Reduced Myocardial Sarcoplasmic Reticulum Ca 2+ -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 Ca 2+ -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 Ca 2+ -ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na + /Ca 2+ 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 max 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 + /Ca 2+ exchanger were similar in all groups. Conclusions — These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca 2+ handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction.