Abstract-Increases in Ca2ϩ influx through the L-type Ca 2ϩ channel (LTCC, Cav1.2) augment sarcoplasmic reticulum (SR) Ca 2ϩ loading and the amplitude of the cytosolic Ca 2ϩ transient to enhance cardiac myocyte contractility. Our hypothesis is that persistent increases in Ca 2ϩ influx through the LTCC cause apoptosis if the excessive influx results in SR Ca 2ϩ overload. Feline ventricular myocytes (VMs) in primary culture were infected with either an adenovirus (Ad) containing a rat Cav1.2 ␤ 2a subunit-green fluorescent protein (GFP) fusion gene (Ad␤ 2a ) to increase Ca 2ϩ influx or with AdGFP as a control. Significantly fewer ␤ 2a -VMs (21.4Ϯ5.6%) than GFP-VMs (99.6Ϯ1.7%) were viable at 96 hours. A fraction of ␤ 2a -VMs (20.8Ϯ1.8%) contracted spontaneously (SC-␤ 2a -VMs), and viability was significantly correlated with the percentage of SC-␤ 2a -VMs. Higher percentages of apoptotic nuclei, DNA laddering, and cytochrome C release were detected in ␤ 2a -VMs. This apoptosis was prevented with pancaspase or caspase-3 or caspase-9 inhibitors. L-type calcium current (I Ca-L ) density was greater in ␤ 2a -VMs (23.4Ϯ2.8 pA/pF) than in GFP-VMs (7.6Ϯ1.6 pA/pF). SC-␤ 2a -VMs had higher diastolic intracellular Ca 2ϩ (Indo-1 ratio: 1.1Ϯ0.1 versus 0.7Ϯ0.03, PϽ0.05) and systolic Ca 2ϩ transients (1.89Ϯ0.27 versus 0.80Ϯ0.08) than GFP-VMs. Inhibitors of Ca 2ϩ influx, SR Ca 2ϩ uptake and release, mitochondrial Ca 2ϩ uptake, mitochondrial permeation transition pore, calpain, and Bcl-2-associated X protein protected ␤ 2a -VMs from apoptosis. These results show that persistent increases in Ca 2ϩ influx through the I Ca-L enhance contractility but lead to apoptosis through a mitochondrial death pathway if SR Ca 2ϩ overload is induced. Key Words: L-type calcium channel Ⅲ ␤ 2a subunit Ⅲ apoptosis Ⅲ ventricular myocyte Ⅲ primary culture I ncreased myocyte contractility is a central feature of the cardiac response to hypertension, valvular disease, and myocardial infarction. 1,2 Increased myocyte Ca 2ϩ both causes enhanced contractility and contributes to the associated pathological hypertrophy. 3 In this study, we explore the possibility that increased Ca 2ϩ influx also promotes apoptosis. Apoptosis is a critical component of myocyte death after myocardial infarction, persistent hemodynamic stress, and aging and in congestive heart failure. 4 The contributions of increased intracellular Ca 2ϩ ([Ca 2ϩ ] i ), which is needed to support enhanced contractility during hemodynamic stress, to myocyte apoptosis have not been adequately explored. A critical role for excessive Ca 2ϩ influx through the L-type calcium channel (LTCC or Cav1.2) and/or the Na ϩ /Ca 2ϩ exchanger in cardiomyocyte apoptosis induced by adrenergic agonists, 5-7 angiotensin II, 8 and ischemia/reperfusion 9 has been established. A modulatory role for Ca 2ϩ influx through the B-type Ca 2ϩ channel in cardiomyocyte apoptosis induced by ceramide has also been reported. 10 In nonmyocytes, increased Ca 2ϩ influx has been associated with both apoptosis 11-13 and protection from...

Abstract-Depressed contractility of failing myocytes involves a decreased rate of rise of the Ca 2ϩ transient. Synchronization of Ca 2ϩ release from the junctional sarcoplasmic reticulum (SR) is responsible for the rapid rise of the normal Ca 2ϩ transient. This study examined the idea that spatially and temporally dyssynchronous SR Ca 2ϩ release slows the rise of the cytosolic Ca 2ϩ transient in failing feline myocytes. Left ventricular hypertrophy (LVH) with and without heart failure (HF) was induced in felines by constricting the ascending aorta. Ca 2ϩ transients were measured in ventricular myocytes using confocal line scan imaging. Ca 2ϩ transients were induced by field stimulation, square wave voltage steps, or action potential (AP) voltage clamp. SR Ca 2ϩ release was significantly less well spatially and temporally synchronized in field-stimulated HF versus control or LVH myocytes. Surprisingly, depolarization of HF cells to potentials where Ca 2ϩ currents (I Ca ) were maximal resynchronized SR Ca 2ϩ release. Correspondingly, decreases in the amplitude of I Ca desynchronized SR Ca 2ϩ release in control, LVH, and HF myocytes to the same extent. HF myocytes had significant loss of phase 1 AP repolarization and smaller I Ca density, which should both reduce Ca 2ϩ influx. When normal myocytes were voltage clamped with HF AP profiles SR Ca 2ϩ release was desynchronized. SR Ca 2ϩ release becomes dyssynchronized in failing feline ventricular myocytes because of reductions in Ca 2ϩ influx induced in part by alterations in early repolarization of the AP. Therefore, therapies that restore normal early repolarization should improve the contractility of the failing heart. (Circ Res. 2005;96:543-550.) Key Words: heart failure Ⅲ excitation contraction coupling Ⅲ sarcoplasmic reticulum Ⅲ calcium transients H emodynamic overload induces cardiac hypertrophy and alterations in the contractile properties of the resident cardiac myocytes, both of which can help the heart maintain cardiac output. However, when the hemodynamic stress is persistent, the heart usually makes a transition from compensated hypertrophy to a progressively deteriorating functional state termed congestive heart failure (CHF). This transition is known to be associated with alterations in the magnitude, duration, and kinetics of the systolic Ca 2ϩ transient. Multiple cellular and molecular changes are thought to underlie the abnormal Ca 2ϩ transient of the hypertrophied/ failing myocyte. [1][2][3][4][5][6][7] The reduced size and prolonged duration of the Ca 2ϩ transient involves reduced sarcoplasmic reticulum (SR) Ca 2ϩ stores 1,7-9 resulting from a slowed rate of SR Ca 2ϩ uptake. This reduced SR function is thought to be caused by reductions in the density of the SR Ca 2ϩ ATPase (SERCA) 10 -12 and by reduced phosphorylation of the SERCA inhibitory protein phospholamban (PLB). [13][14][15] There is also some evidence for an increased rate of Ca 2ϩ "leak" from the SR through "hyperphosphorylated" Ca 2ϩ release channels (ryanodine receptors, RYR). 16,17 R...

BackgroundType 2 diabetes presents a major morbidity and mortality burden in the United States. Diabetes self-management education (DSME) is an intervention associated with improved hemoglobin A1c(HbA1c) and quality of life(QOL), and is recommended for all individuals with type 2 diabetes. African-Americans have disproportionate type 2 diabetes morbidity and mortality, yet no prior meta-analyses have examined DSME outcomes exclusively in this population. This systematic review and meta-analysis examined the impact of DSME on HbA1c and QOL in African-Americans compared to usual care.MethodsRandomized controlled trials, cluster-randomized trials, and quasi-experimental interventions were included. 352 citations were retrieved; 279 abstracts were reviewed, and 44 full-text articles were reviewed. Fourteen studies were eligible for systematic review and 8 for HbA1c meta-analysis; QOL measures were too heterogeneous to pool. Heterogeneity of HbA1c findings was assessed with Cochran’s Q and I2.ResultsHbA1c weighted mean difference between intervention and usual care participants was not significant: − 0.08%[− 0.40–0.23];χ2 = 84.79 (p < .001), I2 = 92%, (n = 1630). Four of five studies measuring QOL reported significant improvements for intervention participants.ConclusionsMeta-analysis results showed non-significant effect of DSME on HbA1c in African-Americans. QOL did show improvement and is an important DSME outcome to measure in future trials. Further research is needed to understand effectiveness of DSME on HbA1c in this population.Trial registrationPROSPERO registration: CRD42017057282.Electronic supplementary materialThe online version of this article (10.1186/s12913-018-3186-7) contains supplementary material, which is available to authorized users.