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The 2021 guidelines of the European Society of Cardiology for the diagnosis and treatment of heart failure recommend the early implementation of all four mortality-lowering drug classes for heart failure with reduced ejection fraction (HFrEF), i. e. angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor II blocker-neprilysin inhibitor (ARNI), betablocker (BB), mineralocorticoid receptor-antagonists (MRA), and sodium-glucose linked transporter-2 inhibitors (SGLT2i). This article aims to give a practical compendium supporting physicians to enable safe and efficacious treatment for patients with HFrEF.

Purpose Recurrent stroke is considered to increase the incidence of severe disability and death. For correct risk assessment and patient management it is essential to identify the origin of stroke at an early stage. Transthoracic echocardiography (TTE) is the initial standard of care for evaluating patients in whom a cardioembolic source of stroke (CES) is suspected but its diagnostic capability is limited. Transesophageal echocardiography (TEE) is considered as gold standard; however, this approach is time consuming, semi-invasive and not always feasible. We hypothesized that adding a delayed-phase cardiac computed tomography (cCT) to initial multimodal CT might represent a valid alternative to routine clinical echocardiographic work-up. Material and Methods Patients with suspected acute cardioembolic stroke verified by initial multimodal CT and subsequently examined with cCT were included. The cCT was evaluated for presence of major CES and compared to routine clinical echocardiographic work-up. Results In all, 102 patients with suspected acute CES underwent cCT. Among them 60 patients underwent routine work-up with echocardiography (50 TTE and only 10 TEE). By cCT 10/60 (16.7%) major CES were detected but only 4 (6.7%) were identified by echocardiography. All CES observed by echocardiography were also detected by cCT. In 8 of 36 patients in whom echocardiography was not performed cCT also revealed a major CES. Conclusion These preliminary results show the potential diagnostic yield of delayed-phase cCT to detect major CES and therefore could accelerate decision-making to prevent recurrence stroke. To confirm these results larger studies with TEE as the reference standard and also compared to TTE would be necessary.

ObjectiveVentricular secondary mitral regurgitation (SMR) (Carpentier type IIIb) results from left ventricular (LV) remodelling, displacement of papillary muscles and tethering of mitral leaflets. The most appropriate treatment approach remains controversial. We aimed to assess the safety and efficacy of standardised relocation of both papillary muscles (subannular repair) at 1-year follow-up (FU).MethodsREFORM-MR (Reform-Mitral Regurgitation) is a prospective, multicentre registry that enrolled consecutive patients with ventricular SMR (Carpentier type IIIb) undergoing standardised subannular mitral valve (MV) repair in combination with annuloplasty at five sites in Germany. Here, we report survival, freedom from recurrence of MR >2+, freedom from major adverse cardiac and cerebrovascular events (MACCEs), including cardiovascular death, myocardial infarction, stroke, MV reintervention and echocardiographic parameters of residual leaflet tethering at 1-year FU.ResultsA total of 94 patients (69.1% male) with a mean age of 65.1±9.7 years met the inclusion criteria. Advanced LV dysfunction (mean left ventricular ejection fraction 36.4±10.5%) and severe LV dilatation (mean left ventricular end-diastolic diameter 61.0±9.3 mm) resulted in severe mitral leaflet tethering (mean tenting height 10.6±3.0 mm) and an elevated mean EURO Score II of 4.8±4.6 prior to surgery. Subannular repair was successfully performed in all patients, without operative mortality or complications. One-year survival was 95.5%. At 12 months, a durable reduction of mitral leaflet tethering resulted in a low rate (4.2%) of recurrent MR >2+. In addition to a significant improvement in New York Heart Association (NYHA) class (22.4% patients in NYHA III/IV vs 64.5% patients at baseline, pConclusionsOur study demonstrates the safety and feasibility of standardised subannular repair to treat ventricular SMR (Carpentier type IIIb) in a multicentre setting. By addressing mitral leaflet tethering, papillary muscle relocation results in very satisfactory 1-year outcomes and has the potential to durably restore MV geometry; nevertheless, long-term FU is mandatory.Trial registration numberNCT03470155.

Background: Venoarterial 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. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock 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% CI, 0.63–0.98]; P =0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site–related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

BACKGROUND Free-breathing noncontrast-enhanced (non-CE) magnetic resonance angiography (MRA) techniques are of considerable interest for the diagnosis of acute pulmonary embolism (APE), due to the possibility for repeated examinations, avoidance of side effects from iodine-based contrast agents, and the absence of ionizing radiation exposure as compared to CE-computed tomographic angiography (CTA). PURPOSE To analyze the clinical performance of free-breathing and electrocardiogram (ECG)-gated radial quiescent-interval slice-selective (QISS)-MRA compared to CE-CTA and to Cartesian balanced steady-state free precession (bSSFP)-MRA. STUDY TYPE Prospective. SUBJECTS Thirty patients with confirmed APE and 30 healthy volunteers (HVs). FIELD STRENGTH/SEQUENCE Radial QISS- and bSSFP-MRA at 1.5T. ASSESSMENT Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were computed to compare the pulmonary imaging quality between MRA methods. The pulmonary arterial tree was divided into 25 branches and an ordinal scoring system was used to assess the image quality of each pulmonary branch. The clinical performance of the two MRA techniques in accurately assessing APE was evaluated with respect to CE-CTA as the clinical reference standard. STATISTICAL TESTS Wilcoxon signed-rank and Spearman's correlation tests were performed. Sensitivity and specificity of the MRA techniques were determined using CE-CTA as the clinical reference standard. RESULTS Thrombus-mimicking artifacts appeared more frequently in lobar and peripheral arteries of patients with Cartesian bSSFP than with radial QISS-MRA (pulmonary trunk: 12.2% vs. 14.0%, P = 0.64; lobar arteries: 35.6% vs. 22.0%, P = 0.005, peripheral arteries: 74.4% vs. 49.0%, P

Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combinations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from “bench to bedside” can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel “personalized” therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby represents another example for the complex genetic and phenotypic continuum of these diseases.

Recurrent stroke is considered to increase the incidence of severe disability and death. For correct risk assessment and patient management it is essential to identify the origin of stroke at an early stage. Transthoracic echocardiography (TTE) is the initial standard of care for evaluating patients in whom a cardioembolic source of stroke (CES) is suspected but its diagnostic capability is limited. Transesophageal echocardiography (TEE) is considered as gold standard; however, this approach is time consuming, semi-invasive and not always feasible. We hypothesized that adding a delayed-phase cardiac computed tomography (cCT) to initial multimodal CT might represent a valid alternative to routine clinical echocardiographic work-up. Patients with suspected acute cardioembolic stroke verified by initial multimodal CT and subsequently examined with cCT were included. The cCT was evaluated for presence of major CES and compared to routine clinical echocardiographic work-up. In all, 102 patients with suspected acute CES underwent cCT. Among them 60 patients underwent routine work-up with echocardiography (50 TTE and only 10 TEE). By cCT 10/60 (16.7%) major CES were detected but only 4 (6.7%) were identified by echocardiography. All CES observed by echocardiography were also detected by cCT. In 8 of 36 patients in whom echocardiography was not performed cCT also revealed a major CES. These preliminary results show the potential diagnostic yield of delayed-phase cCT to detect major CES and therefore could accelerate decision-making to prevent recurrence stroke. To confirm these results larger studies with TEE as the reference standard and also compared to TTE would be necessary.

Heart failure is one of the major causes of death worldwide. Its pathophysiology is complex and involves alterations in calcium cycling and hypertrophic signaling, as well as subsequent loss of cardiomyocytes due to apoptosis, cardiac fibrosis and progressive contractile dysfunction. The Striatin-interacting phosphatase and kinase (STRIPAK) complex is a mammalian multiprotein complex that consists of phosphatases, kinases and various adaptor proteins. Yet, the STRIPAK complex has so far not been studied in cardiomyocytes. Now we show in cardiomyocytes that the STRIPAK associated kinase MST4 directly interacts with a recently described novel cardiac STRIPAK protein, Myoscape/STRIP2. Multi tissue immunoblot experiments showed that Mst4 abundance is also highly enriched in heart and skeletal muscle. Immunoblot analyses in human biopsy samples form patients with dilated (DCM n=10) or ischemic cardiomyopathy (ICM n=10) revealed that MST4 is strongly upregulated in DCM (12-fold pin vitro by 30% (pin vivo (-45%, n=6; P

This work focuses on implementing a standardized and symptom-oriented flowchart for advanced cardiac imaging in a 24/7 emergency setting using a dual-layer spectral detector CT system. This flowchart was designed to optimize patient management and standardize imaging workflow. It includes acquisition parameters and contrast agent protocols for the most relevant clinical questions regarding cardiac CT imaging in the interdisciplinary emergency department. The automated reconstruction of symptom-oriented spectral images represents an additional strength here. This implementation is designed to be time-efficient and user-friendly and improves diagnostic quality, independent of the qualification level of clinical and technical personnel.

BACKGROUND The MitraClip procedure requires transseptal access of the left atrium with a 24F guiding sheath. We evaluated invasively whether a MitraClip induced iatrogenic atrial septal defect (IASD) leads to development of a relevant interatrial shunt and right ventricular overload. METHODS A total of 69 patients who underwent a MitraClip procedure due to a severe mitral valve regurgitation (MVR) were included in the observational, retrospective cohort study. All pressures were directly measured throughout the procedure. Cardiac index (CI), systemic (Qs) and pulmonary (Qp) flow were calculated using the Fick method. RESULTS Successful MitraClip implantation increased CI (2.5 ± 0.62 vs 3.05 ± 0.77 L/min/m2 ; P

Biomarkers may significantly improve risk stratification algorithms for patients undergoing transcatheter aortic valve implantation (TAVI). While N-terminal pro-B-type natriuretic peptide (NT-proBNP) is established as a biomarker in the context of heart failure, its prognostic implications in patients with normal left ventricular ejection fraction (LVEF) undergoing TAVI are unclear.A total of 504 TAVI patients with normal LVEF were analyzed. Based on preprocedural NT-proBNP levels, patients were stratified into two groups comparing the upper quartile ("Q4", n = 126) with the lower three quartiles ("Q1-3", n = 378). The primary outcome of our study was survival.The "Q4" group included more men (46.8% vs. 34.9%, p = 0.017), had higher rates of atrial fibrillation (55.6% vs. 28.3%, p 0.001) and showed features of more advanced aortic stenosis (mean pressure gradient 49 mmHg vs. 40 mmHg, aortic valve area 0.6 cmNT-proBNP is associated with survival in TAVI patients with normal LVEF. In this patient group, preprocedural NT-proBNP levels do not only correlate with aortic stenosis, but reflect advanced cardiovascular dysfunction, including HFpEF, that might not be completely reversible after TAVI.

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5&ndash, 7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin&rsquo, s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.

The implications of prosthesis-patient mismatch (PPM) in the context of transcatheter aortic valve implantation (TAVI) are still controversial. The objective of our study was thus to investigate the incidence and prognostic impact of PPM after TAVI.Our analysis included 613 TAVI patients in whom the indexed effective orifice area (iEOA) after TAVI was obtained in vivo using echocardiography. Prosthesis sizing was guided by pre-procedural ECG-gated computed tomography. Based on VARC-2 established criteria for significant PPM (iEOA ≤ 0.85 cmWe observed PPM after TAVI in 192 patients (31.3%) with moderate PPM being present in 150 subjects (24.5%) and severe PPM in 42 patients (6.9%). EuroSCORE, impaired LV function, and male gender were associated with PPM status. The "No PPM" group was characterized by higher rates of self-expandable valves (40.4% vs. 25.5%, p 0.001). In a multivariate analysis age 81.2 years, chronic obstructive pulmonary disease, peripheral artery disease, impaired LV function, acute kidney failure stage 3 as well as periprocedural myocardial infarction emerged as independent risk predictors for all-cause mortality after TAVI. After a median follow-up of 12.2 months PPM failed to show a significant association with overall survival (79.2% vs. 79.3%, p = 0.692).The incidence of PPM after TAVI seems to be substantially lower than after SAVR. PPM was less common using self-expandable valves. In our analysis, patients with PPM following TAVI did not have higher rates of all-cause mortality.

INTRODUCTION With subgroups of patients with hypertrophic cardiomyopathy (HCM) confers a 4% to 5% risk for adverse prognosis. Besides left-ventricular muscle mass (LV-MM) myocardial fibrosis (MF) assessable by late gadolinium enhancement in cardiovascular magnetic resonance (LGE-CMR) has been related to that. Myocardial fibrosis can also be demonstrated by late enhancement (LE) in late-enhanced multislice computed tomography (leMDCT). This analysis investigates leMDCT whether to enable quantification of LE load in terms of LE mass by percent LV-MM in HCM. METHODS In a prospective validation study, we included 30 consecutive patients with HCM who underwent leMDCT (64 slice) and LGE-CMR (1.5 T). The leMDCT scan was performed 7 minutes after injection of iodine contrast (Iopromid). Endocardial and epicardial planimetry served for the assessment of LV-MM. Visually detectable LE was quantified using the manual quantification method resulting in LE by percent LV-MM (%LE). The LGE-CMR data served for validation. RESULTS Mean (SD) age was 64.1 (13.9) years. Myocardial fibrosis prevalence was 63.3% (19/30 patients indentified by both leMDCT and LGE-CMR). In leMDCT, tissue density in LE areas compared with normal myocardium was higher (138.2 [23.9] HU vs 98.4 [16.5] HU, P < 0.001) but lower than in the LV cavity (138.2 [23.9] HU vs 169.2 [35.9] HU, P < 0.001). Late enhancement mass in leMDCT seemed to be 7.9 (8.5) g LE versus 8.6 [11] g LGE in CMR (P = 0.497, r = 0.95) resulting in a leMDCT/LGE-CMR relation of 1.2. Referring LE mass to LV-MM gave an LE proportion measured by leMDCT of 4 (3.9) %LE versus 3.9 (4.1) %LGE in LGE-CMR (r = 0.88, P = 0.75). Intraobserver/interobserver reliability of LE mass assessment showed an intraclass correlation coefficient of 0.99 and 0.97. CONCLUSIONS In patients with HCM, leMDCT provides volumetric assessment of LE mass-absolutely and by percent LV-MM.

The intercalated disc (ID) is a major component of the cell-cell contact structures of cardiomyocytes and has been recognized as a hot spot for cardiomyopathy. We have previously identified Myozap as a novel cardiac-enriched ID protein, which interacts with several other ID proteins and is involved in RhoA/SRF signaling in vitro. To now study its potential role in vivo we generated a mouse model with cardiac overexpression of Myozap. Transgenic (Tg) mice developed cardiomyopathy with hypertrophy and LV dilation. Consistently, these mice displayed upregulation of the hypertrophy-associated and SRF-dependent gene expression. Pressure overload (transverse aortic constriction, TAC) caused exaggerated cardiac hypertrophy, further loss of contractility and LV dilation. Similarly, a physiological stimulus (voluntary running) also led to significant LV dysfunction. On the ultrastructural level, Myozap-Tg mouse hearts exhibited massive protein aggregates composed of Myozap, desmoplakin and other ID proteins. This aggregate-associated pathology closely resembled the alterations observed in desmin-related cardiomyopathy. Interestingly, desmin was not detectable in the aggregates, yet was largely displaced from the ID. Molecular analyses revealed induction of autophagy and dysregulation of the unfolded protein response (UPR), associated with apoptosis. Taken together, cardiac overexpression of Myozap leads to cardiomyopathy, mediated, at least in part by induction of Rho-dependent SRF signaling in vivo. Surprisingly, this phenotype was also accompanied by protein aggregates in cardiomyocytes, UPR alteration, accelerated autophagy and apoptosis. Thus, this mouse model may also offer additional insight into the pathogenesis of protein-aggregate-associated cardiomyopathies and represents a new candidate gene itself.

The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~107 primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.

Excessive stress, e.g. due to biomechanical overload or ischemia/reperfusion is a potent inductor of cardiomyocyte apoptosis, which contributes to maladaptive remodeling. Despite substantial progress in the understanding of the molecular pathophysiology, many components of the signaling pathways underlying remodeling in general and apoptosis in particular still remain unknown. Recent evidence suggests that microRNAs (miRs) play an important role in the heart's response to increased cardiac stress. To identify novel modulators of stress-dependent remodeling, we conducted a genome-wide miR-screen of mechanically stretched neonatal rat cardiomyocytes (NRCM). Out of 351 miRs, eight were significantly regulated by biomechanical stress, including microRNA-20a, which is part of the miR17-92 cluster. Interestingly, further expression analyses also revealed upregulation of microRNA-20a in an in vitro hypoxia/"reperfusion" model. Given the potential apoptosis-modulating properties of the miR17-92 cluster, we subjected NRCM to hypoxia and subsequent reoxygenation. AdmiR-20a significantly inhibited hypoxia-mediated apoptosis in a dose-dependent fashion, while targeted knockdown of miR-20a in NRCM induced cardiomyocyte apoptosis. Mechanistically, the antiapoptotic effect of miR-20a appears to be mediated through direct targeting and subsequent downregulation of the proapoptotic factor Egln3. Thus, miR-20a is upregulated in acute biomechanical stress as well as hypoxia and inhibits apoptosis in cardiomyocytes. These properties reveal miR-20a as a cardioprotective micro-RNA and a potential target for novel therapeutic strategies to prevent cardiac remodeling.

The dilated cardiomyopathy (DCM) is a major cause for heart failure. A causative genetic background is suspected in up to 50% of all DCM cases. However, the underlying molecular pathways remain incompletely understood. Here we analyze a calsarcin-1 deficient (CS1ko) mouse line as a model for DCM. These mice showed strong upregulation of fetal genes (e.g., Nppa, Nppb ) and the calcineurin-dependent gene Rcan1.4. Interestingly, we could not detect any signes of hypertrophy. In addition, there was no increase of fibrosis in CS1ko mice compared to wildtype controls. A screening experiment revealed upregulation of Cofilin2 (Cfl2), an actin depolymerisation factor and member of the ADF/Cofilin family, in Cs1ko mice (2.6-fold, pNppa and Nppb , which could be further increased by co-stimulation with phenylephrine (PE). In contrast to these findings, cell size analysis revealed a Cfl2-mediated decrease in cell size with and without PE, while knockdown of Cfl2 did not influence cellular hypertrophy. Taken together, our data imply a role for Cfl2 in the pathogenesis of DCM. Cs-1ko mice show a dilated phenotype, strong upregulation of the fetal gene program without a change in cell size. This correlates with the findings of overexpression of Cfl2 in NRVCM. Furthermore, increased Cfl2 levels induce SRF activity with potential influence on cardiomyocyte function. Further analyses are required to delineate the involved molecular pathways.

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Background: We recently showed that the intercalated disc (ID) protein Myozap activates Rho-dependent SRF signaling both in vitro, and in vivo. Conversely, knockdown of its ortholog in Zebrafish led to severe contractile dysfunction and cardiomyopathy. Methods and Results: We generated a Myozap null mutant (MZP-ko) by global deletion of Myozap in mice. The absence of Myozap caused neither structural defects nor a baseline cardiac phenotype and led only to mild cardiac hypertrophy upon aging. Of note, induction of SRF target genes and the activation of SRF per se were markedly inhibited in MZP-ko mice. Nevertheless, biomechanical stress induced by transverse aortic constriction (TAC) triggered an excessive increase in cardiac hypertrophy (43% or 36% increased heart wt:body wt or LV wt:body wt ratios, p Conclusions: We here show that myozap deficiency in vivo inhibits SRF- and ERK1/2-signaling leading to a maladaptative response to increased biomechanical stress, followed by cardiomyopathy, heart failure and cardiac death. Moreover, myozap deficiency severely altered the expression of its direct ID interaction partners such as Dysbindin and Desmoplakin. In a broader perspective, our data identify signaling at the level of the intercalated disc as a critical component of cardiac remodeling.

Patients (pts) with hypertrophic cardiomyopathy (HCM) may present with a variety of symptoms, including sudden cardiac death. Sudden cardiac death due to ventricular fibrillation correlates with the extent of intramural fibrosis (IF). IF can be detected using cardiac magnetic resonance (CMR) by

Rationale and Objective: The M-band represents a transverse structure in the center of the sarcomeric A-band and provides an anchor for the myosin-containing thick filaments. In contrast to other sarcomeric structures, eg, the Z-disc, only few M-band–specific proteins have been identified to date, and its exact molecular composition remains unclear. Methods and Results: Using a bioinformatic approach to identify novel heart- and muscle-specific genes, we found a leucine rich protein, myomasp ( Myo sin-interacting, M -band- a ssociated s tress-responsive p rotein)/LRRC39. RT-PCR and Northern and Western blot analyses confirmed a cardiac-enriched expression pattern, and immunolocalization of myomasp revealed a strong and specific signal at the sarcomeric M-band. Yeast 2-hybrid screens, as well as coimmunoprecipitation experiments, identified the C terminus of myosin heavy chain (MYH)7 as an interaction partner for myomasp. Knockdown of myomasp in neonatal rat ventricular myocytes (NRVCMs) led to a significant upregulation of the stretch-sensitive genes GDF-15 and BNP. Conversely, the expression of MYH7 and the M-band proteins myomesin-1 and -2 was found to be markedly reduced. Mechanistically, knockdown of myomasp in NRVCM led to a dose-dependent suppression of serum response factor–dependent gene expression, consistent with earlier observations linking the M-band to serum response factor–mediated signaling. Finally, downregulation of myomasp/LRRC39 in spontaneously beating engineered heart tissue constructs resulted in significantly lower force generation and reduced fractional shortening. Likewise, knockdown of the myomasp/LRRC39 ortholog in zebrafish resulted in severely impaired heart function and cardiomyopathy in vivo. Conclusions: These findings reveal myomasp as a previously unrecognized component of an M-band–associated signaling pathway that regulates cardiomyocyte gene expression in response to biomechanical stress.

Data from the Women’s Health Study show that serum levels of growth-differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-β superfamily, are an independent risk indicator for adverse cardiovascular events. However, the cellular sources, upstream regulators, and functional effects of GDF-15 in the cardiovascular system have not been elucidated. We have identified GDF-15 by cDNA expression array analysis as a gene that is strongly upregulated by nitrosative stress in cultured cardiomyocytes isolated from 1- to 3-day-old rats. GDF-15 mRNA and pro-peptide expression levels were also induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO–peroxynitrite-dependent signaling pathways. GDF-15 was actively secreted into the culture supernatant, suggesting that it might exert autocrine/paracrine effects during I/R. To explore the in vivo relevance of these findings, mice were subjected to transient or permanent coronary artery ligation. Myocardial GDF-15 mRNA and pro-peptide abundance rapidly increased in the area-at-risk after ischemic injury. Similarly, patients with an acute myocardial infarction had enhanced myocardial GDF-15 pro-peptide expression levels. As shown by immunohistochemistry, cardiomyocytes in the ischemic area contributed significantly to the induction of GDF-15 in the infarcted human heart. To delineate the function of GDF-15 during I/R, Gdf-15 gene-targeted mice were subjected to transient coronary artery ligation for 1 hour followed by reperfusion for 24 hours. Gdf-15 –deficient mice developed greater infarct sizes and displayed more cardiomyocyte apoptosis in the infarct border zone after I/R compared with wild-type littermates, indicating that endogenous GDF-15 limits myocardial tissue damage in vivo. Moreover, treatment with recombinant GDF-15 protected cultured cardiomyocytes from apoptosis during simulated I/R as shown by histone ELISA, TUNEL/Hoechst staining, and annexin V/propidium iodide fluorescence-activated cell sorting (FACS) analysis. Mechanistically, the prosurvival effects of GDF-15 in cultured cardiomyocytes were abolished by phosphoinositide 3-OH kinase inhibitors and adenoviral expression of dominant-negative Akt1 (K179M mutation). In conclusion, our study identifies induction of GDF-15 in the heart as a novel defense mechanism that protects from I/R injury.