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

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/dt(max)) and the LV pressure half-time (T-1/2) 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/dt(max) with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate-LV dP/dt,,,, relation was biphasic at physiological pacing rates. Both the mean maximal wall thick-ness and the LV hypertrophy score in group B were greater than in group A (20 +/-5 versus 15 +/-3 nun 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.