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CLINICAL STUDIES

Human SERCA2a levels correlate inversely with age in senescent human myocardium

^a Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA

Manuscript received November 10, 1997; revised manuscript received April 3, 1998, accepted April 22, 1998.

Address for correspondence: Brian S. Cain, MD, Department of Surgery, C-320, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado 80262

Objectives. This study sought to characterize functional impairment after simulated ischemia-reperfusion (I/R) or Ca²⁺ bolus in senescent human myocardium and to determine if age-related alterations in myocardial concentrations of SERCA2a, phospholamban, or calsequestrin participate in senescent myocardial dysfunction.

Background. Candidates for elective cardiac interventions are aging, and an association between age and impairment of relaxation has been reported in experimental animals. Function of the sarcoplasmic reticulum resulting in diastolic dysfunction could be dysregulated at the level of cytosolic Ca²⁺ uptake by SERCA2a, its inhibitory subunit (phospholamban), or at the level of Ca²⁺ binding by calsequestrin.

Methods. Human atrial trabeculae from 17 patients (45–75 years old) were suspended in organ baths, field simulated at 1 Hz, and force development was recorded during I/R (45/120 min). Trabeculae from an additional 12 patients (53–73 years old) were exposed to Ca²⁺ bolus (2–3 mmol/L bath concentration). Maximum ± dF/dt and the time constant of force decay (tau) were measured before and after I/R or Ca²⁺ bolus and related to age. SERCA2a, phospholamban, and calsequestrin from 12 patients (39–77 years old) were assessed by immunoblot.

Results. Functional results indicated that maximum ±dF/dt and tau were prolonged in senescent (>60 years) human myocardium after I/R (p < 0.05). Calcium bolus increased the maximum ±dF/dt and decreased tau in younger, but not older patients (p < 0.05). SERCA2a and the ratio of SERCA2a to either phospholamban or calsequestrin were decreased in senescent human myocardium (p < 0.05).

Conclusions. Senescent human myocardium exhibits decreased myocardial SERCA2a content with age, which may, in part, explain impaired myocardial function after either I/R or Ca²⁺ exposure.

Abbreviations and Acronyms   SERCA2a = sarcoendoplasmic reticulum Ca2+-ATPase   I/R = ischemia-reperfusion   T = tau, the time constant of force decay   SI = simulated ischemia   [Ca2+]i = intramyocellular calcium   CAD = coronary artery disease   HTN = hypertension   IDDM = insulin-dependent diabetes mellitus   NIDDM = non–insulin-dependent diabetes mellitus   GERD = gastro-esophageal reflux disease   COPD = chronic obstructive pulmonary disease   CHF = congestive heart failure   LAD = left anterior descending coronary artery   RCA = right coronary artery   Cx = circumflex coronary artery   LVEF = left ventricular ejection fraction

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