Abstract 19483: Oxidative Posttranslational Modification of SERCA2 Mediates Heart Failure Exacerbation in Young Patients With Non-Ischemic Cardiomyopathy

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Abstract

Background: Sarcoplasmic/Endoplasmic Reticulum (SR) Ca2+ ATPase (SERCA) uptakes cytosolic calcium into SR. SERCA2 is present in the myocardium. Oxidative posttranslational modifications (OPTM) impair the function of SERCA2, resulting in dysregulation of calcium and cardiac function. We investigated the extent of OPTM of SERCA2 in patients with non-ischemic cardiomyopathy (NIC).

Methods: Endomyocardial biopsies (EMB) were obtained in 40 consecutive patients (median age: 65.5) with NIC. We examined total SERCA2 expression and OPTM of SERCA2 such as sulfonylation at cysteine 674 (S-SERCA2) and nitration at tyrosine 294/295 (N-SERCA2) by immunohistochemistry. Evaluation of total SERCA2 and OPTM of SERCA2 were determined as a percentage of a positively stained area by each antibody to the total area of EMB tissue. We analyzed the correlation between OPTM of SERCA2 and demographic data of the patients, echocardiographic parameters, and late gadolinium enhancement (LGE) of cardiac magnetic resonance imaging.

Results: (1) S-SERCA2 expression increased in the LGE-positive hearts (P=0.008). (2) Total SERCA2 expression increased with aging (P=0.04) in parallel with the elevation of OPTM of SERCA2. In young patients of age < 65 at the time of EMB, there was no correlation between age and total SERCA2 expression, whereas, the aged patients of age > 65, there was a strong positive correlation between them (P=0.003). (3) Univariate analyses revealed that OPTM of SERCA2 had a positive relationship with BNP value (P=0.01, versus S-SERCA2/total SERCA2; P=0.02, versus N-SERCA2+S-SERCA2/total SERCA2) in young patients, whereas, aged patients showed no correlation between them. (4) Unexpectedly, LVEF showed no significant correlation with OPTM of SERCA2. (5) Medications of angiotensin receptor blockers or angiotensin-converting enzyme inhibitor tended to decrease OPTM of SERCA2.

Conclusions: Increased OPTM of SERCA2 was detected in LGE-positive hearts. SERCA2 expression of the hearts was increased with aging in parallel with the elevation of OPTM of SERCA2. In young patients with NIC, OPTM of SERCA2 correlated with the elevation of BNP value. OPTM of SERCA2 may be a potential marker for active myocardial dysfunction in young patients with heart failure.

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