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 funct ional reserve and gene expression of Ca2+-handling proteins in patients wit h hypertrophic cardiomyopathy (HCM) remains to be clarified. Methods and Results-We calculated the maximum first derivative of LV pressu re (LV dP/dt(max)) and the LV pressure half-time (T-1/2) during pacing in 1 4 patients with nonobstructive HCM (LV ejection fraction > 55%) and 7 contr ol subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcopl asmic reticulum Ca2+-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na+/Ca2+, exchanger were quantified by use of a real-tim e quantitative reverse transcription-polymerase chain reaction method. Grou p 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 w hom the heart rate-LV dP/dt,,,, relation was biphasic at physiological paci ng rates. Both the mean maximal wall thick-ness and the LV hypertrophy scor e 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 signific antly lower in group B (SERCA2/GAPDH ratio 0.34 +/-0.15) compared with grou p A (0.72 +/-0.27) and control subjects (0.85 +/-0.47), whereas the mRNA ex pression of ryanodine receptor-2, phospholamban. calsequestrin, and Na+/Ca2 + exchanger were similar in all groups. Conclusions-These results suggest that downregulation of SERCA2 mRNA, resul ting in altered Ca2+ handling, may contribute to impaired LV contractile re serve in HCM patients with severe hypertrophy, even in the absence of detec table baseline systolic dysfunction.