Reduced myocardial sarcoplasmic reticulum Ca2+-ATPase mRNA expression and biphasic force-frequency relations in patients with hypertrophic cardiomyopathy

Abstract

Background - The relationship between left ventricular (LV) contractile functional reserve and gene expression of Ca2+-handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified. Methods and Results - We calculated the maximum first derivative of LV pressure (LV dP/dtmax) and the LV pressure half-time (T1/2) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction >55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na+/Ca2+ exchanger were quantified by use of a real-time quantitative reverse transcription-polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dtmax with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate-LV dP/dtmax relation was biphasic at physiological pacing rates. Both the mean maximal wall thickness and the LV hypertrophy score in group B were greater than in group A (20±5 versus 15±3 mm and 7±1 versus 5±2 points, respectively). SERCA2 mRNA levels were significantly lower in group B (SERCA2/GAPDH ratio 0.34±0.15) compared with group A (0.72±0.27) and control subjects (0.85±0.47), whereas the mRNA expression of ryanodine receptor-2, phospholamban, calsequestrin, and Na±/Ca2+ exchanger were similar in all groups. Conclusions - These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca2+ handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction.