Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension
What is the contribution of atrophy and contractility of cardiomyocytes to left ventricular (LV) dysfunction in patients with pulmonary arterial hypertension (PAH)?
LV function was assessed by cardiac magnetic resonance imaging (MRI). In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated. Cardiac MRI measurements, CSA, phosphorylation, and protein content of the sarcomeric proteins were analyzed by independent Student t-test or Mann-Whitney U test for non-normally distributed values.
MRI analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (∼30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (∼25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed a ∼30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation.
The authors concluded that contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients.
This study reports that LV cardiomyocytes from PAH patients have smaller CSA, indicating atrophy; reduced force-generating capacity that persists after correction for atrophy, which is partly caused by loss of the major contractile protein myosin; and reduced phosphorylation levels of key sarcomeric proteins, which may be responsible for the increased Ca2+ sensitivity of force. It appears that these changes at the cardiomyocyte level contribute to the reduction of in vivo contractility of the LV in PAH patients. Future therapeutic strategies aimed at targeting the contractile impairment and atrophy may help ameliorate LV dysfunction in PAH patients.
Keywords: Myosins, Atrophy, Actins, Hypertension, Pulmonary, Heart Ventricles, Myocytes, Cardiac, Phosphorylation, Magnetic Resonance Imaging, Muscle Contraction
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