Abstract-Cardiac hypertrophy and heart failure are known to be associated with a reduction in Ca 2ϩ -ATPase pump levels of the sarcoplasmic reticulum (SR). To determine whether, and to what extent, alterations in Ca 2ϩ pump numbers can affect contraction and relaxation parameters of the heart, we have overexpressed the cardiac SR Ca 2ϩ -ATPase specifically in the mouse heart using the ␣-myosin heavy chain promoter. Analysis of 2 independent transgenic lines demonstrated that sarco(endo)plasmic reticulum Ca 2ϩ -ATPase isoform (SERCA2a) mRNA levels were increased 3.88Ϯ0.4-fold and 7.90Ϯ0.2-fold over those of the control mice. SERCA2a protein levels were increased by 1.31Ϯ0.05-fold and 1.54Ϯ0.05-fold in these lines despite high levels of mRNA, suggesting that complex regulatory mechanisms may determine the SERCA2a pump levels. The maximum velocity of Ca 2ϩ uptake (V max ) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca 2ϩ uptake function. However, the apparent affinity of the SR Ca 2ϩ -ATPase for Ca 2ϩ remains unchanged in transgenic hearts. To evaluate the effects of overexpression of the SR Ca 2ϩ pump on cardiac contractility, we used the isolated perfused work-performing heart model. The transgenic hearts showed significantly higher myocardial contractile function, as indicated by increased maximal rates of pressure development for contraction (ϩdP/dt) and relaxation (-dP/dt), together with shortening of the normalized time to peak pressure and time to half relaxation. Measurements of intracellular free calcium concentration and contractile force in trabeculae revealed a doubling of Ca 2ϩ transient amplitude, with a concomitant boost in contractility. The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca 2ϩ transport. (Circ Res. 1998;83:1205-1214.)Key Words: sarcoplasmic reticulum Ca 2ϩ -ATPase Ⅲ transgenic mice Ⅲ Ca 2ϩ uptake Ⅲ working heart model T he sarcoplasmic reticulum (SR) plays a central role in the contraction-and-relaxation cycle of the heart by regulating intracellular calcium (Ca 2ϩ ) concentrations (reviewed in Reference 1). Ca 2ϩ release from the SR via the ryanodine receptor initiates muscle contraction, whereas Ca 2ϩ reuptake into the lumen of the SR leads to muscle relaxation. The Ca 2ϩ uptake function of the SR is driven by an ATP-dependent Ca 2ϩ transport pump, the sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA). Molecular cloning analyses have identified a family of SERCA pumps encoded by 3 highly homologous genes (SERCA1, SERCA2, and SERCA3). [2][3][4][5][6][7][8] The SERCA2 gene encodes 2 isoforms, SERCA2a and SERCA2b, which differ at the COOH terminus as a result of alternative splicing (SERCA2a comprises 4 amino acids, and SERCA2b comprises 49 amino acids). [5][6][7] SERCA2a is the primary SERCA isoform expressed in the heart and is also present in slow-twitch skeletal muscle, smooth muscle, and fetal fast-twitch muscle. 9,10 In the rat heart, SERCA2a expr...

Abstract-To elucidate the role of intracellular Na ϩ kinetics during ischemia and reperfusion in postischemic contractile dysfunction, intracellular Na ϩ concentration ([Na ϩ ] i ) was measured in isolated perfused rat hearts using 23 Na nuclear magnetic resonance spectroscopy. The extension of the ischemic period from 9 minutes to 15, 21, and

Background-Chronic congestive heart failure is a common, often lethal disorder of cardiac contractility. The fundamental pathophysiology of the contractile failure remains unclear, the focus being on abnormal Ca 2ϩ cycling despite emerging evidence for depressed myofilament function. to activate the myofilaments in failing muscle, partially compensating for the marked dysfunction of the contractile machinery. Conclusions-Our results indicate that myofilament activation is severely blunted in heart failure, but concomitant changes in [Ca 2ϩ ] i kinetics minimize the contractile depression. These results challenge prevailing concepts regarding the pathophysiology of heart failure: the myofilaments emerge as central players, whereas changes in Ca 2ϩ cycling are reinterpreted as compensatory rather than causative.

he combination of angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) has been reported to offer more complete blockade of the effect of angiotensin II than treatment with ACEI alone, while retaining the benefits of bradykinin potentiation obtained from ACEI treatment. 1,2 In the clinical setting, the combination of ACEI and ARB is more beneficial in preventing left ventricular remodeling and decreasing the plasma concentrations of aldosterone and brain natriuretic peptide (BNP) than either ACEI or ARB alone. 3,4 In addition, the combination therapy has recently been proved to improve prognosis to a greater extent than the monotherapy. 4,5 However, the doses of ACEI and ARB in large-scale trials performed in the USA and Europe have been 3-4-fold higher than the standard doses prescribed in Japan. The aim of this study was to Circulation Journal Vol.68, April 2004 investigate the effects of the combination of ACEI and ARB at the standard doses prescribed in Japan on left ventricular remodeling and neurohumoral factors in patients with chronic heart failure. Methods Study DesignThis is a multicenter, randomized, open-labeled trial to compare the clinical effects of ACEI or ARB monotherapy and their combination for 6 months. All the patients treated in the 26 institutes gave their written informed consent to participate in the trial, which was approved by the institutional review board of the National Cardiovascular Center, Osaka, Japan. EligibilityMen and women, 18 years old or older, with stable chronic heart failure for at least 3 months before the screening were eligible to participate in this study. In addition, they had to have documented left ventricular (LV) systolic dysfunction with an LV ejection fraction (EF) equal to or less than 45%, determined by echocardiography or LV venCirc J 2004; 68: 361 -366 (Received November 13, 2003; revised manuscript received January 20, 2004; accepted January 27, 2004) The institutes particpating in the study are listed in Appendix 1. Background The present multicenter study investigated whether the combination of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) is more beneficial for preventing left ventricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone. Methods and ResultsOne hundred and six patients with mild-to-moderate congestive heart failure treated in 26 Japanese institutes were randomly assigned to the combination therapy or monotherapy. Changes in physical activity (New York Heart Association functional classes, Specific Activity Scale (SAS)), concentrations of neurohumoral factors (plasma renin activity, angiotensin II, aldosterone, and brain natriuretic peptide (BNP)), and cardiac function for 6 months were compared between the 2 groups. It was found that the combination therapy, which was administered at doses standard in Japan, increased the SAS score (4.5±1.5 to 4.9±1.5, p<0.05) and decreased the plasma BNP concentration (183±163 to 135±1...