Obstructive Sleep Apnea in Heart Failure: Review of Prevalence, Treatment with Continuous Positive Airway Pressure, and Prognosis.

Obstructive sleep apnea is a sleep-related breathing disorder that has a major impact on cardiovascular function. It has been associated with hypertension, coronary artery disease, cardiac arrhythmias, sudden cardiac death, and heart failure. This review focuses on the relationship between obstructive sleep apnea and heart failure with either reduced or preserved ejection fraction. We discuss the pathophysiology of obstructive sleep apnea, as well as its prevalence, treatment outcomes with continuous positive airway pressure, and prognosis in these 2 distinct types of heart failure. We also identify areas in which further work is needed to improve our understanding of this association in heart failure patients.

Heart failure performance measures: do they have an impact on 30-day readmission rates?

Congestive heart failure (CHF) accounts for more health care costs than any other diagnosis. Readmissions contribute to this expenditure. The authors evaluated the relationship between adherence to performance metrics and 30-day readmissions. This was a retrospective study of 6063 patients with CHF between 2001 and 2008. Data were collected for 30-day readmissions and compliance with CHF performance measures at discharge. Rates of readmission for CHF increased from 16.8% in 2002 to 24.8% in 2008. Adherence to performance measures increased concurrently from 95.8% to 99.9%. Except for left ventricular function (LVF) assessment, the 30-day readmission rate was not associated with adherence to performance measures. Readmitted patients had twice the odds of not having their LVF assessed (odds ratio = 2.0; P < .00005; 95% confidence interval = 1.45-2.63). CHF performance measures, except for the LVF assessment, have little relationship to 30-day readmissions. Further studies are needed to identify performance measures that correlate with quality of care.

Comparison of the 2006 and 2010 cardiac CT appropriateness criteria in a real-world setting.

BACKGROUND: Coronary CT angiography (CCTA) is a relatively new technique whose role has yet to be fully defined. The initial appropriateness criteria (AC) guidelines published in 2006 have already been revised. There is paucity of data on the effect of the AC on the use of CCTA at academic centers and none for the private sector. METHODS: All CCTA studies ordered at one institution (a large community hospital with internal medicine and cardiovascular training programs) from 2006 to 2008 were retrospectively evaluated, and the ordering indications were categorized per the published AC for both 2006 and 2010. RESULTS: There were 384 studies, of which 243 were included in this study. The majority of the studies were ordered for chest pain (67.1% of patients). A significant proportion of studies (43.2%) were classified as inappropriate on the basis of the 2006 published criteria. Uncertain indications made up 39.1%, and appropriate indications were a minority. There was a significant regrading of appropriateness using the 2010 guidelines. Inappropriate testing remained similar at 48.1%, but uncertain cases decreased to only 2.8%, while appropriateness increased to 49.0% (P = .0001 for trend). CONCLUSIONS: The updated 2010 AC guidelines for CCTA resulted in a significant reclassification of the indications for ordering CCTA from the previous 2006 guidelines. This shift in the AC reflects increased familiarity and confidence with this new technology across the imaging community. A large proportion of CCTA studies were ordered for inappropriate indications using both sets of criteria. Further research and enhanced education are needed to disseminate the appropriate role of CCTA in cardiovascular imaging.

Comparative effectiveness analysis of anticoagulant strategies in a large observational database of percutaneous coronary interventions.

BACKGROUND: Percutaneous coronary intervention (PCI) is the most commonly used procedure for coronary revascularization. There are multiple adjuvant anticoagulation strategies available. In this era of cost containment, we performed a comparative effectiveness analysis of clinical outcomes and cost of the major anticoagulant strategies across all types of PCI procedures in a large observational database. METHODS: A retrospective, comparative effectiveness analysis of the Premier observational database was conducted to determine the impact of anticoagulant treatment on outcomes. Multiple linear regression and logistic regression models were used to assess the association of initial antithrombotic treatment with outcomes while controlling for other factors. RESULTS: A total of 458,448 inpatient PCI procedures with known antithrombotic regimen from 299 hospitals between January 1, 2004 and March 31, 2008 were identified. Compared to patients treated with heparin plus glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin was associated with a 41% relative risk reduction (RRR) for inpatient mortality, a 44% RRR for clinically apparent bleeding, and a 37% RRR for any transfusion. Furthermore, treatment with bivalirudin alone resulted in a cost savings of $976 per case. Similar results were seen between bivalirudin and heparin in all end-points. Combined use of both bivalirudin and GPI substantially attenuated the cost benefits demonstrated with bivalirudin alone. CONCLUSION: Bivalirudin use was associated with both improved clinical outcomes and decreased hospital costs in this large "real-world" database. To our knowledge, this study is the first to demonstrate the ideal comparative effectiveness end-point of both improved clinical outcomes with decreased costs in PCI.

The relationship between childhood trauma and borderline personality symptomatology in a consecutive sample of cardiac stress test patients.

OBJECTIVE: In this study, we examined relationships between five types of childhood trauma and two measures of borderline personality symptomatology in a non-psychiatric clinical population in order to assess a potential association between these variables in a non-psychiatric-treatment-seeking population. METHOD: Using a cross-sectional sample and a survey approach in 250 consecutive patients presenting for cardiac stress testing, we explored self-reported histories of five types of childhood trauma (i.e. witnessing violence, physical neglect, emotional abuse, physical abuse, sexual abuse), several aspects of past mental healthcare, and borderline personality symptomatology using two self-report measures (the borderline personality disorder scale of the Personality Diagnostic Questionnaire-4 and the Self-Harm Inventory). RESULTS: All relationships between the individual forms of trauma and total number of childhood traumas, and measures of borderline personality symptomatology, attained statistical significance. Using multiple regression analysis, sexual abuse in childhood was an independent predictor for borderline personality symptomatology in addition to past psychiatric/counseling care, with the latter finding suggesting some inter-drift of psychiatric patients into this cardiac stress test sample. CONCLUSIONS: In this non-psychiatric-treatment-seeking population, there appear to be relationships between various forms of trauma (especially sexual abuse) and borderline personality symptomatology, reinforcing the role of childhood trauma in borderline personality disorder.

Prevalence and self-reported medical history of overweight in a cardiac stress testing population.

OBJECTIVES: To determine the prevalence of overweight in a cardiac stress testing population, and the percentage of subjects who indicate a history of overweight. METHODS: A total of 251 consecutive subjects presenting for cardiac stress testing in a 450-bed community hospital from June to September 2010 were asked to complete a survey booklet. The survey included all patients presenting for stress testing, regardless of indication. Participants were subjects, ages 18 or older, and male or female. Exclusion criteria were medical (eg, pain), psychiatric (eg, psychosis), or intellectual disturbances that would preclude the successful completion of a survey booklet. RESULTS: Of the 251 participants 76.5% were overweight (BMI ≥ 25). Among the overweight participants, only 16.1% indicated a history of overweight. CONCLUSIONS: A high prevalence of overweight/obese individuals exists in a cardiac stress test population. A majority of overweight and obese patients did not indicate a history of overweight. These results indicate poor patient recognition and/or ineffective physician-to-patient education concerning unhealthy body weight. Greater and more effective efforts are needed to effectively educate patients about this modifiable risk factor for a myriad of health problems.

The prevalence of self-harm behaviors in a consecutive sample of cardiac stress test patients.

While self-harm behavior has been studied in various psychiatric populations, particularly the behaviors of suicide attempts and completions, little empirical data exists on the lifetime prevalence of various self-harm behaviors in non-psychiatric populations. In the present study, using a cross-sectional approach and a self-report survey methodology, we examined the lifetime prevalence of 22 self-harm behaviors in a consecutive sample of 250 patients undergoing cardiac stress testing. Results indicated that abuse alcohol was most common (17.2%) followed by promiscuity (10.4%); 6% reported a previous suicide atatempt. Findings indicate areas of clinician inquiry for self-harm behaviors in non-psychiatric patients.

Multiple interactions between the alpha 2C- and beta1-adrenergic receptors influence heart failure survival.

BACKGROUND: Persistent stimulation of cardiac beta1-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the alpha 2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively) on the risk of death/transplant in heart failure patients. METHODS: Sixteen sequence variations in ADRA2C and 17 sequence variations in ADRB1 were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation. RESULTS: Three polymorphisms in ADRA2C and five polymorphisms in ADRB1 were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18) relative to all other genotype classes. CONCLUSION: Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.

A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure.

Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.

Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice.

Following myocardial infarction, nonischemic myocyte death results in infarct expansion, myocardial loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes ventricular remodeling in the mouse, despite having no effect on early or late infarct size. We evaluated the effects of ablating Bnip3 on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia/reperfusion (IR) injury in mice. Immediately following IR, no significant differences were observed between Bnip3(-/-) and WT mice. However, at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium, and at 3 weeks after IR, Bnip3(-/-) mice exhibited preserved LV systolic performance, diminished LV dilation, and decreased ventricular sphericalization. These results suggest myocardial salvage by inhibition of apoptosis. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice, causing progressive LV dilation and diminished systolic function. Conditional Bnip3 overexpression prior to coronary ligation increased apoptosis and infarct size. These studies identify postischemic apoptosis by myocardial Bnip3 as a major determinant of ventricular remodeling in the infarcted heart, suggesting that Bnip3 may be an attractive therapeutic target.

A functional polymorphism of the Galphaq (GNAQ) gene is associated with accelerated mortality in African-American heart failure.

Galphaq, encoded by the human GNAQ gene, is an effector subunit of the Gq heterotrimeric G-protein and the convergence point for signaling of multiple Gq-coupled neurohormonal receptors. To identify naturally occurring mutations that could modify GNAQ transcription, we examined genomic DNA isolated from 355 normal subjects for genetic variants in transcription factor binding motifs. Of seven variants identified, the most common was a GC to TT dinucleotide substitution at -694/-695 (allele frequency of 0.467 in Caucasians and 0.329 in African Americans) within a GC-rich domain containing consensus binding sites for Sp-1, c-rel and EGR-1. In promoter-reporter analyses, the TT substitution increased promoter activity in cultured neonatal rat cardiac myocytes and human HEK fibroblasts by approximately 30% at baseline and after stimulation with phorbol ester. Two other relatively common polymorphisms, -173G/A and -168G/A, did not affect promoter activity. Since altered expression/activity of Galphaq is implicated in heart disease, we re-sequenced the GNAQ promoter in 1052 prospectively followed heart failure patients. The TT variant was not increased in heart failure, but was associated with decreased survival time among African Americans, with an adjusted RR of death/cardiac transplant of 1.95 (95% CI = 1.21-3.13) for heterozygotes and 2.4 (95% CI = 1.36-4.26) for homozygotes. Gel mobility shift assays showed that this GC/TT substitution eliminated Sp-1 binding without affecting c-rel or EGR-1 binding to this promoter fragment. Thus, the GNAQ -694/-695 promoter polymorphism alters transcription factor binding, increases promoter activity and adversely affects outcome in human heart failure.

Quantitative left ventricular systolic function: from chamber to myocardium.

One of the most common indications for obtaining a Doppler echocardiographic study is to ascertain left ventricular (LV) systolic function. There are many ways in which LV function can be determined, but an important assumption that is often overlooked is that every measure that we commonly use is only a surrogate marker of LV function due to the fact that it is impossible to characterize the complex geometric and volumetric function of the ventricle (or myocyte) in a single number. Stated in another way, there is no one perfect measure of LV function. The ejection fraction has emerged as the preeminent method to express LV performance, but although ejection fraction is universally accepted, there are a number of other techniques that can assess LV function and, when taken together, provide a more comprehensive picture both of global and regional LV function. Each of these measures (including ejection fraction) has variable dependence on loading conditions, heart rate, and geometric position that limits its accuracy. Understanding the limitations of each measure will allow the physician to more intelligently understand the true status of the myocardium.

Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by a wide spectrum of defects, which most frequently include proportionate short stature, craniofacial anomalies, and congenital heart disease (CHD). NS is the most common nonchromosomal cause of CHD, and 80%-90% of NS patients have cardiac involvement. Mutations within the protein tyrosine phosphatase Src homology region 2, phosphatase 2 (SHP2) are responsible for approximately 50% of the cases of NS with cardiac involvement. To understand the developmental stage- and cell type-specific consequences of the NS SHP2 gain-of-function mutation, Q79R, we generated transgenic mice in which the mutated protein was expressed during gestation or following birth in cardiomyocytes. Q79R SHP2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, while, in the postnatal cardiomyocyte, Q79R SHP2 expression was completely benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding of the Q79R transgenics into ERK1/2-null backgrounds confirmed the pathway's necessity and sufficiency in mediating mutant SHP2's effects. Our data establish the developmental stage-specific effects of Q79R cardiac expression in NS; show that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities; and suggest that ERK1/2 modulation could have important implications for developing therapeutic strategies in CHD.

Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis.

Regulating the balance between synthesis and proteasomal degradation of cellular proteins is essential for tissue growth and maintenance, but the critical pathways regulating protein ubiquitination and degradation are incompletely defined. Although participation of calpain calcium-activated proteases in post-necrotic myocardial autolysis is well characterized, their importance in homeostatic turnover of normal cardiac tissue is controversial. Hence, we evaluated the consequences of physiologic calpain (calcium-activated protease) activity in cultured cardiomyocytes and unstressed mouse hearts. Comparison of in vitro proteolytic activities of cardiac-expressed calpains 1 and 2 revealed calpain 1, but not calpain 2, activity at physiological calcium concentrations. Physiological calpain 1 activation was evident in adenoviral transfected cultured cardiomyocytes as proteolysis of specific substrates, generally increased protein ubiquitination, and accelerated protein turnover, that were each inhibited by coexpression of the inhibitor protein calpastatin. Conditional forced expression of calpain 1, but not calpain 2, in mouse hearts demonstrated substrate-specific proteolytic activity under basal conditions, with hyperubiquitination of cardiac proteins and increased 26S proteasome activity. Loss of myocardial calpain activity by forced expression of calpastatin diminished ubiquitination of 1 or more specific myocardial proteins, without affecting overall ubiquitination or proteasome activity, and resulted in a progressive dilated cardiomyopathy characterized by accumulation of intracellular protein aggregates, formation of autophagosomes, and degeneration of sarcomeres. Thus, calpain 1 is upstream of, and necessary for, ubiquitination and proteasomal degradation of a subset of myocardial proteins whose abnormal accumulation produces autophagosomes and degeneration of cardiomyocytes with functional decompensation.

Impact of Preoperative 64-Slice CT Scanning on Mini-Maze Atrial Fibrillation Surgery.

BACKGROUND: : Multidetector computed tomography (MDCT) is emerging as a powerful noninvasive diagnostic tool. The appropriate role of this technique in the preoperative evaluation of cardiovascular disease has yet to be fully defined. Atrial fibrillation is the most common sustained cardiac arrhythmia, and novel minimally invasive surgical techniques have been developed to treat this condition by electrically isolating the pulmonary veins. The ideal methodology to preoperatively evaluate these patients remains debatable. We hypothesized that 64-slice CT could significantly affect perioperative planning. METHODS: : Thirty-six consecutive patients who consented to undergo minimally invasive pulmonary vein isolation at our institution underwent a preoperative 64-slice cardiac CT scan. All cardiac and noncardiac abnormalities were recorded, and modifications to the initial surgical plan were documented. RESULTS: : The mean patient age was 64.4 ± 11.9 years [26 men (72.2%), 17 with known coronary artery disease (47.2%)]. Preoperative CT scanning detected 12 patients with abnormal pulmonary venous anatomy (33.3%), 3 with left atrial thrombus (8.3%), and 17 with significant coronary artery disease (47.2%). Furthermore, 20 studies (55.6%) detected pulmonary abnormalities (including 11 nodules). Preoperative scanning significantly altered surgical planning in 10 cases (27.8%). Alterations in patient treatment included preoperative invasive angiography, conversion of the mini-maze to an open chest procedure, alteration of surgical approach, and postponement/cancellation. CONCLUSIONS: : Sixty-four-slice CT scanning is a safe, rapid, and accurate procedure with important ramifications for surgical planning. This methodology could become an alternative approach to screen preoperative cardiac surgical patients.

STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium.

The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 +/- 58 vs. 1,028 +/- 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/dt(max); 4,648 +/- 309 vs. 2,737 +/- 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum -dP/dt (-dP/dt(min); -2,239 +/- 205 vs. -1,215 +/- 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/dt(max) (4,648 +/- 309 vs. 3,241 +/- 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and -dP/dt(min) (-2,239 +/- 205 vs. -1,323 +/- 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.

The presence of Lys27 instead of Asn27 in human phospholamban promotes sarcoplasmic reticulum Ca2+-ATPase superinhibition and cardiac remodeling.

BACKGROUND: Phospholamban (PLN) is an inhibitor of the Ca2+ affinity of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2). The amino acid sequence of PLN is highly conserved, and although all species contain asparagine (Asn), human PLN is unique in containing lysine (Lys) at amino acid 27. METHODS AND RESULTS: Human PLN was introduced in the null background. Expression of human PLN, at similar levels to mouse wild-type PLN, resulted in significant decreases in the affinity of SERCA2 for Ca2+, attributed to unique spatial conformation of this PLN form and increases in its monomeric active unit compared with mouse PLN. The increased inhibition by human PLN was associated with attenuated cardiac contractility in the intact-animal, organ, and cardiomyocyte levels and with depressed calcium kinetics. These inhibitory effects could not be fully reversed even on maximal isoproterenol stimulation. There were no alterations in the expression levels of SERCA2, calsequestrin, ryanodine receptor, and FKBP12, although the sodium/calcium exchanger and the L-type Ca2+ channel expression levels were upregulated. The depressed function resulted in increased heart/body weight ratios and phosphorylation levels of Akt, p38, and Erk1/2. CONCLUSIONS: Human PLN may play a more inhibitory role than that of other species in Ca2+ cycling. Expression of human PLN in the mouse is compensated by alterations in Ca2+-handling proteins and cardiac remodeling in an effort to normalize cardiac contractility. Thus, the unique amino acid sequence of human PLN may be critical in maintaining a high cardiac reserve, which is of paramount importance in the regulation of human cardiac function.

Sarcoplasmic reticulum adenosine triphosphatase overexpression in the L-type Ca2+ channel mouse results in cardiomyopathy and Ca2+ -induced arrhythmogenesis.

BACKGROUND: Overexpression of the L-type voltage-dependent calcium channel alpha(1C)-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months of age. Overexpressing SERCA to manipulate calcium (Ca(2+)) cycling and prevent pathologic phenotypes in some models of heart failure has been proven to be a promising genetic strategy. OBJECTIVE: In this study we investigated whether genetic manipulation that increases Ca(2+) uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca(2+) cycling, contractile dysfunction, and electrical remodeling in the heart failure phenotype. RESULTS: We found that the survival rate of L-VDCC OE/SERCA1a OE double transgenic mice decreased by 50%. L-VDCC OE/SERCA1a OE mice displayed an accelerated phenotype of severe dilation of both ventricles associated with deteriorated left ventricular function. Voltage clamp experiments revealed enhanced increased inward Ca(2+) current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early after depolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca(2+)/calmodulin-dependent kinase II (CaMKII) was increased while connexin43 expression was decreased, defining an important putative mechanism in the electrophysiologic disturbances and mortality. CONCLUSIONS: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca(2+) cycling in arrhythmogenesis.