Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. The aim of this study was to evaluate if left ventricular unloading in cardiogenic shock patients treated with VA-ECMO was associated with lower mortality. Methods: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading (using an Impella) at 16 tertiary-care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity-score-matched cohort. Results: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio 0.79, 95% confidence interval 0.63-0.98, p=0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading; e.g. severe bleeding in 98 (38.4%) vs. 45 (17.9%), access-site related ischemia in 55 (21.6%) vs. 31 (12.3%), abdominal compartment in 23 (9.4%) vs. 9 (3.7%) and renal replacement therapy in 148 (58.5%) vs. 99 (39.1%). Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in cardiogenic shock patients treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in cardiogenic shock patients treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

The perception of the Z-disc in striated muscle has undergone significant changes in the past decade. Traditionally, the Z-disc has been viewed as a passive constituent of the sarcomere, which is important only for the cross-linking of thin filaments and transmission of force generated by the myofilaments. The recent discovery of multiple novel molecular components, however, has shed light on an emerging role for the Z-disc in signal transduction in both cardiac and skeletal muscles. Strikingly, mutations in several Z-disc proteins have been shown to cause cardiomyopathies and/or muscular dystrophies. In addition, the elusive cardiac stretch receptor appears to localize to the Z-disc. Various signalling molecules have been shown to interact with Z-disc proteins, several of which shuttle between the Z-disc and other cellular compartments such as the nucleus, underlining the dynamic nature of Z-disc-dependent signalling. In this review, we provide a systematic view on the currently known Z-disc components and the functional significance of the Z-disc as an interface between biomechanical sensing and signalling in cardiac and skeletal muscle functions and diseases.

Signaling by the calcium-dependent phosphatase calcineurin profoundly influences the growth and gene expression of cardiac and skeletal muscle. Calcineurin binds to calsarcins, a family of muscle-specific proteins of the sarcomeric Z-disc, a focal point in the pathogenesis of human cardiomyopathies. We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1. As a consequence of inappropriate calcineurin activation, mice with a null mutation in calsarcin-1 showed an excess of slow skeletal muscle fibers. The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload. In contrast, cardiac adaptation to other hypertrophic stimuli, such as chronic catecholamine stimulation or exercise, was not affected. These findings show important roles for calsarcins as modulators of calcineurin signaling and the transmission of a specific subset of stress signals leading to cardiac remodeling in vivo.

Cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signalling pathways dependent on extracellular calcium (Ca2+) influx that control normal and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the Ca2+ release-activated Ca2+ (CRAC) channel Orai1 and stromal interaction molecule 1 (Stim1) in postnatal cardiomycoyte store-operated Ca2+ entry (SOCE) and impact on normal and hypertrophic postnatal cardiomyocyte growth. Employing a combination of siRNA-mediated gene silencing, cultured neonatal rat ventricular cardiomyocytes together with indirect immunofluorescence, epifluorescent Ca2+ imaging and site-specific protein phosphorylation and real-time mRNA expression analysis, we show for the first time that both Orai1 and Stim1 are present in cardiomyocytes and required for SOCE due to intracellular Ca2+ store depletion by thapsigargin. Stim1-KD but not Orai1-KD significantly decreased diastolic Ca2+ levels and caffeine-releasable Ca2+ from the sarcoplasmic reticulum (SR). Conversely, Orai1-KD but not Stim1-KD significantly diminished basal NRCM cell size, anp and bnp mRNA levels and activity of the calcineurin (CnA) signaling pathway although diminishing both Orai1 and Stim1 protein similarly attenuated calmodulin kinase II (CamKII) and ERK1/2 activity under basal conditions. Both Orai1- and Stim1-KD completely abrogated phenylephrine (PE) mediated hypertrophic NRCM growth and enhanced natriuretic factor expression by inhibiting Gq-protein conveyed activation of the CaMKII and ERK1/2 signaling pathway. Interestingly, only Orai1-KD but not Stim1-KD prevented Gq-mediated CaN-dependent prohypertrophic signalling. This study shows for the first time that both Orai1 and Stim1 have a key role in cardiomyocyte SOCE regulating both normal and hypertrophic postnatal cardiac growth in vitro.

During the last 15 years, the perception of the cardiac z-disc has undergone substantial changes. Initially viewed as a structural component at the lateral boundaries of the sarcomere, the cardiac z-disc has increasingly become recognized as a nodal point in cardiomyocyte signal transduction and disease. This minireview thus focuses on novel components and recent developments in z-disc biology and their role in cardiac signaling and disease.

The composition of skeletal muscle, in terms of the relative number of slow-and fast-twitch fibers, is tightly regulated to enable an organism to respond and adapt to changing physical demands. The phosphatase calcineurin and its downstream targets, transcription factors of the nuclear factor of activated T cells (NFAT) family, play a critical role in this process by promoting the formation of slow-twitch, oxidative fibers. Calcineurin binds to calsarcins, a family of striated muscle-specific proteins of the sarcomeric Z-disc. We show here that mice deficient in calsarcin-2, which is expressed exclusively by fast-twitch muscle and encoded by the myozenin 1 (Myoz1) gene, have substantially reduced body weight and fast-twitch muscle mass in the absence of an overt myopathic phenotype. Additionally, Myoz1 KO mice displayed markedly improved performance and enhanced running distances in exercise studies. Analysis of fiber type composition of calsarcin-2-deficient skeletal muscles showed a switch toward slow-twitch, oxidative fibers. Reporter assays in cultured myoblasts indicated an inhibitory role for calsarcin-2 on calcineurin, and Myoz1 KO mice exhibited both an excess of NFAT activity and an increase in expression of regulator of calcineurin 1-4 (RCAN1-4), indicating enhanced calcineurin signaling in vivo. Taken together, these results suggest that calsarcin-2 modulates exercise performance in vivo through regulation of calcineurin/NFAT activity and subsequent alteration of the fiber type composition of skeletal muscle.

Abstract-Biomechanical stress ie, attributable to pressure overload, leads to cardiac hypertrophy and may ultimately cause heart failure. Yet, it is still unclear how mechanical stress is sensed and transduced on the molecular level. To systematically elucidate the underlying signal transduction pathways, we analyzed the gene expression profile of stretched cardiomyocytes on a genome-wide scale in comparison with other inducers of hypertrophy such as pharmacological stimulation. Neonatal rat ventricular cardiomyocytes were either stretched biaxially or stimulated with phenylephrine (PE), both resulting in a similar degree of hypertrophy. Microarray analyses revealed 164 genes Ͼ2.0-fold up-and 21 genes Ͻ0.5-fold downregulated (PϽ0.01). Differential expression was confirmed by real-time polymerase chain reaction. Genes of the "fetal gene program" such as BNP were induced by both stretch (4.2ϫ) and PE (2.9ϫ). We also verified upregulation of known stretch-responsive genes, including HSP70 (20.9ϫ) and c-myc (3.0ϫ). Moreover, several genes were found to be preferentially induced by stretch, such as the cardioprotective cytokine GDF15 (24.8ϫ) and heme oxygenase 1 (Hmox1, 10.8ϫ; both confirmed on protein level). Neither PE nor endothelin-1 upregulated GDF15 and Hmox1, whereas angiotensin II significantly induced both genes. Conversely, the AT 1 receptor blocker irbesartan markedly blunted stretch-mediated GDF15 and Hmox1 upregulation, suggesting that the angiotensin receptor tranduces the biomechanical induction of these genes. In conclusion, we report a comprehensive gene expression profile of cardiomyocytes subjected to biomechanical stress in comparison with pharmacologically induced hypertrophy. Our data imply that a stretch-specific gene program exists, which is mediated, at least in part, by angiotensin II-dependent signaling. (Hypertension. 2008;51:309-318.)Key Words: hypertrophy Ⅲ gene expression Ⅲ microarray analysis Ⅲ stress Ⅲ mechanical C ardiac hypertrophy can be induced either by intrinsic stimuli, ie, by inherited mutations of contractile proteins leading to hypertrophic cardiomyopathy or by extrinsic stimuli such as chronic biomechanical stress attributable to arterial hypertension or valvular heart disease. 1 Long standing left ventricular hypertrophy leads to progressive remodeling with fibrosis and cardiomyocyte apoptosis, 2 ultimately resulting in ventricular dilation, heart failure, and increased susceptibility to malignant arrhythmias. 3 Accordingly, cardiac hypertrophy has been shown to be an independent and powerful predictor of cardiovascular morbidity and mortality. 4 -6 The typical cellular features of cardiac hypertrophy comprise an increase in cardiomyocyte size associated with enhanced sarcomerogenesis and protein synthesis, as well as activation of the "fetal" or "hypertrophic" gene program, including the natriuretic peptides ANF and BNP. 7 However, it is still unclear how biomechanical stress, ie, attributable to pressure overload, is sensed and transduced toward initiation of cardiomyo...

Background-Osteopontin, a glycoprotein that can be detected in plasma, was found to be upregulated in several animal models of cardiac failure and may thus represent a new biomarker that facilitates risk stratification in patients with heart failure. We therefore tested whether osteopontin plasma levels are elevated in patients with chronic heart failure and whether they provide independent prognostic information. Methods and Results-We analyzed osteopontin plasma levels in 420 patients with chronic heart failure due to significantly impaired left ventricular systolic function and correlated the results with disease stage and prognostic information (median follow-up of 43 months). We found that osteopontin plasma levels were significantly elevated in patients with heart failure as compared with healthy control subjects (532 versus 382 ng/mL, Pϭ0.008), irrespective of heart failure origin (ischemic versus dilated cardiomyopathy). Furthermore, osteopontin levels were higher in patients with moderate to severe heart failure than in patients with no or mild symptoms (672 ng/mL for New York Heart Association class III/IV versus 479 ng/mL for class I/II, PϽ0.0001). Estimated 4-year death rates in patients with osteopontin levels above or below a cutoff value derived from receiver operating characteristic analyses were 56.5% and 28.4%, respectively (hazard ratio 3.4, 95% confidence interval 2.2 to 5.3, PϽ0.0001). In a multivariable model that included demographic, clinical, and biochemical parameters such as N-terminal prohormone brain natriuretic peptide, osteopontin emerged as an independent predictor of death (hazard ratio 2.3, 95% confidence interval 1.4 to 3.5, PϽ0.001). Conclusion-Our findings suggest that osteopontin might be useful as a novel prognostic biomarker in patients with chronic heart failure. (Circ Heart Fail. 2008;1:43-49.)Key Words: heart failure Ⅲ prognosis Ⅲ biomarker H eart failure is a highly prevalent syndrome throughout the industrialized world and is associated with significant morbidity and mortality. In the United States, heart failure affects more than 5 million people and is responsible for nearly 50 000 deaths each year. 1 Furthermore, annual hospitalizations for heart failure have increased over the past 20 years, from 377 000 to almost 1 million. 2 Clinical Perspective p 49Thus, in patients with heart failure, an accurate diagnosis and prognostic evaluation are critical to identify those at greatest risk for cardiac decompensation and death. Traditional risk stratification by clinical parameters and assessment of left ventricular ejection fraction has proved helpful in the clinical management of heart failure patients. 3 More recently, the natriuretic peptides, in particular brain natriuretic peptide (BNP) or its fragment N-terminal prohormone BNP (NT-pro-BNP), have emerged as biomarkers that convey additional information for diagnosis and prognostication of death. 4 However, even when clinical information is combined with BNP levels, there is considerable variation in the outcome. 5 A...