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Aims Deformation imaging enables optimized risk prediction following acute myocardial infarction (AMI). However, costly and time-consuming post processing has hindered widespread clinical implementation. Since manual left-ventricular long-axis strain (LV LAS) has been successfully proposed as a simple alternative for LV deformation imaging, we aimed at the validation of left-atrial (LA) LAS. Methods and results The AIDA STEMI and TATORT-NSTEMI trials recruited 795 patients with ST-elevation myocardial infarction and 440 with non-ST-elevation myocardial infarction. LA LAS was assessed as the systolic distance change between the middle of a line connecting the origins of the mitral leaflets and either a perpendicular line towards the posterior atrial wall (LAS90) or a line connecting to the O LA posterior portion of the greatest distance irrespective of a predefined angle (LAS). Primary endpoint was major adverse cardiac event (MACE) occurrence within 12 months. There were no significant differences between LA LAS and LAS90, both with excellent reproducibility. LA LAS correlated significantly with LA reservoir function (Es, r = 0.60, P < 0.001). Impaired LA LAS resulted in higher MACE occurrence [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.82-0.88, P < 0.001]. LA LAS (HR 0.90, 95% CI 0.83-0.97, P = 0.005) and LV global longitudinal strain (GLS, P = 0.025) were the only independent predictors o for MACE in multivariate analyses. C-statistics demonstrated incremental value of LA LAS in addition to GLS (P = 0.016) and non- e inferiority compared with FT Es (area under the receiver operating characteristic curve 0.74 vs. 0.69, P = 0.256). Conclusion Left-atrial LAS provides fast and software-independent approximations of quantitative LA function with similar value for risk prediction compared with dedicated deformation imaging. Clinical trial registration ClinicalTrials.gov: NCT00712101 and NCT01612312 [ABSTRACT FROM AUTHOR]

Background Lyme disease is a tick-borne multisystem infection. The most common cardiac manifestation is an acute presentation of Lyme carditis, which often manifests as conduction disorder and rarely as myocarditis. Case summary We report the case of a 37-year-old male with a history of microscopic polyangiitis receiving immunosuppressive therapy. He was admitted for severe dyspnoea secondary to acute heart failure. Echocardiography and cardiac magnetic resonance imaging indicated a severely reduced left ventricular ejection fraction (LVEF) with global hypokinesia. Coronary heart disease was excluded, and endomyocardial biopsies (EMB) were performed. The left ventricular EMB revealed a rare case of fulminant Lyme carditis with evidence of typical lymphocytic myocarditis. Borrelia afzelii -DNA was detected without any relevant atrioventricular blockage or systemic signs of Lyme disease. The patient had no clinically apparent tick-borne infection or self-reported history of a tick bite. Immunological testing revealed a positive ELISA and Immunoblot for anti-Borrelia immunoglobulin G antibodies. After specific intravenous antibiotic therapy and optimized medical therapy for heart failure, the LVEF recovered, and the patient could be discharged in an improved condition. Repeat EMB a few months later revealed a dramatic regression of the cardiac inflammation and absence of Borrelia DNA in the myocardium. Discussion A severely reduced LVEF can be the primary manifestation of Lyme disease even without typical systemic findings and can have a favourable prognosis with antibiotic treatment. A thorough workup for Lyme carditis is required in patients with unexplained heart failure, particularly with EMB, especially in immunosuppressed patients. [ABSTRACT FROM AUTHOR]

Aims The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy. Methods and results We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537–0.865, P  = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class

Aims  Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes. Methods and results  One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson's trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF−) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P  = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n  = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF− patients, P  = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0–369), P  = 0.01]. Conclusion  Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Aims Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation. Methods and results General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis. Conclusion By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes. [ABSTRACT FROM AUTHOR]

Aims Cardiovascular magnetic resonance feature tracking (CMR-FT) global longitudinal strain (GLS) provides incremental prognostic value following acute myocardial infarction (AMI) but requires substantial post-processing. Alternatively, manual global long-axis strain (LAS) can be easily assessed from standard steady state free precession images. We aimed to define the prognostic value of LAS in a large multicentre study in patients following AMI. Methods and results A total of 1235 patients with myocardial infarction [ n  = 795 with ST-elevation myocardial infarction (STEMI) and 440 with non-ST-elevation myocardial infarction (NSTEMI)] underwent cardiovascular magnetic resonance imaging after primary percutaneous coronary intervention in eight centres across Germany. Assessment of LAS was performed in a blinded core-laboratory measuring the systolic shortening between the epicardial apical border and the middle of a line connecting the origins of the mitral leaflets. Primary clinical endpoint was the occurrence of major adverse clinical events (MACE) including death, reinfarction, and congestive heart failure within 1 year after AMI. During 1-year follow-up, 76 patients suffered from MACE. Impaired LAS was associated with higher MACE occurrence both in STEMI (P  < 0.001) and NSTEMI (P  = 0.001) patients. Association of LAS remained significant (P  = 0.017) after correction for univariate significant parameters for MACE prediction. C-statistics revealed incremental value of additional LAS assessment for optimized event prediction compared with left ventricular ejection fraction (MACE P  = 0.044; mortality P  = 0.013) and a combination of established clinical and imaging parameters (MACE P  = 0.084; mortality P  = 0.027), but not CMR-FT GLS (MACE P  = 0.075; mortality P  = 0.380). Conclusion LAS provides software independent, widely available, easy and fast approximation of longitudinal left ventricular shortening early after reperfused AMI with incremental prognostic value beyond established risk stratification parameters. Clinical Trials.gov NCT00712101 and NCT01612312. [ABSTRACT FROM AUTHOR]

Aims The exact pathophysiology of Takotsubo syndrome (TTS) remains not fully understood with most studies focussing on ventricular pathology. Since atrial involvement may have a significant role, we assessed the diagnostic and prognostic potential of atrial cardiovascular magnetic resonance feature tracking (CMR-FT) in TTS. Methods and results This multicentre study recruited 152 TTS patients who underwent CMR on average within 3 days after hospitalization. Reservoir [total strain ε s and peak positive strain rate (SR) SRs], conduit (passive strain ε e and peak early negative SRe), and booster pump function (active strain ε a and peak late negative SRa) were assessed in a core laboratory. Results were compared with 21 control patients with normal biventricular function. A total of 20 patients underwent follow-up CMR (median 3.5 months, interquartile range 3–5). All patients were approached for general follow-up. Left atrial (LA) but not right atrial (RA) reservoir and conduit function were impaired during the acute phase (ε s: P  = 0.043, ε e: P  < 0.001, SRe: P  = 0.047 vs. controls) and recovered until follow-up (ε s: P  < 0.001, SRs: P  = 0.04, ε e: P  = 0.001, SRe: P  = 0.04). LA and RA booster pump function were increased in the acute setting (LA- ε a: P  = 0.045, SRa: P  = 0.002 and RA- ε a: P  = 0.004, SRa: P  = 0.002 vs. controls). LA- ε s predicted mortality [hazard ratio 1.10, 95% confidence interval (CI) 1.01–1.20; P  = 0.037] irrespectively of established cardiovascular risk factors (P  = 0.019, multivariate analysis) including left ventricular ejection fraction (LVEF) (area under the curve 0.71, 95% CI 0.55–0.86, P  = 0.048). Conclusion TTS pathophysiology comprises transient impairments in LA reservoir and conduit functions and enhanced bi-atrial active booster pump functions. Atrial CMR-FT may evolve as a superior marker of adverse events over and above established parameters such as LVEF and atrial volume. [ABSTRACT FROM AUTHOR]

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone. [ABSTRACT FROM AUTHOR]

Aims: Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca(2+) leak is arrhythmogenic, it could represent a cellular basis for this paradox.Methods/results: We evaluated the SR Ca(2+) leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF. Cardiac function did not differ between sexes in both cardiac pathologies. Human cardiomyocytes isolated from female patients with Hy showed a significantly lower Ca(2+) spark frequency (CaSpF, confocal microscopy, Fluo3-AM) compared with men (P < 0.05). As Ca(2+) spark width and duration were similar in women and men, this difference in CaSpF did not yet translate into a significant difference of the calculated SR Ca(2+) leak between both sexes at this stage of disease (P = 0.14). Epifluorescence measurements (Fura2-AM) revealed comparable Ca(2+) cycling properties (diastolic Ca(2+) levels, amplitude of systolic Ca(2+) transients, SR Ca(2+) load) in patients of both sexes suffering from Hy. Additionally, the increased diastolic CaSpF in male patients with Hy did not yet translate into an elevated ratio of cells showing arrhythmic events (Ca(2+) waves, spontaneous Ca(2+) transients) (P = 0.77). In the transition to HF, both sexes showed an increase of the CaSpF (P < 0.05) and the sex dependence was even more pronounced. Female patients had a 69 ± 10% lower SR Ca(2+) leak (P < 0.05), which now even translated into a lower ratio of arrhythmic cells in female HF patients compared with men (P < 0.001).Conclusion: These data show that the SR Ca(2+) leak is lower in women than in men with comparable cardiac impairment. Since the SR Ca(2+) leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca(2+) leak. [ABSTRACT FROM AUTHOR]

Aims: Implantable cardioverter-defibrillators (ICDs) have been shown to improve survival, although a considerable number of patients never receive therapy. Implantable cardioverter-defibrillators are routinely implanted regardless of sex. There is continuing controversy whether major outcomes differ between men and women.Methods and Results: In this retrospective single-centre study, 1151 consecutive patients (19% women) undergoing ICD implantation between 1998 and 2010 were followed for mortality and first appropriate ICD shock over 4.9 ± 2.7 years. Sex-related differences were investigated using multivariable Cox models adjusting for potential confounders. During follow-up, 318 patients died, a rate of 5.9% per year among men and 4.6% among women (uncorrected P = 0.08); 266 patients received a first appropriate ICD shock (6.3% per year among men vs. 3.6% among women, P = 0.002). After multivariate correction, independent predictors of all-cause mortality were age (hazard ratio, HR = 1.04 per year of age, 95% confidence interval (CI) [1.03-1.06], P < 0.001), left ventricular ejection fraction (HR = 0.98 per %, 95% CI [0.97-1.00], P = 0.025), renal function (HR = 0.99 per mL/min/1.73 m(2), 95% CI [0.99-1.00], P = 0.009), use of diuretics (HR = 1.81, 95% CI [1.29-2.54], P = 0.0023), peripheral arterial disease (HR = 2.21, 95% CI [1.62-3.00], P < 0.001), and chronic obstructive pulmonary disease (HR = 1.48, 95% CI [1.13-1.94], P = 0.029), but not sex. Female sex (HR = 0.51, 95% CI [0.33-0.81], P = 0.013), older age (HR = 0.98, 95% CI [0.97-0.99], P < 0.001), and primary prophylactic ICD indication (HR = 0.69, 95% CI [0.52-0.93], P = 0.043) were independent predictors for less appropriate shocks.Conclusion: Women receive 50% less appropriate shocks than men having similar mortality in this large single-centre population. These data may pertain to individually improved selection of defibrillator candidates using risk factors, e.g. sex as demonstrated in this study. [ABSTRACT FROM AUTHOR]

Aims: Cardiac angiogenesis is an important determinant of heart failure. We examined the hypothesis that protein tyrosine phosphatase (PTP)-1B, a negative regulator of vascular endothelial growth factor (VEGF) receptor-2 activation, is causally involved in the cardiac microvasculature rarefaction during hypertrophy and that deletion of PTP1B in endothelial cells prevents the development of heart failure. Methods and results: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in mice with endothelial-specific deletion of PTP1B (End.PTP1B-KO) and controls (End.PTP1B-WT). Survival up to 20 weeks after TAC was significantly improved in mice lacking endothelial PTP1B. Serial echocardiography revealed a better systolic pump function, less pronounced cardiac hypertrophy, and left ventricular dilation compared with End.PTP1B-WT controls. Histologically, banded hearts from End.PTP1B-KO mice exhibited increased numbers of PCNA-positive, proliferating endothelial cells resulting in preserved cardiac capillary density and improved perfusion as well as reduced hypoxia, apoptotic cell death, and fibrosis. Increased relative VEGFR2 and ERK1/2 phosphorylation and greater eNOS expression were present in the hearts of End.PTP1B-KO mice. The absence of PTP1B in endothelial cells also promoted neovascularization following peripheral ischaemia, and bone marrow transplantation excluded a major contribution of Tie2-positive haematopoietic cells to the improved angiogenesis in End.PTP1B-KOmice. Increased expression of caveolin-1 as well as reduced NADPH oxidase- 4 expression, ROS generation and TGFb signalling were observed and may have mediated the cardioprotective effects of endothelial PTP1B deletion. Conclusions: Endothelial PTP1B deletion improves cardiac VEGF signalling and angiogenesis and protects against chronic afterloadinduced heart failure. PTP1B may represent a useful target to preserve cardiac function during hypertrophy. [ABSTRACT FROM AUTHOR]

Aims: Enhanced cardiac late Na-current (late INa) and increased sarcoplasmic reticulum (SR) Ca2+-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late INa and SR-Ca2+-leak in atrial cardiomyocytes (CMs). Methods and Results: In murine atrial CMs SR-Ca2+-leak was increased by the late INa enhancer ATX-II. An inhibition of Ca2+/calmodulin-dependent protein-kinase II (AIP), Protein kinase A (H89), or late INa (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca2+-leak. The SR-Ca2+-leak induction by ATX-II was neither detected when the Na+/Ca2+-exchanger was inhibited (KBR) nor in CaMKIIdc-knockout mice. FRET-measurements revealed increased cAMP-levels upon ATX-II stimulation, which could be prevented by inhibition of adenylylcyclase 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA-activation via an adenylylcyclase-dependent increase of cAMP-levels. Western blots showed late INa-dependent hyperphosphorylation of CaMKII- as well as PKA target-sites at RyR2 (-S2815, -S2809) and PLB (-Thr17, -S16). Enhancement of late INa did not alter Ca2+-transient amplitude or SR-Ca2+-load. However, upon late INa activation and simultaneous CaMKII inhibition, Ca2+-transient amplitude and SR-Ca2+-load were increased whereas PKA-inhibition reduced Ca2+ transient amplitude and load and slowed Ca2+-elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late INa, CaMKII, or PKA reduced the SR-Ca2+-leak. Conclusion: Late INa exerts distinct effects on Ca2+-homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late INa represents a potential approach to attenuate CaMKII-activation and decrease SR-Ca2+-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA-system further increases the antiarrhythmic potential of late INa-inhibition. [ABSTRACT FROM AUTHOR]

Aims Methylation of CpG island promoters is a prototypical epigenetic mechanism to stably control gene expression. The aim of this study was to elucidate the contribution of aberrant promoter DNA methylation in pathological endothelial to mesenchymal transition (EndMT) and subsequent cardiac fibrosis. Methods and results In human coronary endothelial cells, TGFβ1 causes aberrant methylation of RASAL1 promoter, increased Ras-GTP activity, and EndMT. In end-stage failing vs. non-failing human myocardium, increased fibrosis was associated with significantly increased RASAL1 promoter methylation, decreased RASAL1 expression, increased Ras-GTP activity, and increased expression of markers of EndMT. In mice with pressure overload due to ascending aortic constriction, BMP7 significantly reduced RASAL1 promoter methylation, increased RASAL1 expression, and decreased EndMT markers as well as decreased cardiac fibrosis. The ten eleven translocation (TET) family enzyme TET3, which demethylates through hydroxymethylation, was significantly decreased in fibrotic mouse hearts, restored with BMP7, and BMP7 effects were absent in coronary endothelial cells with siRNA knockdown of TET3. Conclusion Our study provides proof-in-principle evidence that transcriptional suppression of RASAL1 through aberrant promoter methylation contributes to EndMT and ultimately to progression of cardiac fibrosis. Such aberrant methylation can be reversed through Tet3-mediated hydroxymethylation, which can be specifically induced by BMP7. This may reflect a new treatment strategy to stop cardiac fibrosis. [ABSTRACT FROM PUBLISHER]

Aim Activation of the kinase RAF and its downstream targets leads to cardiomyocyte hypertrophy. It has been hypothesized that B-RAF might be the main activator of MEK in various cell types. Therefore, the aim of this study was to investigate the role of B-RAF and its modulating factors in cardiomyocyte hypertrophy. Methods and results Neonatal rat cardiomyocytes were pre-treated with and without the specific B-RAF inhibitor SB590885 and then stimulated with phenylephrine to induce hypertrophy. Inhibition of B-RAF completely impeded the hypertrophic response and led to a significant reduction of MEK1/2 phosphorylation. By applying a eukaryotic cDNA expression screen, based on a dual-luciferase reporter assay for B-RAF activity measurement, we identified RCN1 as a new negative modulator of B-RAF activity. Adenovirus-mediated overexpression of reticulocalbin 1 (RCN1) completely impeded phenylephrine-induced hypertrophy and led to significantly reduced MEK1/2 phosphorylation. Conversely, adenoviral knockdown of RCN1 with a specific synthetic miRNA induced cardiomyocyte hypertrophy and significantly increased MEK1/2 phosphorylation. Conclusions In summary, our results show that the inhibition of B-RAF abolishes cardiomyocyte hypertrophy and we identified RCN1 as novel negative modulator of cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. Our results show that B-RAF kinase activity is essential for cardiac hypertrophy and RCN1, its newly identified negative regulator, abolishes hypertrophic response of cardiomyocytes in vitro. [ABSTRACT FROM PUBLISHER]

Aims To evaluate passive-fixation lead failure rates and long-term patient survival in subjects implanted with Sprint Fidelis electrodes. Methods and results We identified 748 subjects who received a Sprint Fidelis (n = 429; Medtronic models 6948: 94.8%, 6949: 2.6%, 6930: 1.9%, 6931: 0.7%) or a Sprint ‘non-Fidelis’ implantable cardioverter defibrillator lead (n = 319, Medtronic models 6944: 68.6%, 6947: 17.9%, 6942: 7.8%, 6943: 3.4%, 6945: 2.2%) at our centre between 1998 and 2008. Kaplan–Meier patient survival was lower in the Fidelis group than in the Control cohort (68.4 vs. 77.0% at 5 years, P = 0.0061), but multivariate analyses revealed no significant association between mortality and implanted lead type. Passive-fixation lead failure rate at 5 years was 14.4% (95% confidence interval (CI) [9.2, 19.3]) in the Fidelis (n = 414) group and 1.8% (95% CI [0.0–3.8]) in the Control (n = 241) cohort (P < 0.001 upon multivariate comparison). Conclusion Failure rates of passive-fixation Sprint Fidelis leads are increased and similar to those previously reported for active-fixation Fidelis electrodes. Despite the elevated risk for lead failure and its potential sequelae, the Sprint Fidelis has no obvious impact on long-term mortality. [ABSTRACT FROM PUBLISHER]

Aims Induced pluripotent stem cells (iPSCs) provide a unique opportunity for the generation of patient-specific cells for use in disease modelling, drug screening, and regenerative medicine. The aim of this study was to compare human-induced pluripotent stem cells (hiPSCs) derived from different somatic cell sources regarding their generation efficiency and cardiac differentiation potential, and functionalities of cardiomyocytes. Methods and results We generated hiPSCs from hair keratinocytes, bone marrow mesenchymal stem cells (MSCs), and skin fibroblasts by using two different virus systems. We show that MSCs and fibroblasts are more easily reprogrammed than keratinocytes. This corresponds to higher methylation levels of minimal promoter regions of the OCT4 and NANOG genes in keratinocytes than in MSCs and fibroblasts. The success rate and reprogramming efficiency was significantly higher by using the STEMCCA system than the OSNL system. All analysed hiPSCs are pluripotent and show phenotypical characteristics similar to human embryonic stem cells. We studied the cardiac differentiation efficiency of generated hiPSC lines (n = 24) and found that MSC-derived hiPSCs exhibited a significantly higher efficiency to spontaneously differentiate into beating cardiomyocytes when compared with keratinocyte-, and fibroblast-derived hiPSCs. There was no significant difference in the functionalities of the cardiomyocytes derived from hiPSCs with different origins, showing the presence of pacemaker-, atrial-, ventricular- and Purkinje-like cardiomyocytes, and exhibiting rhythmic Ca2+ transients and Ca2+ sparks in hiPSC-derived cardiomyocytes. Furthermore, spontaneously and synchronously beating and force-developing engineered heart tissues were generated. Conclusions Human-induced pluripotent stem cells can be reprogrammed from all three somatic cell types, but with different efficiency. All analysed iPSCs can differentiate into cardiomyocytes, and the functionalities of cardiomyocytes derived from different cell origins are similar. However, MSC-derived hiPSCs revealed a higher cardiac differentiation efficiency than keratinocyte- and fibroblast-derived hiPSCs. [ABSTRACT FROM PUBLISHER]

Aims Apolipoprotein E (apoE) may act as a vasculoprotective factor by promoting plasma lipid clearance and cholesterol efflux. Moreover, apoE accumulates at sites of vascular injury and modulates the effect of growth factors on smooth muscle cells (SMCs). Experimental data suggested that hypothalamic apoE expression is reduced in obesity and associated with leptin resistance. In this study, we examined the role of apoE in mediating the effects of leptin on vascular lesion formation. Methods and results Leptin was administered to apoE knockout (apoE−/−) mice via osmotic pumps to increase its circulating levels. Morphometric analysis revealed that leptin did not alter neointima formation and failed to increase α-actin- or PCNA-immunopositive SMCs after vascular injury. Similar findings were obtained after analysis of atherosclerotic lesions. Comparison of apoE−/−, wild-type, or LDL receptor−/− mice and functional analyses in aortic SMCs from WT or apoE−/− mice or human arterial SMCs after treatment with small interfering (si)RNA or heparinase revealed that leptin requires the presence of apoE, expressed, secreted and bound to the cell surface, to fully activate leptin receptor signalling and to promote SMC proliferation and neointima formation. Mechanistically, leptin induced the phosphorylation and membrane translocation of caveolin (cav)-1, and apoE down-regulation or caveolae disruption inhibited the leptin-induced p47phox activation, ROS formation and SMC proliferation. Finally, leptin failed to increase neointima formation in mice lacking cav-1. Conclusion Our findings suggest that apoE mediates the effects of leptin on vascular lesion formation by stabilizing cav-1-enriched cell membrane microdomains in SMCs, thus allowing NADPH oxidase assembly and ROS-mediated mitogenic signalling. [ABSTRACT FROM PUBLISHER]

Aims The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca2+, Na+, K+) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes. Methods and results Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis. Conclusion The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. [ABSTRACT FROM PUBLISHER]

Aims Bone marrow (BM) progenitors participate in new vessel formation and endothelial repair. The leptin receptor (ObR) is expressed on hematopoietic cells; however, the effects of leptin on BM progenitor cells and their angiogenic potential are unknown. Methods and results In the present study, we show that the short-term administration of leptin (over five consecutive days) into wild-type mice increased the number of circulating, BM-derived sca-1+, flk-1+ vascular progenitors, 95 ± 1.7% of which also expressed ObR. Ex vivo stimulation of BM cells with leptin enhanced the expression of NADPH oxidase isoform 2 (NOX2), and the leptin-induced increase in reactive oxygen species production, matrix metalloproteinase-9 (MMP9) expression and circulating soluble KitL levels was absent in mice lacking NOX2. Furthermore, intraperitoneal injections of leptin improved perfusion and increased the number of BM-derived, CD31-positive endothelial cells in ischaemic hindlimbs after femoral artery ligation. The effects of leptin on the mobilization of sca-1+, flk-1+ cells and neovascularization were abolished in mice transplanted with BM from ObR-deficient and in NOX2−/− mice. Conclusion Our findings suggest that the angiogenic effects of leptin involve sca-1+, flk-1+ vascular progenitor cells mobilized from the BM in response to ObR-mediated activation of NOX2, increased MMP9 expression, and sKitL release. [ABSTRACT FROM AUTHOR]

Intrinsic inotropic stimulation of the heart is central to the regulation of cardiovascular function, and exogenous inotropic therapies have been used clinically for decades. Unfortunately, current inotropic drugs have consistently failed to show beneficial effects beyond short-term haemodynamic improvement in patients with heart failure. To address these limitations, new agents targeting novel mechanisms are being developed: (i) istaroxime has been developed as a non-glycoside inhibitor of the sodium-potassium-ATPase with additional stimulatory effects on the sarcoplasmic reticulum calcium pump (SERCA) and has shown lusitropic and inotropic properties in experimental and early clinical studies; (ii) from a mechanistic point of view, the cardiac myosin activators, directly activating the acto-myosin cross-bridges, are most appealing with improved cardiac performance in both animal and early clinical studies; (iii) gene therapy approaches have been successfully employed to increase myocardial SERCA2a; (iv) nitroxyl donors have been developed and have shown evidence of positive lusitropic and inotropic, as well as potent vasodilatory effects in early animal studies; (v) the ryanodine receptor stabilizers reduce pathological leak of calcium from the sarcoplasmic reticulum with initial promising pre-clinical results; and finally, (vi) metabolic energy modulation may represent a promising means to improve contractile performance of the heart. There is an urgent clinical need for agents that improve cardiac performance with a favourable safety profile. These current novel approaches to improving cardiac function provide the hope that such agents may soon be available. [ABSTRACT FROM PUBLISHER]

Aims The calcineurin and nuclear factor of activated T cells (NFAT) pathway can mediate pro-hypertrophic signalling in the heart. Recently, it has been shown that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates NFAT, which limits calcineurin/NFAT signal transduction in T cells and hypertrophy in cultured cardiomyocytes. The hypothesis tested in this study was that DYRK1A prevents calcineurin/NFAT-mediated cardiac hypertrophy in vivo. Methods and results In cultured rat cardiomyocytes, adenovirus-mediated overexpression of DYRK1A antagonized calcineurin-mediated nuclear NFAT translocation and the phenylephrine-induced hypertrophic growth response. To test the ability of DYRK1A to reduce hypertrophic cardiac growth in vivo, we created tetracycline-repressible Dyrk1a transgenic mice to avoid the cardiac developmental defects associated with embryonic DYRK1A expression. However, in the mouse model, histological determination of myocyte diameter, heart weight/body weight ratio, and echocardiographic measurements revealed that myocardial expression of DYRK1A failed to reduce hypertrophy induced via aortic banding or co-expression of calcineurin. This discrepancy is explained, at least in part, by insufficient long-term inhibition of NFAT and the activation of DYRK1A-resistant maladaptive genes in vivo. Conclusion Isolated augmentation of DYRK1A can be compensated for in vivo, and this may significantly limit anti-hypertrophic interventions aimed at enhancing DYRK1A activity. [ABSTRACT FROM AUTHOR]

Aims Remote magnetic catheter navigation (RMN) may facilitate catheter ablation. However, as the system uses permanent magnets, interference (INF) with devices for pacing [pacemaker (PM)], defibrillation [implantable cardioverter defibrillators (ICD)], or cardiac resynchronisation [cardiac resynchronization therapy (CRT)] may occur. We investigated the effects of the RMN system on implanted arrhythmia devices in a prospective series. Methods and results Prior to RMN-guided electrophysiological procedures, devices were fully interrogated and programmed to VVI 40/min with tachycardia detection off (if applicable). Periprocedural device performance was monitored by 12-lead electrocardiogram, and duration and effect of asynchronous stimulation resulting from INF were evaluated. Following the procedure, devices were again interrogated and system integrity verified. A total of 21 procedures in 18 patients with implanted devices [PM n = 12, ICD n = 3, CRT-pacemaker (P) n = 1, CRT-defibrillation (D) n = 2] were evaluated. No relevant changes in lead parameters or device programming were observed after the procedure. No INF was noted in ICD/CRT-D devices (tachycardia detection off) and in 2 PMs, whereas 10 PMs and 1 CRT-P switched to asynchronous stimulation for 1.8 ± 0.3 h (63 ± 13% of RMN duration) without clinical adverse effects. In one patient, ventricular tachycardia (VT) degenerating in ventricular fibrillation occurred, but no causal relation between INF and VT initiation could be ascertained. Conclusion This prospective data provide no evidence that using RMN in patients with implanted arrhythmia devices may cause persistent device dysfunction. Asynchronous PM stimulation is common without negative clinical consequences. Although a causal role of INF for the VT observed seems unlikely, risks and benefits of RMN utilization should carefully be weighed for each patient with an implanted arrhythmia device. [ABSTRACT FROM PUBLISHER]

Aims: To assess the role of cardiac troponin T (cTnT) levels on admission using a new, highly sensitive assay (hsTnT) in the risk assessment of normotensive patients with acute pulmonary embolism (PE). [ABSTRACT FROM PUBLISHER]

Aims: We tested the hypothesis that, in heart failure with normal ejection fraction (HFNEF), diastolic dysfunction is accentuated at increasing heart rates, and this contributes to impaired frequency-dependent augmentation of cardiac output. [ABSTRACT FROM PUBLISHER]

Introduction:: Prevention of smoking-related disease is a major challenge to medicine. Although interventions delivered by clinicians can reduce smoking rates, the teaching of smoking cessation methods is not a top priority in most medical curricula. [ABSTRACT FROM PUBLISHER]

Aims We investigated the value of a novel early biomarker, heart-type fatty acid-binding protein (H-FABP), in risk stratification of patients with acute pulmonary embolism (PE). [ABSTRACT FROM PUBLISHER]

Aims Obstructive sleep apnoea (OSA) is associated with oxygen desaturation, blood pressure increase, and neurohumoral activation, resulting in possible detrimental effects on the cardiovascular system. Continuous positive airway pressure (CPAP) is the therapy of choice for OSA. In a recent study, nocturnal atrial overdrive pacing (pacing) reduced the severity of sleep apnoea in pacemaker patients. We compared the effects of CPAP with those of pacing in patients with OSA but without pacemaker indication or clinical signs of heart failure. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: This study investigated the role of calsequestrin (CSQ) in the control of excitation–contraction (E–C) coupling in the heart. Methods: CSQ over-expression was induced in isolated rabbit ventricular cardiomyocytes using an adenovirus coding for rabbit CSQ (Ad-CSQ). After 24 h of culture, CSQ protein expression was increased by 58±18% (n =10). An adenovirus coding for β-galactosidase (Ad-LacZ) was used as a control. Results: In voltage-clamped, Fura-2-loaded cardiomyocytes, L-type Ca2+ current (I Ca,L) and Ca2+ transient amplitude were both increased in the Ad-CSQ group by ∼78%. Doubling the external Ca2+ concentration in the control group (Ad-LacZ) increased the LTCC amplitude to a similar degree (85±6%), but increased the Ca2+ transient amplitude by 149±13%. This suggests that SR Ca2+ release may be inhibited upon CSQ over-expression. Alternatively, nifedipine (0.5 μM) was used to reduce I Ca,L in Ad-CSQ-transfected cells to values comparable to control (Ad-LacZ). Under these conditions, Ca2+ transient amplitude was not different from Ad-LacZ, but the SR Ca2+ content was ∼60% higher as assessed by both the caffeine-induced Ca2+ release and the accompanying Na+/Ca2+ exchanger current (I NCX). The cause of the increased I Ca,L is unknown. No change in the expression level of the α1-subunit of the L-type Ca channel was observed. β-Escin-permeabilized cardiomyocytes were used to study Ca2+ sparks imaged with Fluo-3 at 145–155 nmol/L [Ca2+]. Spontaneous Ca2+ spark frequency, duration, width, and amplitude were unchanged in the Ad-CSQ group, but SR Ca2+ content was 48% higher than Ad-LacZ. Conclusions: CSQ over-expression increased SR Ca2+ content but reduced the gain of E–C coupling in rabbit cardiomyocytes. [Copyright &y& Elsevier]

Aims Recent studies have suggested that human extracardiac progenitor cells are capable of differentiating into cardiomyocytes. In animal studies, myocardial infarction attracted bone marrow stem cells and enhanced their differentiation into cardiomyocytes. Based on these findings, we hypothesised that myocardial infarction stimulates the invasion of progenitor cells and their differentiation into endothelial and cardiac cells in the human heart. [ABSTRACT FROM PUBLISHER]

Objective: In heart failure (HF), the generation of reactive oxygen species (ROS) is enhanced. It was shown that failing cardiac myocytes are more susceptible to ROS-induced damage, possibly due to increased expression of the sarcolemmal Na–Ca exchanger (NCX). Methods: We investigated the consequences of increased expression levels of NCX in adult rabbit ventricular cardiomyocytes (via adenovirus-mediated gene transfer, Ad-NCX1-GFP) with respect to tolerance towards ROS. After 48-h incubation, cells were monitored for morphological changes on an inverted microscope. ROS were generated via hydrogen peroxide (H2O2) (100 μmol/l) and Fe3+/nitrilotriacetate (Fe3+/NTA, 100/200 μmol/l) for 4 min and cell morphology was followed over 30 min. [Na+]i and [Ca2+]i in native cells were measured using SBFI-AM and Indo1-AM, respectively. Results: In native myocytes, exposure to ROS induced hypercontracture. This was accompanied by a 1.3-fold increase in diastolic Indo1 fluorescence ratio (P<0.05). Overexpression of NCX significantly enhanced development of hypercontracture. After 15 min, the percentage of cells that had undergone hypercontracture (Fhyper) was 85±4% vs. only 44±10% in control cells (P<0.05). Inhibition of NCX-mediated Ca2+ entry with KB-R7943 (5 μmol/l) reduced Fhyper to 33±11% (P<0.05). [Na+]i was increased 2.9-fold 1 min prior to hypercontracture (P<0.05). Conclusions: ROS-induced hypercontracture is due to Ca2+ entry via NCX which could be triggered by a concomitant substantial increase in [Na+]i. Elevated NCX levels predispose to ROS-induced injury, a mechanism likely contributing to myocyte dysfunction and death in heart failure. [Copyright &y& Elsevier]

Objective: Increased levels of inhibitory G proteins have been observed in heart failure, but their physiological relevance in mediating the reduced β-adrenergic response is largely unknown. Methods: To evaluate the functional consequences of Gαi2 overexpression, we studied myocardial contraction in intact isometric contracting cardiac rabbit trabeculae and isolated myocytes after adenovirus-mediated gene transfer of Gαi2. Results: Neither Gαi2 nor lacZ (control) overexpression altered baseline contractile force. After 72 h of continuous contractions, developed force (Fdev) increased after addition of 1 μM isoproterenol by 28.5±9.7 mN/mm2 in the control group, which was unchanged from the initial response at t=0 h (23.7±3.8 mN/mm2). In sharp contrast, in preparations transfected with AdGαi2, the response to isoproterenol was significantly attenuated (5.9±2.0 vs. 27.6±4.2 mN/mm2, t=72 vs. 0 h, respectively, P<0.01). In a primary culture of transfected isolated myocytes from a nearly identical baseline, isoproterenol increased cell shortening by 3.1±0.6% in the lacZ transfected myocytes, but only by 1.3±0.5% in Gαi2 transfected myocytes (t=72 h, P<0.01). In Gαi2 transfected myocytes, pertussis toxin restored β-adrenergic responsiveness, indicating specificity of attenuation by the transgene. Conclusions: Overexpression of Gαi2 attenuates the positive inotropic effects of β-adrenergic stimulation in myocardium. In addition, the method we developed allows investigation of a causal link between altered protein expression and subsequent alterations in contractile function in a physiological relevant in vitro manner. [Copyright &y& Elsevier]

Background: Pyruvate has been shown to increase contractile function in isolated myocardium and to improve hemodynamics in patients with congestive heart failure. We tested the hypothesis that pyruvate potentiates the inotropic response to β-adrenergic stimulation and to elevated extracellular calcium, since this may be of potential therapeutic value in the clinical setting of acute heart failure in order to circumvent deleterious effects on energy demand as can occur during catecholamine therapy. Methods and Results: We investigated isometrically contracting isolated multicellular muscle preparations from terminal failing human hearts at 37°C, pH 7.4, and a stimulation frequency of 1 Hz. At an extracellular calcium concentration of 1.25 mM, pyruvate (10 mM) alone increased developed force (Fdev) from 9.0±2.3 to 21.1±4.3 mN/mm2 (n=9, P<0.001) and isoproterenol (1 μM) alone increased Fdev from 9.5±2.0 to 31.3±5.4 mN/mm2 (P<0.001), whereas the combination of pyruvate and isoproterenol increased Fdev over-proportionally from 9.0±2.3 to 47.4±6.4 mN/mm2 (P<0.01). In a separate series we assessed the combination of pyruvate and calcium. Although Fdev did not increase from 12 to 16 mM [Ca2+]o, 10 mM pyruvate further increased Fdev from 25.8±5.0 to 30.6±4.7 mN/mm2 (P<0.01). Rapid cooling contractures revealed that altered myofilament responsiveness and/or sarcoplasmic reticulum (SR) calcium load must underlie the positive inotropic effect of pyruvate. Conclusion: A combination of pyruvate and β-adrenergic stimulation may be of therapeutic value in acute heart failure by reducing the concentrations of potential deleterious catecholamines that are currently necessary to maintain adequate tissue perfusion. [ABSTRACT FROM PUBLISHER]

Objective: Protein kinase C (PKC) is thought to be involved in the regulation of the mammalian cardiac excitation–contraction coupling process by vasoactive peptides like endothelin-1 (ET-1). However, the demonstration of a causal link between activation of specific PKC isoforms and the increase in contractility mediated by ET-1 is still inferential. Methods: By means of adenovirus-mediated gene transfer, we specifically overexpressed PKCϵ in cultured adult rabbit ventricular myocytes (Ad-PKCϵ). Myocyte shortening and [Ca2+]i transients under basal and ET-1-stimulated conditions were measured in Ad-PKCϵ and Ad-LacZ control transfected cells. Results: Infection with Ad-PKCϵ resulted in a strong, virus dose-dependent increase in PKCϵ protein levels, whereas protein expression of other PKC isoforms remained unchanged. Using a multiplicity of infection of 100 plaque-forming units/myocyte, basal and cofactor-dependent PKCϵ kinase activity was increased 28- and 90-fold, respectively, when compared to control. Myocyte basal fractional shortening and [Ca2+]i transient amplitude were both increased by 21% (P<0.05 each) in Ad-PKCϵ transfected myocytes when compared to Ad-LacZ transfected control myocytes. The positive inotropic effect of ET-1 in control myocytes was markedly blunted in PKCϵ-overexpressing myocytes. Conclusion: Specific overexpression of PKCϵ in rabbit ventricular myocytes increases basal myocyte contractility and [Ca2+]i transients, and modifies their responsiveness to ET-1. [ABSTRACT FROM PUBLISHER]

Objective:The immunosuppressive drug Cyclosporine A (CsA) is a key substance in pharmacological therapy following solid organ transplantation and has been suggested to prevent cardiac hypertrophy. We investigated the direct effects of CsA on myocardial function, because these are largely unknown. Methods: In multicellular cardiac muscle preparations from end-stage failing and non-failing human hearts as well as from non-failing rabbit hearts we investigated the effects of CsA on contractile performance, sarcoplasmic reticulum (SR) Ca2+-load, cytosolic calcium transients, calcium sensitivity of the myofilaments, and myocardial oxygen consumption. Results: In failing human muscle preparations there was a concentration dependent decrease in contractile force; the maximal effect amounted to 55.6±6.4% of control while EC50 was reached at 1.0±0.3 nM (n=6). These concentrations are at and even below the therapeutic plasma levels. CsA decreased the aequorin light signal in human failing trabeculae to 71.5±5.9% (n=5), indicating decreased calcium transients. Estimation of the SR calcium load via measurement of rapid cooling contractures revealed a decrease to 84.4±6.5% in failing human preparations (n=6). Measurements of both decreased SR calcium load and force development in presence of CsA were also observed in four non-failing human muscle preparations. In rabbit muscle preparations (n=8), developed force decreased to 50.2±7.7% (n=8, EC50: 1.9±0.4 nM) and rapid cooling contractures to 74.0±7.4% of control at 100 nmol/l CsA. No direct effects were observed on myofilament calcium sensitivity nor on maximal force development of permeabilized preparations from the rabbit (n=7). Oxygen consumption measurements showed that CsA decreased the economy of contraction to 76.4±7.9% in rabbit preparations (n=8). Conclusions: CsA causes a direct cardio-depressive effect at clinically relevant concentrations, most likely due to altered handling of Ca2+ by the SR. [ABSTRACT FROM PUBLISHER]

Objective: Human heart failure is associated with a disturbed intracellular calcium (Ca2+) homeostasis. In this regard, ventricular wall stress is considered to be a determinant for expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a). In the present study, we analyzed the transmural protein and/or mRNA levels of SERCA2a, other Ca2+-handling proteins, and of atrial and brain natriuretic peptides (ANP and BNP) in the human heart. Methods: Subepicardial (epi), midmyocardial (mid), and subendocardial (endo) sections of the left ventricular free wall from end-stage failing (n=17) and nonfailing (n=5) human hearts were analyzed by Western blot for immunoreactive protein levels of SERCA2a, phospholamban (PLN), and calsequestrin (CS). Subepi- and subendocardial sections were analyzed by Northern blot for steady-state mRNA levels of SERCA2a, Na+-Ca2+ exchanger (NCX1), ANP, and BNP. Results: SERCA2a protein and mRNA levels were reduced by 40±5% (P<0.01) and 25±7% (P<0.05) in endo compared to epi in the failing heart and by 27±14% and 16±12% (non-significant) in the nonfailing heart, respectively. PLN protein levels were reduced by 23±6% (P<0.05) in endo compared to epi in the failing heart and by 17±25% (non-significant) in the nonfailing heart, whereas CS protein levels and NCX1 mRNA levels were similar across the left ventricular wall. Strikingly, in the failing heart, both BNP and ANP mRNA levels were upregulated predominantly in endo. Conclusions: In the failing human heart, SERCA2a and PLN, as well as natriuretic peptides but not CS and NCX1 are differentially expressed across the left ventricular wall, implicating (1) different susceptibility of subendocardium and subepicardium to factors affecting expression of these proteins and (2) differences in regulation of the distinct calcium-cycling proteins. [ABSTRACT FROM PUBLISHER]

The progress made in our understanding of the pathophysiology and treatment of congestive heart failure (CHF) would not have been possible without a number of animal models of heart failure and hypertrophy, each one having unique advantages as well as disadvantages. The species and interventions used to create CHF depends on the scientific question as well as on factors such as ethical and economical considerations, accessibility and reproducibility or the model. How closely the model should mimic the human syndrome of CHF depends on the scientific question under investigation. If the goal is to study pathophysiological processes like remodeling or the function of subcellular systems such as excitation contraction-coupling processes, contractile protein function or energetics, the model of heart failure should mimic the clinical setting as closely as possible. However, if defined causal connections are under investigation such as structure–function analyses or regulation of gene expression, exact reflection of the clinical setting by the animal model may be less important. In this review, animal models of heart failure are discussed with particular focus on similarities between the animal model and the failing human heart regarding myocardial function as well as molecular and subcellular mechanisms. In addition, new models of heart failure and hypertrophy, and finally some recent animal models of myocarditis are reviewed. [ABSTRACT FROM PUBLISHER]

Objective: The aim was to study the effect of three positive inotropic interventions on myocardial force development and heat production in guinea pig papillary muscles in order to investigate the energetic consequences. Methods: The positive inotropic agents used were epinine (β adrenoceptor stimulation), E-1020 (phosphodiesterase inhibition), and ouabain (sodium-potassium ATPase inhibition). Heat measurements were accomplished using antimony-bismuth thermopiles, and initial heat was separated into tension dependent and tension independent heat using the butanedione-monoxime (BDM) and the shortening methods. Results: Optimal concentrations of epinine, E-1020, and ouabain increased peak developed force from 20.0(SD 6.6) to 55.5(9.3) (n = 5; p < 0.01), from 20.9(9.1) to 27.2(7.2) (n = 6; p < 0.05), and from 23.4(9.2) to 44.9(18.0) mN·mm−2(n = 6; p < 0.01). respectively. Epinine and E-1020 decreased the tension-time integral per unit initial heat, ie, the economy of isometric contraction, from 5.5(1.4) to 3.6(0.5) (p < 0.01) and from 5.5(1.4) to 3.1(0.9) N·m·s·J−1 (p < 0.01). respectively: no significant change was observed with ouabain [6.7(1.4) to 8.3(0.5) N·m·s·J−1]. The tension independent heat (calcium turnover) was measured in two different ways using BDM or shortening to abolish force production. It was increased significantly by epinine (by 141-243%), E-1020 (by 77-114%), and ouabain (by 23-38%). The first measurement in brackets is the BDM estimate, the second is the shortening estimate. From the tension-time integral and the tension dependent heat the crossbridge force-time integral was analysed: epinine and E-1020 decreased the crossbridge force-time integral from 0.46(0.16) to 0.31(0.06) pN·s (p < 0.01) and from 0.50(0.19) to 0.31 (0.08) pN·s (p < 0.01), respectively, while ouabain left the force-time integral unchanged [0.59(0.27) to 0.63(0.20) pN·s]. Conclusions: (1) The inotropic effect of ouabain results from an increase in muscle activation with no change in crossbridge kinetics; (2) epinine and E-1020 increase the tension independent heat and decrease the crossbridge force-time integral, both effects reducing the overall economy; and (3) the shortening and BDM methods for measuring the tension independent heat give qualitatively similar but quantitatively different results.Cardiovascular Research 1994;28:994-1002 [ABSTRACT FROM PUBLISHER]