Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

Inspiratory function is essential for alveolar ventilation and expulsive behaviors that promote airway clearance (e.g., coughing and sneezing). Current evidence demonstrates that inspiratory dysfunction occurs during healthy aging and is accentuated by chronic heart failure (CHF). This inspiratory dysfunction contributes to key aspects of CHF and aging cardiovascular and pulmonary pathophysiology including: (1) impaired airway clearance and predisposition to pneumonia; (2) inability to sustain ventilation during physical activity; (3) shallow breathing pattern that limits alveolar ventilation and gas exchange; and (4) sympathetic activation that causes cardiac arrhythmias and tissue vasoconstriction. The diaphragm is the primary inspiratory muscle; hence, its neuromuscular integrity is a main determinant of the adequacy of inspiratory function. Mechanistic work within animal and cellular models has revealed specific factors that may be responsible for diaphragm neuromuscular abnormalities in CHF and aging. These include phrenic nerve and neuromuscular junction alterations as well as intrinsic myocyte abnormalities, such as changes in the quantity and quality of contractile proteins, accelerated fiber atrophy, and shifts in fiber type distribution. CHF, aging, or CHF in the presence of aging disturbs the dynamics of circulating factors (e.g., cytokines and angiotensin II) and cell signaling involving sphingolipids, reactive oxygen species, and proteolytic pathways, thus leading to the previously listed abnormalities. Exercise-based rehabilitation combined with pharmacological therapies targeting the pathways reviewed herein hold promise to treat diaphragm abnormalities and inspiratory muscle dysfunction in CHF and aging.