in-depth lifetime physical activity survey. The survey identified type and quantity of physical activity from age 20 years until present day. Cumulative lifetime strenuous physical activity was quantified in metabolic equivalents of task (MET-minutes) of strenuous physical activity per active decade. Clinical and biochemical data were obtained retrospectively from the time of initial heart failure diagnosis. Wild-type ATTR amyloidosis was present in 82% (N=41) of ATTR-CM subjects, and 18% (N=9) of ATTR-CM subjects had genotype-confirmed hereditary ATTR amyloidosis. Both the ATTR-CM group and control group were male predominant (94% [N=47] vs 90.9% [N=20], p=0.63). ATTR-CM subjects were older at the time of diagnosis than controls (75.7 ±8.8 years vs. 63.6 ±9.4 years, p<0.0001). Left ventricular ejection fraction at the time of diagnosis was higher in ATTR-CM subjects than controls (49 ±14% vs. 32 ±15%, p<0.0001). Cumulative lifetime strenuous physical activity was higher in the ATTR-CM subjects than controls (1.44 × 106 MET-minutes per active decade vs. 0.751 × 106 MET-minutes per active decade, p=0.04). Findings from this study suggest that increased cumulative lifetime strenuous physical activity per active decade is associated with ATTR-CM compared to other types of CM. Though larger prospective studies are needed to confirm this association, identifying strenuous exercise as a novel risk factor for ATTR-CM may offer new insight into the pathophysiology of this disease.