Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload.

Induction of the cell cycle is emerging as an intervention to treat heart failure. Here, we tested the hypothesis that enhanced cardiomyocyte renewal in transgenic mice expressing cyclin D2 would be beneficial during hemodynamic overload. We induced pressure overload by transthoracic aortic constriction (TAC) or volume overload by aortocaval shunt in cyclin D2-expressing and WT mice. Although cyclin D2 expression dramatically improved survival following TAC, it did not confer a survival advantage to mice following aortocaval shunt. Cardiac function decreased following TAC in WT mice, but was preserved in cyclin D2-expressing mice. On the other hand, cardiac structure and function were compromised in response to aortocaval shunt in both WT and cyclin D2-expressing mice. The preserved function and improved survival in cyclin D2-expressing mice after TAC was associated with an approximately 50% increase in cardiomyocyte number and exaggerated cardiac hypertrophy, as indicated by increased septum thickness. Aortocaval shunt did not further impact cardiomyocyte number in mice expressing cyclin D2. Following TAC, cyclin D2 expression attenuated cardiomyocyte hypertrophy, reduced cardiomyocyte apoptosis, fibrosis, calcium/calmodulin-dependent protein kinase IIδ phosphorylation, brain natriuretic peptide expression, and sustained capillarization. Thus, we show that cyclin D2-induced cardiomyocyte renewal reduced myocardial remodeling and dysfunction after pressure overload but not after volume overload.

Mid- to long-term outcome of patients treated with everolimus-eluting bioresorbable vascular scaffolds: Data of the BVS registry Göttingen predominantly from ACS patients.

BACKGROUND: Bioresorbable vascular scaffolds (BVS) are widely used in routine clinical practice. While previous studies reported acceptable short- to midterm outcome after BVS implantation, data on longer-term outcome are rare. METHODS: Patients treated with at least one Absorb®-BVS were consecutively enrolled. Follow-up data were assessed after 834.0 [769.0-1026.0] days. The primary device-oriented composite endpoint (DOCE) was defined as cardiovascular death, myocardial infarction (MI) and/or target lesion revascularization (TLR). RESULTS: Between 2012 and 2014, 195 patients were included into study analysis. Overall, 244 BVS were implanted. Mean patient age was 64.0[54.3-74.0] years. Three-quarter of patients had an ACS; of those 42.9% had ST-elevation-MI and 40.8% had non-ST-elevation-MI. DOCE occurred in 3.1%, 6.7%, 11.8% and 15.4% of patients during hospital stay, within 6-months, 18-months or during the complete follow-up period, respectively. In those patients, median time until DOCE was 211.5[43.25-567.25] days. In 11 (36.7%) patients DOCE occurred after >12months. Using univariable analysis, bifurcation stenting was associated with a hazard ratio (HR) of 11.8[2.38-58.57] for TLR (p=0.002) and 2.1[1.02-4.49] for DOCE (p=0.045). Similarly, in ACS patients, bifurcation stenting was associated with an increased risk for TLR (HR=10.4[2.01-53.56]; p=0.005) and for DOCE (HR=2.4[1.09-5.32]; p=0.029) and in multivariable analysis, it remained an independent predictor of DOCE (HR=3.0; p=0.018). CONCLUSIONS: Although, the rates of (potentially) device-related complications following BVS implantation are acceptable, they are nonetheless not negligible. Interestingly, they did not decline over time. Bifurcation stenting could be found as relevant procedure-related predictor of DOCE, especially in ACS patients. Randomized trials are warranted to confirm these findings.

Feasibility and outcomes of interventional treatment for vascular access site complications following transfemoral aortic valve implantation.

BACKGROUND: Despite the completion of more than 60,000 transcutaneous aortic valve implantations (TAVI) per year and an approximately 10-15 % incidence of vascular access site complications (VAC), there is a paucity of data on the efficacy and safety of percutaneous VAC treatment. HYPOTHESIS: Percutaneous endovascular treatment will be an effective treatment of VAC and associated with a low rate of surgical repair. Despite stent placement in proximity to the hip joint, endovascular treatment will be only rarely associated with disabling symptoms or complications. METHODS: We conducted a retrospective database analysis including 355 patients who underwent TAVI from January 2011 to October 2015. To facilitate the detection of secondary complications of interventional VAC repair, we conducted structured telephone interviews with a focus on new diagnoses or symptoms of peripheral artery disease. RESULTS: Only four patients (1.1 %) required surgical treatment for VAC. Percutaneous balloon angioplasty (PTA) or stent implantation was required for VAC in 44 patients (12.4 %). The technical success rate of percutaneous VAC treatment was 93 %. Four patients died within 30 days of VAC treatment, but only one fatality was directly attributable to VAC. Post procedure mean hospital stay was numerically prolonged by 2.4 days in the VAC treatment group (P = 0.06). During a median follow-up of 385 days (range 89-909 days) none of the patients were diagnosed with a late VAC or reported a new diagnosis or symptoms of perfusion deficit or peripheral artery disease. CONCLUSION: Percutaneous treatment of VAC during TAVI is safe and effectively helps to minimize the need for surgery in the vast majority of VAC. During short- and mid-term follow-up, percutaneous VAC management is associated with low complication rates and good clinical outcomes.

Early pneumonia and timing of antibiotic therapy in patients after nontraumatic out-of-hospital cardiac arrest.

BACKGROUND: While early pneumonia is common in patients after out-of-hospital cardiac arrest (OHCA), little is known about the impact of pneumonia and the optimal timing of antibiotic therapy after OHCA. METHODS: We conducted a 5-year retrospective cohort study, including patients who suffered from OHCA and were treated with therapeutic hypothermia. ICU treatment was strictly standardized with defined treatment goals and procedures. Medical records, chest radiographic images and microbiological findings were reviewed. RESULTS: Within the study period, 442 patients were admitted to our medical ICU after successfully resuscitated cardiac arrest. Of those, 174 patients fulfilled all inclusion and no exclusion criteria and were included into final analysis. Pneumonia within the first week could be confirmed in 39 patients (22.4%) and was confirmed or probable in 100 patients (57.5%), without a difference between survivors and non-survivors (37.8% vs. 23.1% confirmed pneumonia, p = 0.125). In patients with confirmed pneumonia a tracheotomy was performed more frequently (28.2 vs. 12.6%, p = 0.026) compared to patients without confirmed pneumonia. Importantly, patients with confirmed pneumonia had a longer ICU- (14.0 [8.5-20.0] vs. 8.0 [5.0-14.0] days, p < 0.001) and hospital stay (23.0 [11.5-29.0] vs. 15.0 [6.5-25.0] days, p = 0.016). A positive end expiratory pressure (PEEP) > =10.5 mbar on day 1 of the hospital stay was identified as early predictor of confirmed pneumonia (odds ratio 2.898, p = 0.006). No other reliable predictor could be identified. Median time to antibiotic therapy was 8.7 [5.4-22.8] hours, without a difference between patients with or without confirmed pneumonia (p = 0.381) and without a difference between survivors and non-survivors (p = 0.264). Patients receiving antibiotics within 12 hours after admission had a shorter ICU- (8.0 [4.0-14.0] vs. 10.5 [6.0-16.0] vs. 13.5 [8.0-20.0] days, p = 0.004) and hospital-stay (14.0 [6.0-25.0] vs. 16.5 [11.0-27.0] vs. 21.0 [17.0-28.0] days, p = 0.007) compared to patients receiving antibiotics after 12 to 36 or more than 36 hours, respectively. CONCLUSIONS: Early pneumonia may extend length of ICU- and hospital-stay after OHCA and its occurrence is difficult to predict. A delayed initiation of antibiotic therapy in OHCA patients may increase the duration of the ICU- and hospital-stay.

Rationale and Design of the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (Reduce LAP-HF) Trial.

OBJECTIVE: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left atrial pressure during rest and/or exercise. The Reduce LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial will evaluate the safety and performance of the Interatrial Shunt Device (IASD) System II, designed to directly reduce elevated left atrial pressure, in patients with HFpEF. METHODS: The Reduce LAP-HF Trial is a prospective, nonrandomized, open-label trial to evaluate a novel device that creates a small permanent shunt at the level of the atria. A minimum of 60 patients with ejection fraction ≥40% and New York Heart Association functional class III or IV heart failure with a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg at rest or ≥25 mm Hg during supine bike exercise will be implanted with an IASD System II, and followed for 6 months to assess the primary and secondary end points. Safety and standard clinical follow-up will continue through 3 years after implantation. Primary outcome measures for safety are periprocedural and 6-month major adverse cardiac and cerebrovascular events (MACCE) and systemic embolic events (excluding pulmonary thromboembolism). MACCE include death, stroke, myocardial infarction, or requirement of implant removal. Primary outcome measures for device performance include success of device implantation, reduction of PCWP at rest and during exercise, and demonstration of left-to-right flow through the device. Key secondary end points include exercise tolerance, quality of life, and the incidence of heart failure hospitalization. CONCLUSION: Reduce LAP-HF is the first trial intended to lower left atrial pressure in HFpEF by means of creating a permanent shunt through the atrial septum with the use of a device. Although the trial is primarily designed to study safety and device performance, we also test the pathophysiologic hypothesis that reduction of left atrial pressure will improve symptoms and quality of life in patients with HFpEF.

Impact of frailty on short- and long-term morbidity and mortality after transcatheter aortic valve implantation: risk assessment by Katz Index of activities of daily living.

AIMS: Transcatheter aortic valve implantation (TAVI) represents a less invasive treatment option for elderly patients. Therefore, we aimed to determine the impact of frailty measured by the Katz Index of activities of daily living (ADL) on short- and long-term mortality after TAVI. METHODS AND RESULTS: Our study included 300 consecutive patients (mean age, 82±5 years) who had undergone TAVI at our institution (158 transapical, 142 transfemoral procedures). At baseline, 144 patients were impaired in at least one ADL and therefore defined as frail (Katz Index <6). Regarding in-hospital outcome, all serious complications except for stage 3 acute kidney injury were equally distributed in both groups, but early mortality was significantly higher in frail persons (5.5% vs. 1.3%, p=0.04 for immediate procedural mortality; 17% vs. 5.8%, p=0.002 for 30-day mortality; and 23% vs. 6.4%, p<0.0001 for procedural mortality). The risk-score-based 30-day mortality estimates (29% vs. 24% for log. EuroSCORE I, 9.5% vs. 7.5% for EuroSCORE II, and 8.8% vs. 5.9% for STS score) reflected neither the observed 30-day mortality in both groups nor the threefold risk elevation in frail patients. In contrast, the Katz Index <6 was identified as a significant independent predictor of long-term all-cause mortality by multivariate analysis (HR 2.67 [95% CI: 1.7-4.3], p<0.0001). During follow-up (median observation period 537 days) 56% of frail vs. 24% of non-frail patients died. CONCLUSIONS: Frailty status measured by the Katz Index represents a powerful predictor of adverse early and late outcome after TAVI, whereas commonly used risk scores lack calibration and discrimination in a TAVI-specific patient cohort. Therefore, we propose the incorporation of this simple and reproducible measure into pre-TAVI risk assessment.

Failure of acute procedural success predicts adverse outcome after percutaneous edge-to-edge mitral valve repair with MitraClip.

AIMS: MitraClip implantation is evolving as a potential alternative treatment to conventional surgery in high-risk patients with significant mitral regurgitation (MR). However, outcome predictors are under-investigated. The aim of this study was to identify predictors of midterm mortality and heart failure rehospitalisation after percutaneous mitral valve repair with MitraClip. METHODS AND RESULTS: A total of 150 consecutive patients were followed for a median of 463 days. Survival analyses were performed for baseline characteristics, risk scores and failure of acute procedural success (APS) defined as persisting MR grade 3+ or 4+. Univariate significant risk stratifiers were tested in multivariate analyses using a Cox proportional hazards model. Overall survival was 96% at 30 days, 79.5% at 12 months, and 62% at two years. Multivariate analysis identified APS failure (HR 2.13, p=0.02), NYHA Class IV at baseline (HR 2.11, p=0.01) and STS score ≥12 (HR 2.20, p<0.0001) as significant independent predictors of all-cause mortality, and APS failure (HR 2.31, p=0.01) and NYHA Class IV at baseline (HR 1.89, p=0.03) as significant independent predictors of heart failure rehospitalisation. Furthermore, a post-procedural significant decrease in hospitalisation rate could only be observed after successful interventions (0.89±1.07 per year before vs. 0.54±0.96 after implantation, p=0.01). Patients with severely dilated and overloaded ventricles who did not meet EVEREST II eligibility criteria were at higher risk of APS failure. CONCLUSIONS: The failure of acute procedural success proved to have the most important impact on outcome after MitraClip implantation.

Uncommon delayed and late complications after percutaneous left atrial appendage closure with Amplatzer(®) Cardiac Plug.

AIMS: Percutaneous left atrial appendage closure with Amplatzer(®) Cardiac Plug (St. Jude Medical Inc.) for the prevention of stroke in patients with atrial fibrillation is rapidly propagating. We sought to provide additional safety data. METHODS AND RESULTS: We have screened our database of patients having been treated with Amplatzer(®) Cardiac Plug and found 3 cases with uncommon complications that have not been reported previously. One patient experienced an embolisation of the occluder about 12 months after implantation that potentially resulted from mismatch of occluder size and landing zone. Another patient developed cardiac tamponade 9 days after implantation. This case of delayed effusion was probably not a result of interventional trauma, but might have been provoked by scratching of the inner pericardial membrane. A third patient developed a large thrombus in the left atrium which was considered to be caused by injury of the endothelial wall during implantation. The first two cases could be treated by a percutaneous procedure, the last case by cardiac surgery without any sequelae. CONCLUSIONS: Complications after left atrial appendage closure not related to a device-related thrombus can occur later after implantation. With appropriate percutaneous or surgical management these complications can be handled without sequelae.

Preclosure of femoral vein access site with the suture-mediated Proglide device during MitraClip implantation.

UNLABELLED: This study was designed to show the feasibility, safety, and efficacy of venous access-site closure with a single 6 Fr suture-mediated Proglide (Abbott Vascular) during MitraClip procedures. METHODS: Preclosure of the right femoral vein with Proglide used for access with the 24 Fr guiding catheter was performed. A total of 72 patients undergoing MitraClip were enrolled in this study (28 patients retrospectively and 44 patients prospectively), of whom 42 patients underwent a groin examination with ultrasound 2 days after the procedure. RESULTS: Only 1 patient (1.4%) needed transfusion of packed cells because of bleeding and hematoma in the groin due to Proglide failure. None of the patients that were examined with ultrasound revealed an arteriovenous fistula or a spurious aneurysm, a local thrombosis, or a local stenosis related to the Proglide device. CONCLUSION: This study demonstrates that vascular closure with the suture-mediated Proglide system is feasible, safe, and efficacious in large venous sites of 24 Fr as needed in patients undergoing MitraClip implantation despite the necessity of anticoagulation or platelet inhibition.

Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII.

Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction.

Acute outcomes after MitraClip therapy in highly aged patients: results from the German TRAnscatheter Mitral valve Interventions (TRAMI) Registry.

AIMS: The influence of age on baseline demographics and outcomes of patients selected for MitraClip has not been previously investigated. METHODS AND RESULTS: Baseline demographics and acute outcomes in 1,064 patients from the German TRAMI registry were stratified by age (525 patients ≥76 years and 539 patients <76 years). In elderly patients, logistic EuroSCORE was higher (25[15-40]% vs. 18[10-31]%, p<0.0001) and the proportion of women was greater (47.2% vs. 29.3%, p<0.0001). Elderly patients were more likely to have preserved left ventricular ejection fraction >50% (40.1% vs. 21.8%, p<0.0001) and degenerative mitral regurgitation (DMR, 35.3% vs. 25.6%, p<0.01). Age was the most frequent reason for non-surgical treatment in the elderly (69.4% vs. 36.1%, p<0.0001). The intrahospital MACCE (death, myocardial infarction, stroke) was low in both groups (3.5% vs. 3.4%, p=0.93) and the proportion of non-severe mitral regurgitation at discharge was similar (95.8% vs. 96.4%, p=0.73). A logistic regression model did not reveal any significant impact of age on acute efficacy and safety of MitraClip therapy. In both groups, the majority of patients were discharged home (81.8% vs. 86.2%, p=0.06). CONCLUSIONS: Elderly and younger patients have similar benefits from MitraClip therapy. Age was the most frequent cause for denying surgery in elderly patients.

Prosthetic valve endocarditis after transcatheter aortic valve implantation: the incidence in a single-centre cohort and reflections on clinical, echocardiographic and prognostic features.

AIMS: Transcatheter aortic valve implantation (TAVI) has recently developed into an accepted alternative to conventional surgery in high-risk patients. According to current data, post-TAVI prosthetic valve endocarditis (PVE) seems to occur very rarely. METHODS AND RESULTS: We followed the first 180 consecutive patients who underwent TAVI at our institution to assess safety and efficacy of the procedure. During follow-up (median, 319 days), PVE was seen more frequently than expected. By applying modified Duke criteria five cases could be confirmed (four early-onset and one late-onset PVE, four cases with "definite diagnosis" and one with "possible diagnosis") representing an estimated PVE incidence of 3.4% at one year. Two patients died subsequently. Clinical summaries of all cases are reported and compared to previously published case reports. CONCLUSIONS: According to our hypothesis, PVE might be particularly difficult to diagnose after TAVI, whereas TAVI-specific elderly patients might be exceptionally vulnerable. There exists little experience of TEE interpretation in post-TAVI endocarditis which should possess unique characteristics regarding, e.g., valve dehiscence or abscess formation. Therefore, echocardiography as a diagnostic tool often remains initially inconclusive. Because of incongruence between prosthetic device and calcified native aortic valve, some degree of paravalvular leak is common after TAVI. These paravalvular leaks as a nidus for infection, advanced age and abundant comorbidities might predispose TAVI patients for infective endocarditis.

Targeted disruption of Hspa4 gene leads to cardiac hypertrophy and fibrosis.

Failure of molecular chaperones to direct the correct folding of newly synthesized proteins leads to the accumulation of misfolded proteins in cells. HSPA4 is a member of the heat shock protein 110 family (HSP110) that acts as a nucleotide exchange factor of HSP70 chaperones. We found that the expression of HSPA4 is upregulated in murine hearts subjected to pressure overload and in failing human hearts. To investigate the cardiac function of HSPA4, Hspa4 knockout (KO) mice were generated and exhibited cardiac hypertrophy and fibrosis. Hspa4 KO hearts were characterized by a significant increase in heart weight/body weight ratio, elevated expression of hypertrophic and fibrotic gene markers, and concentric hypertrophy with preserved contractile function. In response to pressure overload, cardiac hypertrophy and remodeling were further aggravated in the Hspa4 KO compared to wild type (WT) mice. Cardiac hypertrophy in Hspa4 KO hearts was associated with enhanced activation of gp130-STAT3, CaMKII, and calcineurin-NFAT signaling. Protein blot and immunofluorescent analyses showed a significant accumulation of polyubiquitinated proteins in cardiac cells of Hspa4 KO mice. These results suggest that the myocardial remodeling of Hspa4 KO mice is due to accumulation of misfolded proteins resulting from impaired chaperone activity. Further analyses revealed a significant increase in cross sectional area of cardiomyocytes, and in expression levels of hypertrophic markers in cultured neonatal Hspa4 KO cardiomyocytes suggesting that the hypertrophy of mutant mice was a result of primary defects in cardiomyocytes. Gene expression profile in hearts of 3.5-week-old mice revealed a differentially expressed gene sets related to ion channels, muscle-specific contractile proteins and stress response. Taken together, our in vivo data demonstrate that Hspa4 gene ablation results in cardiac hypertrophy and fibrosis, possibly, through its role in protein quality control mechanism.

Impact of the learning curve on outcomes after percutaneous mitral valve repair with MitraClip and lessons learned after the first 75 consecutive patients.

AIMS: Mitral valve regurgitation plays a significant role in the aetiology and course of heart failure. We investigated the impact of the learning curve on outcomes after percutaneous mitral valve repair with MitraClip. METHODS AND RESULTS: Outcomes of the first 75 consecutive patients treated with MitraClip at our centre were stratified by subsequent treatment periods (25 patients each). Median total procedure time and device time decreased from 180 and 105 min in period 1 to 95 and 55 min in period 3 (P < 0.005 each). There was an excess of total safety events in period 1 (n = 16) that decreased in periods 2 and 3 (n = 6 and 3, P = 0.0003). Acute procedural success [APS; clip successfully placed and mitral regurgitation (MR) grade ≤2+ at discharge] was 80% in periods 1 and 2, but 92% in period 3 (P = 0.46). At 6 months, improvement in durability and completeness of mitral valve repair was evident: 89.4% of patients in period 3 and 65.0% in period 1 had MR ≤2+ at 6 months (P = 0.03). Within 30 days, no patient sustained myocardial infarction or stroke, and mortality was 2.7% for all patients without significant differences regarding periods. Furthermore, while treatment period did not affect mid-term survival and hospitalization for heart failure, failure of APS, STS (Society of Thoracic Surgeons) score ≥15%, and overt right heart failure at baseline predicted increased mortality. CONCLUSION: MitraClip showed a learning curve regarding mid-term durability and completeness of mitral valve repair, and APS predicted mortality. Recently published studies should be interpreted in consideration of these findings.

Overexpression of CaMKIIδc in RyR2R4496C+/- knock-in mice leads to altered intracellular Ca2+ handling and increased mortality.

OBJECTIVES: We investigated whether increased Ca(2+)/calmodulin-dependent kinase II (CaMKII) activity aggravates defective excitation-contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2). BACKGROUND: RyR2 dysfunction is associated with arrhythmic events in inherited and acquired cardiac disease. METHODS: CaMKIIδc transgenic mice were crossbred with RyR2(R4496C+/-) knock-in mice. RESULTS: Heart weight-to-body weight ratio in CaMKIIδc/RyR2(R4496C) and CaMKIIδc mice was similarly increased approximately 3-fold versus wild-type mice (p < 0.05). Echocardiographic data showed comparable cardiac dilation and impaired contractility in CaMKIIδc/RyR2(R4496C) and CaMKIIδc mice. Sarcoplasmic reticulum Ca(2+) content in isolated myocytes was decreased to a similar extent in CaMKIIδc/RyR2(R4496C) and CaMKIIδc mice. However, relaxation parameters and Ca(2+) decay at 1 Hz were prolonged significantly in CaMKIIδc mice versus CaMKIIδc/RyR2(R4496C) mice. Sarcoplasmic reticulum Ca(2+) spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca(2+) leak in CaMKIIδc/RyR2(R4496C) versus CaMKIIδc myocytes (p < 0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKIIδc/RyR2(R4496C) versus CaMKIIδc mice. Increased arrhythmias in vivo (67% vs. 25%; p < 0.05) may explain the increased mortality in CaMKIIδc/RyR2(R4496C) mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIδc, p < 0.05) after 14 weeks. CONCLUSIONS: CaMKIIδc overexpression in RyR2(R4496C+/-) knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor.

Intracoronary pyruvate in cardiogenic shock as an adjunctive therapy to catecholamines and intra-aortic balloon pump shows beneficial effects on hemodynamics.

AIMS: Pyruvate was shown to increase cardiac performance in isolated human and animal myocardium and in patients with chronic heart failure. We sought to investigate the effects of pyruvate in acute heart failure. METHODS AND RESULTS: Patients presenting with cardiogenic shock because of acute myocardial infarction were subjected to standard care with primary PCI and intra-aortic balloon pump (IABP). Then, a Swan-Ganz catheter was placed in the pulmonary artery and hemodynamics was analyzed before, during and after intracoronary administration of 300 mmol/L pyruvate (360 ml/h). Pyruvate induced a significant increase in cardiac index (CI 2.23 ± 0.53 vs. 1.95 ± 0.45 L min(-1) m(-2); p < 0.05), stroke volume index (SVI, 29 ± 6 vs. 26 ± 5 mL m(-2); p < 0.05), and mean systemic arterial pressure (mean SAP, 95 ± 9 vs. 87 ± 9 mmHg; p < 0.05), whereas heart rate did not significantly change. The effects occurred rapidly within 30 min and were reversible within 10 min. CONCLUSION: Intracoronary pyruvate might show beneficial effects in severe acute heart failure in addition to treatment with catecholamines and IABP. These effects should be further investigated in randomized controlled trials.

Atrial contractile protein content and function are preserved in patients with coronary artery disease and atrial fibrillation.

OBJECTIVES: Atrial fibrillation (AF) causes atrial contractile dysfunction. The focus of this study was to determine whether the contractile deficit of human AF is the result of altered contractile protein abundance and/or function. METHODS: Atrial tissue from patients with chronic AF undergoing open-heart surgery was compared with the tissue from patients in normal sinus rhythm (NSR). Myosin isoform composition and content were determined. Intact native thin filament and cardiac myosin contractile protein performance were independently assessed in an in-vitro motility assay. RESULTS: Myosin isoform expression and total myosin content were not different between AF and NSR. Calcium-activated native thin filament function was similar between AF and NSR as measured by calcium sensitivity and maximal activation. Myosin isolated from the atria of AF and NSR groups showed similar unloaded shortening speeds and isometric force generation. CONCLUSION: Unlike human ventricular dysfunction where contractile protein function is directly affected, the contractile deficit of AF is not the result of alterations in myosin content or contractile protein function.

Recent in vitro findings of negative inotropy of pantoprazole did not translate into clinically relevant effects on left ventricular function in healthy volunteers.

PURPOSE: Reports on cardiac problems with oral proton pump inhibitors have caused extensive safety reviews by the US Food and Drug Administration. We provide additional data on acute cardiac effects of an intravenous application. METHODS: Echocardiography was performed in 18 healthy volunteers after administration of a common high-dose regimen of pantoprazole (80 mg i.v. bolus followed by 8 mg/h for 1 h) or placebo. DESIGN: The design included a randomized, double-blind, placebo-controlled cross-over trial. RESULTS: Ejection fraction (%, mean +/- SE) in the treatment group (placebo group) was 60.7 +/- 1.1 (61.2 +/- 1.7) at baseline, and 62.6 +/- 1.1 (62.1 +/- 1.9), 64.7 +/- 1.6 (63.5 +/- 1.3), 62.6 +/- 1.6 (61.0 +/- 1.6) and 63.0 +/- 1.4 (61.8 +/- 1.5) at 7.5, 15, 30 and 60 min after bolus application, respectively (p = n.s.). Similarly, no significant changes were found for cardiac output, cardiac index, blood pressure and heart rate. In contrast, gastric pH that was used as a treatment control was significantly increased 60 min after the application of pantoprazole as compared to baseline and to placebo. CONCLUSIONS: Pantoprazole as injection is safe in healthy subjects with respect to cardiac contractile function. However, in view of recent reports of negative inotropy of the drug, further studies in heart failure patients are required.

Effects of the NO donor sodium nitroprusside on oxygen consumption and energetics in rabbit myocardium.

Nitric oxide (NO) has influence on various cellular functions. Little is known of the influence of NO on myocardial energetics. In the present study oxygen consumption and mechanical parameters of isometrically contracting rabbit papillary muscles (1 Hz stimulation frequency) were investigated at varying interventions while maintaining physiological conditions (37 degrees C; 2.5 mM Ca(2+)) to study the effects of NO on energetics. The NO donor sodium nitroprusside (SNP) showed a negative inotropic effect. SNP decreased the maximal force in normal rabbit muscle strips by 30%, the force time integral (FTI) by 40% and the relaxation time by 20%. In addition the oxygen consumption decreased by 60%, a notably disproportional decrease compared to the mechanical parameters. Consequently, the economy as a ratio of FTI and oxygen consumption is significantly increased by SNP. In contrast the negative inotropic effect due to a reduction in extracellular Calcium (Ca(2+)) from 2.5 to 1.25 mM reduced FTI and oxygen consumption proportionally by 40% and did not change economy. The effect of NO on force and oxygen consumption could be reproduced by the application of the cyclic guanosine monophosphate (cGMP) analogue 8-bromo-cGMP. In summary, NO increased the economy of isometrically contracting papillary muscles. The improvement in contraction economy under NO seems to be mediated by cGMP as the secondary messenger and maybe due to alterations of the crossbridge cycle.