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Dilated cardiomyopathy associated with lamin A/C (LMNA) gene variants (LMNA-related dilated cardiomyopathy [DCM]) is a life-threatening condition with a high unmet need, accounting for approximately 6% of idiopathic DCM cases. Currently, no disease-specific treatments target the underlying disease mechanism. ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study. This long-term extension study examined the safety and efficacy of ARRY-371797 in patients from the phase 2 study. 6MWT, N-terminal pro-B-type natriuretic peptide concentration, and 12-item Kansas City Cardiomyopathy Questionnaire score were assessed at weeks 48, 72, 96, 120, and 144 from phase 2 study baseline. Eight patients enrolled (mean [SD] age, 51 [10] years, 4 male). Mean 6MWT increased by30 m (10%) from phase 2 study baseline up to week 120. The decrease in N-terminal pro-B-type natriuretic peptide observed in the phase 2 study was maintained throughout the present study. Twelve-item Kansas City Cardiomyopathy Questionnaire Physical Limitation increased from baseline at all visits except week 96 (range: -0.8 [week 96] to 13.8 [week 120]); results for other domains were variable. Treatment was generally well tolerated; 2 patients discontinued because of causes not considered treatment-related. There were no deaths. ARRY-371797 was generally well tolerated over median (range) 155.7 (61 to 327)-week exposure; evidence suggested preserved exercise capacity over the study period. The ongoing, pivotal, phase 3, randomized, placebo-controlled study REALM-DCM investigates the efficacy and safety of ARRY-371797 (PF-07265803) in LMNA-related DCM. (ClinicalTrials.gov Identifier: NCT02351856).

There is little published regarding the association between canine cardiovascular disease and the hepatic system. The objective of the study was to evaluate the relationship between hepatic parameters, survival, and disease stages of dogs with either dilated cardiomyopathy (DCM) or degenerative valvular disease (DVD).Retrospective study analyzing hepatic parameters in dogs with DVD or DCM in American College of Veterinary Internal Medicine stage B or C and healthy control dogs. Associations between liver parameters, type and stage of disease, and survival were investigated.Ninety-nine dogs were included in the study: 61 DVD, 22 DCM, and 16 controls. Differences in liver parameter concentrations between DCM, DVD, and disease stages were found. Univariate analysis identified alanine aminotransferase (P 0.001), aspartate aminotransferase (P = 0.02), and total bilirubin (P = 0.005) as predictors of mortality. In the multivariate analysis, total bilirubin remained an independent predictor of mortality.The observed differences between DCM, DVD, and disease stages are likely consistent with disease-specific hemodynamics and progression of disease. This and the role of total bilirubin as an independent predictor for mortality indicate that in dogs with DVD and DCM the cardiovascular-hepatic interaction might be of relevance for disease progression and outcome, as reported for humans with cardiac disease. Further studies into the role of hepatic function in canine cardiac disease are required.

High-mobility group box protein 1 (HMGB1) is released during tissue damage and activates the innate immune system through toll-like receptor 4. Because mortality in dilated cardiomyopathy (DCM) is associated with activation of the innate immune system, we hypothesized that HMGB1 possesses a prognostic value in estimating mortality in patients with DCM. We determined HMGB1 and N-terminal B-type natriuretic peptide (NT-proBNP) levels in 67 patients with DCM (12 women, mean age 53.6 ± 1.5 years). Kaplan-Meier analyzes revealed that higher levels of HMGB1 and NT-proBNP are related to increased all-cause mortality. Multivariable Cox regression confirmed HMGB1 as a risk factor for mortality in patients with DCM, independent of NT-proBNP, age, and gender (hazard ratio per 1 SD 1.920, 95% confidence interval 1.401 to 2.631, plt;0.001). HMGB1 is a promising candidate to estimate the prognosis of patients with DCM.

Heart transplantation in patients with amyloid cardiomyopathy (ACM) has been historically underused owing to the risk of amyloid recurrence.Using data from the United Network for Organ Sharing database on patients listed for single-organ heart transplant between 2010 and 2019, we evaluated trend in heart transplant and compared waitlist mortality and graft survival between patients with ACM and dilated cardiomyopathy (DCM). Also, we evaluated for independent predictors of outcomes.Over the study period, 411 adult patients with ACM were added to the heart transplant waitlist. In the propensity-matched cohorts, the rates of waitlist mortality were significantly higher for ACM compared with DCM (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.16-2.65). Over the study period, 330 patients with ACM underwent heart transplant. The number of transplants increased from 22 in 2010 to 59 in 2019 (168% increase). The 5-year graft survival rate was, however, significantly worse for ACM (78%) compared with DCM (82%) (HR,1.46, 1.03-2.08). We identified 2 predictors of graft failure among patients with ACM: namely, renal failure requiring dialysis (HR, 5.4, 1.6-17) and previous history of malignancy (HR, 1.6, 1.0-28). Patients with ACM with neither risk factor had 5-year graft survivals of 82%, which is comparable with DCM (HR, 1.28, 0.90-1.91). On the other hand, patients with ACM and either risk factor had worse 5-year graft survivals of 62% (HR, 2.44, 1.39-4.28).Increasing numbers of patients with ACM are undergoing heart transplants. Although patients with ACM experience higher waitlist mortality and worse graft survival compared with DCM, selecting carefully screened ACM patients may result in improved outcomes following heart transplant.

The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported.Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes.Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99).Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Thematic Excellence Programme (Tématerületi Kiválósági Program, 2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary within the framework of the Therapeutic Development and Bioimaging Programs of Semmelweis University Development of Scientific Workshops of Medical, Health Sciences and Pharmaceutical Edication (Project identification number: EFOP- 3.6.3-VEKOP-16- 2017-00009) Project no. NVKP_16-1–2016-0017 (’National Heart Program’) has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme. The research was supported by the Ministry of Innovation and Technology NRDI Office within the framework of the Artificial Intelligence National Laboratory Program. The differentiation of dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC) is a recurring issue during cardiac imaging processes; thus, we aimed to compare the left ventricular (LV) cardiac MRI (CMR) characteristics of DCM and LVNC patients. Thirty-one nonischemic DCM patients, 42 LVNC patients with reduced EF and 42 healthy controls were included in this retrospective study. The LV volumetric, functional and myocardial mass parameters were measured with a threshold-based technique, while global and segmental strain values and rotational patterns were analyzed with feature-tracking strain analysis. Of the LV volumetric and myocardial mass parameters, only the trabeculated and papillary muscle mass (TPMi) values differed significantly between the patient groups and were higher in the LVNC group compared to DCM (DCM vs LVNC: 43.2 ± 8.9 vs 51.6 ± 13.6 g/m2, p The global longitudinal and circumferential strains were similar between the patient groups and significantly worse than those of the controls. In comparing the segmental strain values between the patient groups, only the circumferential apical strain was significantly lower in the LVNC group (DCM vs LVNC: -30.5 ± 13.5 vs -24.5 ± 12.0%, p in the rotational pattern between the patient groups, and both the healthy and patient populations showed heterogeneous rotational patterns. Despite the similarities of DCM and LVNC in volumetric, global strain parameters, and rotational patterns, we found some morphological and functional differences between the patient groups. These minor alterations might be due to the morphological characteristics of LVNC with a trabeculated apical region.

Introduction/objectives Whether the aldosterone antagonist spironolactone has beneficial survival effects in dogs with dilated cardiomyopathy (DCM) is not known. The primary objective of the study was to evaluate the effect of spironolactone, when added to conventional therapy, on survival time in Doberman pinschers with congestive heart failure (CHF) due to DCM. Animals Sixty-seven client-owned Doberman pinschers with CHF due to DCM. Materials and methods The trial design was prospective, randomized, blinded, and placebo controlled. Dogs were randomized to receive 50–75 mg of spironolactone twice daily (n = 34) or a placebo (n = 33), in addition to standard CHF therapy. Follow-up visits were targeted every 1–6 weeks until endpoint. Quality-of-life questionnaire and physical examination were performed at every visit, while renal biochemistry, ECG, echocardiography, and thoracic radiography were reassessed as needed. The primary endpoint was time to cardiac death, defined as death or euthanasia from CHF or sudden death. Results Median time to primary endpoint in the spironolactone group (183 days) was not statistically significantly different than that for the placebo group (124 days) (p = 0.254). The development of atrial fibrillation (AF) was significantly less frequent in the spironolactone group (n = 7) than the placebo group (n = 15, p = 0.037). Conclusions While median time to cardiac death in the spironolactone group was not statistically significantly different than that in the placebo group, adding spironolactone to conventional therapy resulted in reduced occurrence of AF.

Dilated cardiomyopathy (DCM) is the most common cardiac disease in large breed dogs. The disease can start with arrhythmias or with systolic dysfunction of the myocardium.To describe screening methods for DCM in various breeds and provide a new, modified staging system.Screening for occult DCM should start at three years of age and use Holter monitoring in Boxers and Dobermans and might be useful also in other breeds. Single ventricular premature complexes (VPCs) can be detected in many healthy dogs, but healthy animals typically have50 VPCs in 24 h and demonstrate minimal complexity most often occurring only as single ectopic beats. In general,100 VPCs in 24 h was recommended as the cut-off value for establishing a diagnosis of DCM. However, there are breed-specific recommendations related to Holter recording diagnosis of DCM in Dobermans and Boxers. Yearly screening over the life of a dog is recommended, as a one-time screening is not sufficient to rule out the future development of DCM. Several echocardiographic methods such as M-mode derived measurements, the measurement of the left ventricular (LV) volume by Simpson's method of discs (SMOD), and E-point to septal separation (EPSS) are recommended for screening purposes. The value of additional tests such as cardiac biomarkers (troponin I and N-terminal pro-B-type natriuretic peptide) as well as a 5-min resting electrocardiogram (ECG) or newer echocardiographic methods such as strain measurements is discussed.This review suggests some guidelines for screening for DCM in various breeds.

Dilated cardiomyopathy (DCM) is a frequent cause of cardiac disability, congestive heart failure (CHF), and arrhythmic death in dogs. The etiology of DCM is usually idiopathic/genetic, but some causes of a DCM phenotype are reversible. The disease is classified into preclinical (occult) and clinical (overt) stages; the latter stems from heart failure with reduced ejection fraction. DCM is further characterized by clinical, electrocardiographic, circulating biomarker, and imaging abnormalities. The diagnosis of clinical DCM with CHF is straightforward; however, identification of the preclinical stage can be challenging. Echocardiography is central to the diagnosis of both stages and characterized by left ventricular (LV) systolic dysfunction with progressive chamber dilation and variable enlargements of the left atrium and right-sided chambers. Left ventricular dilation is defined by increased LV end-diastolic volumes, areas, and internal dimensions normalized to body size or indexed to the aorta. Systolic dysfunction is characterized by decreased LV ejection fraction, increased end-systolic volume, and reduced shortening across minor and longitudinal LV axes. Dyssynchrony can confound the interpretation of linear indices of systolic function. A comprehensive echocardiogram in DCM includes two-dimensional and M-mode studies, spectral and tissue Doppler imaging, and potentially three-dimensional echocardiography and myocardial strain imaging. Echocardiographic findings should be interpreted within the context of identifiable risks and comorbidities, physical diagnosis, complementary diagnostic testing, and limitations of current reference intervals. Ambiguous examinations should be repeated. Specific echocardiographic criteria for the diagnosis of DCM are proposed to encourage discussion and additional outcome and breed-specific echocardiographic studies of canine DCM.

Dilated cardiomyopathy (DCM) is a heritable and genetically heterogenous disease often idiopathic and a leading cause of heart failure with high morbidity and mortality. DCM caused by RNA binding motif protein 20 (RBM20) mutations is diverse and needs a more complete mechanistic understanding. RBM20 mutation S637G (S639G in mice) is linked to severe DCM and early death in human patients. In this study, we generated a RBM20 S639G mutation knock-in (KI) mouse model to validate the function of S639G mutation and examine the underlying mechanisms. KI mice exhibited severe DCM and premature death with a ~ 50% mortality in two months old homozygous (HM) mice. KI mice had enlarged atria and increased ANP and BNP biomarkers. The S639G mutation promoted RBM20 trafficking and ribonucleoprotein (RNP) granules in the sarcoplasm. RNA Seq data revealed differentially expressed and spliced genes were associated with arrhythmia, cardiomyopathy, and sudden death. KI mice also showed a reduction of diastolic stiffness and impaired contractility at both the left ventricular (LV) chamber and cardiomyocyte levels. Our results indicate that the RBM20 S639G mutation leads to RNP granules causing severe heart failure and early death and this finding strengthens the novel concept that RBM20 cardiomyopathy is a RNP granule disease.

Background Typical late gadolinium enhancement (LGE) patterns in dilated cardiomyopathy (DCM) include intramyocardial and subepicardial distribution. However, the ischemic pattern of LGE (subendocardial and transmural) has also been reported in DCM without coronar y arter y disease (CAD), but its correlates and prognostic significance are still not known. On these bases, this study sought to describe the prevalence and prognostic significance of the ischemic LGE pattern in DCM. Methods A total of 611 DCM patients with available cardiac magnetic resonance were retrospectively analyzed. A composite of all-cause-death, major ventricular arrhythmias (MVAs), heart transplantation (HTx) or ventricular assist device (VAD) implantation was the primary outcome of the study. Secondary outcomes were a composite of sudden cardiac death or MVAs and a composite of death for refractory heart failure, HTx or VAD implantation. Results Ischemic LGE was found in 7% of DCM patients without significant CAD or history of myocardial infarction, most commonly inferior/inferolateral/anterolateral. Compared to patients with non-ischemic LGE, those with ischemic LGE had higher prevalence of hypertension and atrial fibrillation or flutter. Ischemic LGE was associated with worse long-term outcomes compared to non-ischemic LGE (36% vs 23% risk of primary outcome events at 5 years respectively, P = .006), and remained an independent predictor of primary outcome after adjustment for clinically and statistically significant variables (adjusted hazard ratio 2.059 [1.055-4.015], P = .034 with respect to non-ischemic LGE). Conclusions The ischemic pattern of LGE is not uncommon among DCM patients without CAD and is independently associated with worse long-term outcomes. (Am Heart J 2022;246:117-124.)

AIMS: We investigated left ventricular (LV) remodeling, mechanics, systolic and diastolic function, combined with clinical characteristics and heart-failure treatment in association to death or heart-transplant (DoT) in pediatric idiopathic, genetic or familial dilated cardiomyopathy (DCM), using interpretable machine-learning. METHODS AND RESULTS: Echocardiographic and clinical data from pediatric DCM and healthy controls were retrospectively analyzed. Machine-learning included whole cardiac-cycle regional longitudinal strain, aortic, mitral and pulmonary vein Doppler velocity traces, age and body surface area. We used unsupervised multiple kernel learning for data dimensionality reduction, positioning patients based on complex conglomerate information similarity. Subsequently, k-means identified groups with similar phenotypes. The proportion experiencing DoT was evaluated. Pheno-grouping identified 5 clinically distinct groups that were associated with differing proportions of DoT. All healthy controls clustered in groups 1 to 2, while all, but one, DCM subjects, clustered in groups 3 to 5; internally validating the algorithm. Cluster-5 comprised the oldest, most medicated patients, with combined systolic and diastolic heart-failure and highest proportion of DoT. Cluster4 included the youngest patients characterized by severe LV remodeling and systolic dysfunction, but mild diastolic dysfunction and the second-highest proportion of DoT. Cluster-3 comprised young patients with moderate remodeling and systolic dysfunction, preserved apical strain, pronounced diastolic dysfunction and lowest proportion of DoT. CONCLUSIONS: Interpretable machine-learning, using full cardiac-cycle systolic and diastolic data, mechanics and clinical parameters, can potentially identify pediatric DCM patients at high-risk for DoT, and delineate mechanisms associated with risk. This may facilitate more precise prognostication and treatment of pediatric DCM. Patricia Garcia-Canadilla has received funding from the postdoctoral fellowships program Beatriu de Pinos (2018-BP-00201), funded by the Secretary of Universities and Research (Goverment of Catalonia) and by the Horizon 2020 programme of research and innovation of the European Union under the Marie Skłodowska-Curie grant agreement Nº 801370. Pablo Miki Martí-Castellote has received funding from the predoctoral fellowships program FI-SDUR (2020-FISDU-00169) from AGAUR.

Autophagy is a cellular process that degrades a cell's own cytoplasmic components for energy provision and to maintain a proper intracellular environment. Left ventricular reverse remodeling (LVRR) promises a better prognosis for patients with dilated cardiomyopathy (DCM).The authors tested the hypothesis that autophagy is involved in LVRR and has prognostic value in the human failing heart.Using left ventricular endomyocardial biopsy specimens from 42 patients with DCM (21 LVRR-positive and 21 LVRR-negative) and 7 patients with normal cardiac function (control), the authors performed immunohistochemistry and immunofluorescent labeling of LC3 and cathepsin D and electron microscopic observation in addition to general morphometry under light microscopy.The clinical characteristics of LVRR-positive patients were similar to those of the LVRR-negative patients, except for pulmonary artery pressure and left atrial dimension. Morphometry under light microscopy did not differ among specimens from DCM patients, regardless of their LVRR status. Electron microscopy revealed that autophagic vacuoles (autophagosomes and autolysosomes) and lysosomes were abundant within cardiomyocytes from DCM patients. Moreover, cardiomyocytes from LVRR-positive patients contained significantly more autophagic vacuoles with higher autolysosome ratios and cathepsin D expression levels than cardiomyocytes from LVRR-negative patients. Logistic regression analysis adjusted for age showed that increases in autophagic vacuole number and cathepsin D expression were predictive of LVRR. DCM patients who achieved LVRR experienced fewer cardiovascular events during the follow-up period.The authors show that autophagy is a useful marker predictive of LVRR in DCM patients. This provides novel pathologic insight into a strategy for treating the failing DCM heart.

Objective The study objective was to evaluate the short- and long-term outcomes of patients with ischemic cardiomyopathy after surgical ventricular restoration and to identify risk factors related to poor results. Methods Between August 2002 and April 2016, 62 patients affected by ischemic cardiomyopathy underwent surgical left ventricular restoration at our unit. Patients' mean age at operation was 63 years (39-79 years). Mean ejection fraction was 29.6%. The Surgical Treatment for Ischemic Heart Failure trial criteria have been used as indications for surgery. Fifty-seven patients (91%) received surgical myocardial revascularization. Mitral valve repair was performed in 39 patients (63%). The surgical technique consisted of the classic Dor operation or a different approach reducing the equatorial diameter of the left ventricle and avoiding the use of a patch. The data were analyzed retrospectively for perioperative results and short- and long-term clinical outcomes. Results One patient died of noncardiac causes within 30 days (1.6%). All-cause death occurred in 36 patients (58%) during follow-up (0.6-14.7 years; median follow-up time, 7.02 years), of whom 15 died of cardiac causes. Age, need for preoperative intra-aortic balloon pump, reduction less than 35% of postoperative left ventricular end-diastolic and end-systolic volumes, type of surgical technique, and ejection fraction less than 25% were identified as risk factors for late cardiac mortality. Perioperative levosimendan administration and presence of preoperative moderate to severe mitral regurgitation influenced early and intermediate-term outcomes, but no statistical relevance on long-term results was demonstrated. Conclusions Patients with ischemic dilative cardiomyopathy have favorable short- and long-term outcomes after ventricular restoration. Age, preoperative ejection fraction less than 25%, inadequate left ventricular surgical reverse remodeling, and type of surgical technique negatively affect long-term survival.

Introduction /Objectives: The objectives were to conduct a survey of cardiologists on their recent experiences with cats that have dilated cardiomyopathy (DCM), and to retrospectively review individual cases of feline DCM. Animals, Materials and Methods Part One: A survey was distributed to cardiologists with questions regarding caseload and clinical management of cats with DCM diagnosed over the past two years. Part Two: Cardiologists completing the survey were invited to submit data from cats recently diagnosed with DCM. Data on signalment, clinical signs, diet, echocardiographic measurements, and outcome were recorded. Results Part One: From 52 completed surveys, many cardiologists responded that measuring and supplementing taurine and recommending a diet change in cats with DCM are common practices. Few (15%) cardiologists reported an increase in number of feline DCM cases over the past two years, although some had cases that improved even if taurine deficiency was not present. Part Two: Twenty of 37 (54%) cats ate low pea/lentil (low PL) diets and 14/37 (38%) ate high pea/lentil (high PL) diets at the time of diagnosis; three had incomplete diet information. Two of 13 cats (15%) in which taurine was measured had levels below the reference range. After adjusting for other variables, cats eating high PL diets that changed diets post-diagnosis had a significantly longer survival time compared to cats eating high PL diets that did not change diets post-diagnosis (P=0.025). Conclusions Additional research is warranted to determine whether there could be a possible association between diet and DCM in cats.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10(−16)). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.

Heart failure is a leading cause of fatality in Duchenne muscular dystrophy (DMD) patients. Previously, we discovered that cardiac and skeletal-muscle-enriched CIP proteins play important roles in cardiac function. Here, we report that CIP, a striated muscle-specific protein, participates in the regulation of dystrophic cardiomyopathy. Using a mouse model of human DMD, we found that deletion of CIP leads to dilated cardiomyopathy and heart failure in young, non-syndromic mdx mice. Conversely, transgenic overexpression of CIP reduces pathological dystrophic cardiomyopathy in old, syndromic mdx mice. Genome-wide transcriptome analyses reveal that molecular pathways involving fibrogenesis and oxidative stress are affected in CIP-mediated dystrophic cardiomyopathy. Mechanistically, we found that CIP interacts with dystrophin and calcineurin (CnA) to suppress the CnA-Nuclear Factor of Activated T cells (NFAT) pathway, which results in decreased expression of Nox4, a key component of the oxidative stress pathway. Overexpression of Nox4 accelerates the development of dystrophic cardiomyopathy in mdx mice. Our study indicates CIP is a modifier of dystrophic cardiomyopathy and a potential therapeutic target for this devastating disease.

Since RBPs play important roles in the cell, it's particularly important to find new RBPs. We performed iRIP-seq and CLIP-seq to verify two proteins, CLIP1 and DMD, predicted by RBPPred whether are RBPs or not. The experimental results confirm that these two proteins have RNA-binding activity. We identified significantly enriched binding motifs UGGGGAGG, CUUCCG and CCCGU for CLIP1 (iRIP-seq), DMD (iRIP-seq) and DMD (CLIP-seq), respectively. The computational KEGG and GO analysis show that the CLIP1 and DMD share some biological processes and functions. Besides, we found that the SNPs between DMD and its RNA partners may be associated with Becker muscular dystrophy, Duchenne muscular dystrophy, Dilated cardiomyopathy 3B and Cardiovascular phenotype. Among the thirteen cancers data, CLIP1 and another 300 oncogenes always co-occur, and 123 of these 300 genes interact with CLIP1. These cancers may be associated with the mutations occurred in both CLIP1 and the genes it interacts with.

Objectives Myocardial autophagy has been recognized as an important factor in heart failure. It is not known whether changes in ventricular geometry by left ventriculoplasty influence autophagy in ischemic cardiomyopathy. We hypothesized that myocardial autophagy plays an important role in left ventricular (LV) redilation after ventriculoplasty. Methods Four weeks after ligation of the left anterior descending artery, ventriculoplasty or sham operation was performed. The animals were euthanized at 2 days (early) or 28 days (late) after the second operation. Ventricular autophagy was evaluated by protein expression of microtubule-associated protein light chain 3 II, an autophagosome marker. Cardiomyocyte area was assessed by histologic examination. LV function was evaluated by echocardiography. To examine the implications of autophagy, an autophagy inhibitor (3-methyladenine) was injected intraperitoneally for 3 weeks before sacrifice. Results The LV was reduced in size early and redilated late after ventriculoplasty. LV systolic function was improved early and later worsened after ventriculoplasty. Light chain 3 II expression decreased early after ventriculoplasty and increased in the late period. Myocyte area increased from the early to late stage after ventriculoplasty. Autophagic inhibition exaggerated the increased myocyte hypertrophy and LV redilation. Conclusions In a rat model of myocardial infarction, autophagy decreased early after ventriculoplasty and increased again during LV redilation. These results provide new insights into the mechanism underlying the late failure of ventriculoplasty.

The prevalence and contribution of cardiotropic viruses to various expressions of heart failure are increasing, yet primarily underappreciated and underreported due to variable clinical syndromes, a lack of consensus diagnostic standards and insufficient clinical laboratory tools. In this study, we developed an advanced methodology for identifying viruses across a spectrum of heart failure patients. We designed a custom tissue microarray from 78 patients with conditions commonly associated with virus-related heart failure, conditions where viral contribution is typically uncertain, or conditions for which the etiological agent remains suspect but elusive. Subsequently, we employed advanced, highly sensitive in situ hybridization to probe for common cardiotropic viruses: adenovirus 2, coxsackievirus B3, cytomegalovirus, Epstein–Barr virus, hepatitis C and E, influenza B and parvovirus B19. Viral RNA was detected in 46.4% (32/69) of heart failure patients, with 50% of virus-positive samples containing more than one virus. Adenovirus 2 was the most prevalent, detected in 27.5% (19/69) of heart failure patients, while in contrast to previous reports, parvovirus B19 was detected in only 4.3% (3/69). As anticipated, viruses were detected in 77.8% (7/9) of patients with viral myocarditis and 37.5% (6/16) with dilated cardiomyopathy. Additionally, viruses were detected in 50% of patients with coronary artery disease (3/6) and hypertrophic cardiomyopathy (2/4) and in 28.6% (2/7) of transplant rejection cases. We also report for the first time viral detection within a granulomatous lesion of cardiac sarcoidosis and in giant cell myocarditis, conditions for which etiological agents remain unknown. Our study has revealed a higher than anticipated prevalence of cardiotropic viruses within cardiac muscle tissue in a spectrum of heart failure conditions, including those not previously associated with a viral trigger or exacerbating role. Our work forges a path towards a deeper understanding of viruses in heart failure pathogenesis and opens possibilities for personalized patient therapeutic approaches., The prevalence and contribution of viruses to heart failure phenotypes are increasingly recognized, while still underappreciated and underreported. We designed a tissue microarray with cardiac muscle tissue from 78 heart failure patients and probed for common cardiotropic viruses via in situ hybridization. Viral RNA was detected in 46.4% of patients, higher than anticipated for these heart failure conditions that include those not previously associated with a viral trigger or an exacerbating role.

Background Dilated cardiomyopathy (DCM) is a well-described entity for heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Recently, drugs and other substance of abuse have been recognized as potential triggers for DCM. The aim of this study was to assess the survival in patients under 65 years old with toxic cardiomyopathy (TCM). Left ventricular remodeling and the potential usefulness of left ventricular assist device (LVAD) was also assessed. Methods Single center retrospective study from January 2003 to August 2019 at a tertiary care cardiology center identified 553 patients younger than 65 years old with LVEF Results Two hundred and one patients (36%) had a diagnosis of idiopathic DCM. Further analysis identified 38 patients (19%) for which a TCM was the most likely etiology (amphetamine [50%], cocaine [37%], anabolic steroids [8%], and energy drinks [5%]). Despite a mean LVEF of 17±8% at presentation, most patients (n=27, 71%) had an event-free survival with guideline-directed medical therapy, and 61% (n=23) recovered a LVEF ≥40% after a median follow-up of 21±23 months. Seven patients (18%) required a LVAD and 1 (3%) patient a transplantation. All LVAD were explanted or decommissioned after a median support time of 11±4 months following partial or complete LVEF recovery. Conclusion TCM induced by substance abuse is a frequent cause of HF accounting for almost 20% of all patients with DCM of unknown etiology under 65 years of age. Treatment must be tailored on an individual basis. Mechanical circulatory support demonstrated its usefulness in carefully selected patients.

Substance use is common among those with heart failure (HF) and is associated with worse clinical outcomes. Alcohol, tobacco, cannabis, and cocaine are commonly abused substances that can contribute to the development and worsening of HF. Heavy alcohol consumption can lead to dilated cardiomyopathy, whereas moderate intake may decrease incident HF. Tobacco increases the risk of HF through coronary artery disease and coronary artery disease–independent mechanisms. Continued smoking worsens outcomes for those with HF and cessation is associated with an improved risk of major adverse cardiac events. Cannabis has complex interactions on the cardiovascular system depending on the method of consumption, amount consumed, and content of cannabinoids. Delta-9-tetrahydrocannabinol can increase sympathetic tone, cause vascular dysfunction, and may increase the risk of myocardial infarction. Cannabidiol is cardioprotective in preclinical studies and is a potential therapeutic target. Cocaine increases sympathetic tone and is a potent proarrhythmogenic agent. It increases the risk of myocardial infarction and can also lead to a dilated cardiomyopathy. The use of beta-blockers in those with HF and cocaine use is likely safe and effective. Future studies are needed to further elucidate the impact of these substances both on the development of HF and their effects on those who have HF.

Introduction: Recurrent ventricular tachycardia (VT) episodes have a negative impact on the clinical outcome of implantable cardioverter-defibrillator (ICD) patients. Modification of the arrhythmogenic substrate has been used as a promising approach for treating recurrent VTs. However, there are limited data on long-term follow-up. Aim: To analyze long-term results of VT substrate-based ablation using high-density mapping in patients with severe left ventricular (LV) dysfunction and recurrent appropriate ICD therapy. Methods: We analyzed 20 patients (15 men, 55% with non-ischemic cardiomyopathy, age 58±15 years, LV ejection fraction 32±5%) and repeated appropriate shocks or arrhythmic storm (>2 shocks/24 h) despite antiarrhythmic drug therapy and optimal heart failure medication. All patients underwent ventricular programmed stimulation (600 ms/S3) to document VT. A sinus rhythm (SR) voltage map was created with a three-dimensional electroanatomic mapping system (CARTO, Biosense Webster, CA) using a PentaRay® high-density mapping catheter (Biosense Webster, CA) to delineate areas of scarred myocardium (ventricular bipolar voltage ≤0.5 mV – dense scar; 0.5-1.5 mV – border zone; ≥1.5 mV – healthy tissue) and to provide high-resolution electrophysiological mapping. Substrate modification included elimination of local abnormal ventricular activities (LAVAs) during SR (fractionated, split, low-amplitude/long-lasting, late potentials, pre-systolic), and linear ablation to obtain scar homogenization and dechanneling. Pace-mapping techniques were used when capture was possible. The LV approach was retrograde in nine cases, transseptal in five and epi-endocardial in four. In two patients ablation was performed inside the right ventricle. Results: LAVAs and scar areas were modified in all patients. Mean procedure duration was 149 min (105-220 min), with radiofrequency ranging from 18 to 70 min (mean 33 min) and mean fluoroscopy time of 15 min. Non-inducibility was achieved in 75% of cases (in four patients with hemodynamic deterioration and an LV assist device, VT inducibility was not performed). There were two cases of pericardial tamponade, drained successfully. During a follow-up of 50±24 months, 65% had no VT recurrences. Among the seven patients with recurrences, three underwent redo ablation and four, with fewer VT episodes, received appropriate ICD therapy. There were five hospital readmissions due to heart failure decompensation, one patient died in the first week after unsuccessful ablation of a VT storm and three died (stroke and pneumonia) >1 year after ablation. Conclusion: Catheter ablation based on substrate modification is feasible and safe in patients with frequent VTs and severe LV dysfunction. This approach may be of clinical relevance, with potential long-term benefits in reducing VT burden. Resumo: Os episódios de taquicardia ventricular (TV) recorrente têm um impacto negativo na evolução clínica de doentes (D) com cardioversor-desfibrilhador implantável (CDI). A modificação do substrato arritmogénico tem sido usada como uma abordagem promissora para o tratamento de TV recorrente. No entanto, são limitados os dados sobre o seguimento em longo prazo. Objetivo: Analisar os resultados em longo prazo da ablação de TV baseada na modificação do substrato, com recurso a mapeamento de alta densidade em D com disfunção ventricular esquerda (VE) grave e terapia recorrente apropriada via CDI. Métodos: 20D (15 homens, miocardiopatia não isquémica 55%, 58 ± 15 anos, fração de ejeção do VE 32 ± 5%) e choques apropriados recorrentes ou tempestade arrítmica (> 2 choques/24 h) apesar de terapêutica medicamentosa antiarrítmica e otimização da medicação para insuficiência cardíaca. Todos os D foram submetidos a estimulação ventricular programada (600 ms/S3) para documentação da TV. Foi criado um mapa de voltagem em ritmo sinusal (RS) com sistema de mapeamento eletroanatómico 3D (CARTO, Biosense Webster, CA), usando um cateter de mapeamento de alta densidade PentaRay® (Biosense Webster, CA) para delinear áreas de miocárdio com cicatriz (voltagem bipolar ventricular ≤0,5 mV - cicatriz densa; 0,5-1,5 mV - zona de contorno; ≥ 1,5 mV - tecido saudável) e fornecer mapeamento eletrofisiológico de alta resolução. A modificação do substrato incluiu a eliminação de locais com atividade eletrofisiológica ventricular anormal (LAVA: eletrogramas fracionados, com duplo potencial, de baixa amplitude/longa duração, potenciais tardios, pré-sistólicos) durante RS e ablação linear para obter a homogeneização das cicatrizes, com eliminação de canais de condução lenta. A técnica de pace-mapping foi usada sempre que a captura local era possível. A abordagem do VE foi retrógrada em nove casos, transeptal em cinco e endoepicárdica em quatro casos. Em 2D a ablação endocárdica foi realizada no ventrículo direito. Resultados: As áreas de LAVA e cicatriz foram modificadas em todos os D. A duração média do procedimento foi de 149 min (105-220 min), com tempo de radiofrequência variando de 18 a 70 min (média 33 min) e tempo médio de fluoroscopia de 15 min. A não inducibilidade foi obtida em 75% dos casos (em 4P - deterioração hemodinâmica/dispositivo de assistência VE - a inducibilidade de TV não foi realizada). Foram drenados dois tamponamentos pericárdicos com sucesso. Durante um follow-up de 50 ± 24 meses, 65% não tiveram recorrências de TV. Entre os 7D com recorrências, três foram submetidos a «redo» da ablação e 4D, com menos episódios de TV, receberam terapia apropriada do CDI. Houve cinco reinternamentos hospitalares devido à descompensação de insuficiência cardíaca, 1D faleceu na 1.ª semana após ablação sem sucesso, devido a tempestade arrítmica e ocorreram 3 óbitos > 1 ano após a ablação (acidente vascular cerebral e pneumonia). Conclusão: A ablação por cateter baseada na modificação do substrato é exequível, eficaz e segura em D com episódios recorrentes de TV e disfunção VE grave. Esta abordagem pode ter relevância clínica, com benefícios potenciais em longo prazo na redução da carga de TV.

Truncating TTN variants (TTNtv) are the main cause of dilated cardiomyopathy (DCM). The dynamic nature of this entity has previously been described. Based on own empirical observations and previous evidences, this study assessed repolarisation patterns and the possible association with morphological and functional status of TTNtv-DCM patients.Electrocardiograms (ECGs) of index patients with TTNtv-DCM and their relatives were included and matched in time with an echocardiogram. All individuals were classified into five phenotype groups: 1) Reduced left ventricular ejection fraction (LVEF50%); 2) Recovered LVEF: at least 10% increase and LVEF30% after optimal medical treatment; 3) Borderline phenotype (mildly enlarged ventricle and/or hyper-trabeculation); 4) Genotype positive, phenotype negative; and 5) Non-carriers. All electrocardiograms were evaluated by two blinded observers in qualitative and quantitative terms [T index (mm)=Σ T-wave amplitude (V5, V6, II, aVF)] and these data were compared with demographic and clinical information. The Δ T-index was calculated in those individuals with more than one electrocardiogram.Seventy-eight (78) electrocardiograms were included (46% female, mean age 50 years). T-index and prevalence of an abnormal T-wave had significantly different results among the groups (p0.0001). Age and haemodynamic factors were shown to be ECG-modifiers, especially in phenotype-negative patients. T-index enabled individuals with reduced LVEF (2.5) to be identified and to differentiate patients with favourable and unfavourable responses to treatment (Δ T index3.5 and ≤2, respectively).Repolarisation changes enabled characterisation of the spectrum of TTNtv-DCM. The T-index identified potential carriers and patients with the worst profiles of the spectrum of the disease.

Aims Pediatric dilated cardiomyopathy (pDCM) is characterized by unique age-dependent molecular mechanisms that include myocellular responses to therapy. We previously showed that pDCM, but not adult DCM patients respond to phosphodiesterase 3 inhibitors (PDE3i) by increasing levels of the second messenger cAMP and consequent phosphorylation of phospholamban (PLN). However, the molecular mechanisms involved in the differential pediatric and adult response to PDE3i are not clear. Methods and results Quantification of serum response factor (SRF) isoforms from the left ventricle of explanted hearts showed that PDE3i treatment affects expression of SRF isoforms in pDCM hearts. An SRF isoform lacking exon 5 (SRFdel5) was highly expressed in the hearts of pediatric, but not adult DCM patients treated with PDE3i. To determine the functional consequence of expression of SRFdel5, we overexpressed full length SRF or SRFdel5 in cultured cardiomyocytes with and without adrenergic stimulation. Compared to a control adenovirus, expression of SRFdel5 increased phosphorylation of PLN, negatively affected expression of the phosphatase that promotes dephosphorylation of PLN (PP2Ce), and promoted faster calcium reuptake, whereas expression of full length SRF attenuated calcium reuptake through blunted phosphorylation of PLN. Conclusions Taken together, these data indicate that expression of SRFdel5 in pDCM hearts in response to PDE3i contributes to improved function through regulating PLN phosphorylation and thereby calcium reuptake.

Undiagnosed dilated cardiomyopathy (DC) can be asymptomatic or present as sudden cardiac death, therefore pre-emptively identifying and treating patients may be beneficial. Screening for DC with echocardiography is expensive and labor intensive and standard electrocardiography (ECG) is insensitive and non-specific. The performance and applicability of artificial intelligence-enabled electrocardiography (AI-ECG) for detection of DC is unknown. Diagnostic performance of an AI algorithm in determining reduced left ventricular ejection fraction (LVEF) was evaluated in a cohort that comprised of DC and normal LVEF control patients. DC patients and controls with 12-lead ECGs and a reference LVEF measured by echocardiography performed within 30 and 180 days of the ECG respectively were enrolled. The model was tested for its sensitivity, specificity, negative predictive (NPV) and positive predictive values (PPV) based on the prevalence of DC at 1% and 5%. The cohort consisted of 421 DC cases (60% males, 57±15 years, LVEF 28±11%) and 16,025 controls (49% males, age 69 ±16 years, LVEF 62±5%). For detection of LVEF≤45%, the area under the curve (AUC) was 0.955 with a sensitivity of 98.8% and specificity 44.8%. The NPV and PPV were 100% and 1.8% at a DC prevalence of 1% and 99.9% and 8.6% at a prevalence of 5%, respectively. In conclusion AI-ECG demonstrated high sensitivity and negative predictive value for detection of DC and could be used as a simple and cost-effective screening tool with implications for screening first degree relatives of DC patients.

INTRODUCTION AND OBJECTIVES The expression levels of microRNA-16-5p (miR-16) are upregulated in ischemic cardiomyopathy and in animal models of ischemic dilated cardiomyopathy (iDCM), inducing myocardial apoptosis. We investigated the role of miR-16 in the adaptive cellular response associated with endoplasmic reticulum (ER) stress and autophagy in the apoptotic iDCM environment. METHODS We quantified the miR-16 plasma levels of 168 participants-76 controls, 60 iDCM patients, and 32 familial DCM patients with the pathogenic variant of BAG3-by quantitative real-time polymerase chain reaction and correlated the levels with patient variables. The effects of intracellular miR-16 overexpression were analyzed in a human cardiac cell line. Apoptosis and cell viability were measured, as well as the levels of markers associated with ER stress, cardiac injury, and autophagy. RESULTS Plasma miR-16 levels were upregulated in iDCM patients (P=.039). A multivariate logistic regression model determined the association of miR-16 with iDCM clinical variables (P

The optimal screening strategy to prevent sudden cardiac death (SCD) in athletes remains unknown. Pre-participation screening with electrocardiogram (ECG) remains controversial. The utility and accuracy of limb-lead (LL) ECG alone in identifying cardiac abnormalities associated with SCD has not been studied. This study was a comparative secondary data analysis, comparing the interpretation accuracy of 4 physicians evaluating publicly available ECGs of the most common cardiac conditions associated with SCD in athletes. Each physician interpreted a total of 100 ECGs: 50 normal ECGs (25 LL and 25 standard 12L) and 50 abnormal ECGs (25 LL and 25 standard 12L). The agreement between LL ECGs and 12L ECGs was assessed by Cohen's kappa coefficient and the accuracy of identifying an abnormal ECG was compared across LL and 12L ECGs using a chi-squared test. Inter-rater reliability was assessed by estimating the Fleiss's kappa coefficient. The sensitivity of LL ECG and 12L ECG was identical at 86%. The specificity of LL ECG was 75% (95% CI = 65% to 83%) and 12L ECG was 82% (95% CI = 73% to 89%). Substantial agreement was seen between LL ECG and 12L ECG interpretation across all readers (k = 0.63; 95% CI = 0.49 to 0.77). Interpretation accuracy was 81% (95% CI = 74% to 86%) and 84% (95% CI 78% to 89%) using LL ECG and 12L ECG, respectively (p = 0.43). In conclusion, the accuracy, sensitivity, and specificity were high and comparable for both LL ECG and 12L ECG in identifying cardiovascular conditions associated with SCD. Agreement between LL ECG and 12L ECG was substantial.

Using three-dimensional (3D) transesophageal echocardiography (TEE) and isometric handgrip exercise (IHE), we investigated the determinants of exercise-induced mitral regurgitation (MR) according to MR etiologies. Seventy-six patients with more than moderate MR, 40 patients with functional MR (FMR) and 36 patients with degenerative MR (DMR), underwent 3D TEE combined with IHE. Mitral valve (MV) geometry and 3D vena contracta area (3D VCA) were simultaneously evaluated at baseline and during IHE. With regard to exercise-induced MR, Δ3D VCA was calculated as the difference between 3D VCA at baseline and 3D VCA during IHE. IHE caused different changes in MV geometry between etiologies and led to exacerbation of 3D VCA at baseline. Larger Δ3D VCA was observed in the FMR group compared with the DMR group (15.9 ± 10.3 mm2 versus 7.3 ± 4.2 mm2; p < 0.0001). In multivariate analyses, tenting height and 3D VCA were selected as independent factors associated with Δ3D VCA in the FMR group (p = 0.0135 and p = 0.0201, respectively), while flail width was selected as an independent factor associated with Δ3D VCA in the DMR group (p = 0.0066). In conclusion, IHE alters mitral valve geometry and causes exacerbation of MR regardless of MR etiology and the determinants of exercise-induced MR differed between MR etiologies.

Aims The present study aims at analyzing the role of a preimplantation 12-lead electrocardiogram (ECG) on the prediction of inappropriate S-ICD® episodes. Methods N=116 screened patients (pts) with an S-ICD® and a follow-up of at least 6 months were included. A preimplantation 12-lead ECG (50 mm/s, 10 mm/mV) was analyzed with regard to QRS and T-wave amplitude, T wave concordance or discordance and QRS/T wave ratio in all 12 leads. To ensure an exact determination of parameters Datinf® Measure software was used. Results were correlated to the occurrence of oversensing of cardiac signals during follow-up. Results N = 116 pts. (63,8% male, mean age 40,9 ± 15,5 years) were included (primary prevention in 47.4% of pts). The most frequent cardiac diseases were hypertrophic cardiomyopathy (HCM) in n = 25 (21,6%), electrical heart disease in n = 20 (17,2%), and dilated cardiomyopathy in n = 17 (14,7%). Mean follow-up was 740 ± 549 days. During follow- up n = 17 (14.7%) pts. experienced n = 27 inappropriate episodes due to T-wave oversensing. Besides HCM (OR 6.16, CI 1.79–21.15, p = 0.004) a discordance of QRS to T-wave in lead I (OR 6.5, CI 1.86–22.67, p = 0.003) was found to be a strong predictor for inappropriate shocks. In multivariate analysis the pts. with a combination of both had an 8.4-fold higher risk of misclassification of intracardiac signals (p = 0.003) with consecutive inappropriate therapy. Conclusion A discordance of QRS to T-wave in lead I turned out to be a strong predictor for future inappropriate shocks in a typical S-ICD® cohort with special impact on HCM pts.

Background In adult cardiomyopathy (CM), diffuse myocardial fibrosis is associated with adverse clinical outcome. However, its relevance in pediatric patients remains relatively unknown. The study aimed to evaluate myocardial extracellular volume (ECV) reflecting diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) T1 mapping, and to analyze correlations with clinical and functional data in children and adolescents with different CM phenotypes. Methods Patients with primary dilated (DCM), hypertrophic (HCM) or left ventricular non-compaction CM (LVNC) were prospectively enrolled and compared with healthy controls. Study participants underwent standardized CMR with modified Look-Locker Inversion recovery (MOLLI) T1 mapping. Results In total, 33 patients (median age 12.0 years; DCM: n = 10, HCM: n = 13; LVNC: n = 10) and 7 controls (14.5 years) were included. DCM: ECV was higher than in controls (38.1 ± 7.5% vs. 27.2 ± 3.6%; p = 0.014). Patients with elevated ECV were younger than those with normal values (p = 0.044). ECV correlated with N-terminal pro brain natriuretic peptide (r = 0.66, p = 0.038), left ventricular ejection fraction (r = −0.63, p = 0.053), and stroke volume of left (r = −0.75, p = 0.013) and right ventricle (r = −0.67, p = 0.033). During a median follow-up of 25.3 months, 3 patients underwent heart transplantation (HTx), and 2 were listed for HTx. All 5 patients had elevated ECV. HCM/LVNC: ECV was within normal range in HCM (25.5 ± 4.5%) and LVNC (29.6 ± 4.2), and was not related with clinical and/or functional parameters. Conclusions Our results indicate an increased burden of diffuse myocardial fibrosis in relation with younger age in pediatric DCM. ECV was associated with clinical and biventricular functional markers of heart failure in DCM.

This study aimed to depict strain parameters derived from 2-dimensional (2D)- and 3-dimensional (3D) speckle tracking echocardiography and to explore which may best reflect myocardial fibrosis (MF) in dilated cardiomyopathy with advanced heart failure by comparing with histologic fibrosis.We analyzed 75 patients with dilated cardiomyopathy with advanced heart failure who underwent echocardiographic examination before heart transplantation. Strain parameters derived from 2D- and 3D speckle tracking echocardiography were as follows: left ventricular global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS) and tangential strain (TS). The degree of MF was quantified using Masson's staining in left ventricular myocardial samples obtained from all patients. Seventy-five patients were divided into 3 groups according to the tertiles of histologic MF (mild, moderate, and severe MF groups). Patients with severe MF had lower 3DGLS, 3DGRS, 3DTS, and 2DGLS than those with mild and moderate MF. MF strongly correlated with 3DGLS (r = 0.72, P.001), weakly with 3DGRS (r = -0.39, P = .001), 3DGCS (r = 0.30, P = .009), 3DTS (r = 0.47, P.001), and 2DGLS (r = 0.44, P.001), but did not correlate with 2DGCS and 2DGRS. Receiver operating characteristic analysis revealed that the area under the curve of 3DGLS for detecting severe MF was significantly larger than that of other strain parameters (0.86 vs 0.59-0.70, P.05 for all). The multivariate linear regression models using 3DGLS (RThree-dimensional GLS may be an optimal surrogate marker for reflecting MF in patients with dilated cardiomyopathy with advanced heart failure.

Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.

Background Desmin is the major intermediate filament (IF) protein in human heart and skeletal muscle. So-called ‘desminopathies’ are disorders due to pathogenic variants in the DES gene and are associated with skeletal myopathies and/or various types of cardiomyopathies. So far, only a limited number of DES pathogenic variants have been identified and functionally characterized. Methods and results Using a Sanger- and next generation sequencing (NGS) approach in patients with various types of cardiomyopathies, we identified two novel, non-synonymous missense DES variants: p.(Ile402Thr) and p.(Glu410Lys). Mutation carriers developed dilated (DCM) or arrhythmogenic cardiomyopathy (ACM), and cardiac conduction disease, leading to spare out the exercise-induced polymorphic ventricular tachycardia; we moved this variant to data in brief. To investigate the functional impact of these four DES variants, transfection experiments using SW-13 and H9c2 cells with native and mutant desmin were performed and filament assembly was analyzed by confocal microscopy. The DES_p.(Ile402Thr) and DES_p.(Glu410Lys) cells showed filament assembly defects forming cytoplasmic desmin aggregates. Furthermore, immunohistochemical and ultrastructural analysis of myocardial tissue from mutation carriers with the DES_p.(Glu410Lys) pathogenic variant supported the in vitro results. Conclusions Our in vitro results supported the classification of DES_p.(Ile402Thr) and DES_p.(Glu410Lys) as novel pathogenic variants and demonstrated that the cardiac phenotypes associated with DES variants are diverse and cell culture experiments improve in silico analysis and genetic counseling because the pathogenicity of a variant can be clarified.

Background Berlin Heart EXCOR (BH) ventricular assist devices provide mechanical long-term circulatory support in children with end-stage heart failure, as a bridge to transplantation or to recovery. Most studies are from large-volume paediatric cardiac centres. Aim The aim of this study was to analyse the experiences of three French centres and to compare these with available published data. Method We performed a retrospective observational study of three paediatric cardiac intensive care units. All children supported with BH devices were included. Morbidity and mortality data were collected and risk factors analysed. Results Fifty-four (54) patients (54% male) were included. Survival rate was 73% while on a BH device. Median age at BH device implantation was 17 months (range 2–180 months). The predominant indication was dilated cardiomyopathy (61%). Bi-ventricular assist device was used in 25 (46%) cases. The total length of long-term circulatory support was 3,373 days, with a mean length per patient of 62.5 days (range 5–267 days). Thirty-two (32) patients were transplanted (59%) and seven (13%) were successfully weaned. Type and length of support did not influence morbidity. Main complications were renal dysfunction (57%), bleeding (41%), and infection (39%). In multivariate analysis, a weight Conclusions The weight seems to be the most important risk factor of mortality in this precarious condition.

Myocardial strain analysis could provide additional information to left ventricular ejection fraction (LVEF) in nonischemic dilated cardiomyopathy (NIDC). Our aim was to analyze the feasibility of left ventricular strain evaluation using cardiac magnetic resonance feature tracking (FT) in NIDC, and to determine its clinical and prognostic impact.We retrospectively included consecutive patients with NIDC who underwent cardiac magnetic resonance. Left ventricular global longitudinal, circumferential and radial strain were obtained from standard cine sequences using FT analysis software. We evaluated their association with a composite endpoint (heart failure, implantable cardioverter-defibrillator in secondary prevention, or death).FT analysis could be performed in all of the 98 patients (mean age 68±13 years, 72% men). Intra- and interobserver concordance was good for global longitudinal and circumferential strain but was worse for radial strain. Global circumferential strain was independently associated (OR, 1.16; P=.045) with LVEF normalization during follow-up and was the only morphological parameter independently associated with the composite endpoint (OR, 1.15; P=.038). A cutoff value-8.2% was able to predict the incidence of this event during follow-up (log-rank 4.6; P=.032).Left ventricular strain analysis with FT is feasible and reproducible in NIDC. Global circumferential strain was able to predict LVEF recovery and the appearance of major cardiovascular events during follow-up.

Idiopathic dilated cardiomyopathy (DCM) is a common acquired cardiac disease in large breed dogs with a high prevalence in Doberman pinschers. It is characterized histologically by attenuated wavy fibers and fatty infiltration with degeneration. The phenotypic appearance of DCM includes ventricular dilation with systolic dysfunction and ventricular arrhythmias. These changes can be caused by other etiologies, including infectious, toxic, metabolic, and nutritional deficiencies. Chagas disease is the result of an infection with the protozoal parasite, Trypanosoma cruzi, transmitted by an insect vector. Histopathology of the myocardium is characterized by inflammation, fibrosis, and pseudocysts containing T. cruzi amastigotes. Differentiating idiopathic DCM from infectious myocarditis can be challenging when the clinical presentation and diagnostic test results are similar in affected dogs. We present thoracic radiographs, echocardiography, and post-mortem histopathology images obtained from two Doberman pinschers with similar signalment, clinical presentation, and electrocardiographic and echocardiographic appearance but with different appearing radiographs and different etiologies for their heart disease, one with idiopathic DCM and one with myocarditis attributed to Chagas disease, to highlight the value of considering alternative etiologies for DCM to guide additional clinical evaluation and owner counseling.

Our study aimed to comprehensively explore efficient prognostic indicators in idiopathic dilated cardiomyopathy (IDCM) patients with reduced left ventricular ejection fraction (LVEF40%).Prognostic value of cardiac magnetic resonance(CMR) parameters for IDCM have been inconsistent.126 IDCM patients with reduced LVEF (40%) were retrospectively enrolled. Cardiac function parameters, myocardial strain indices and myocardial fibrosis were evaluated. Laboratory data also were analyzed. The endpoint was a combination of major adverse cardiac events (MACEs), including cardiac death, heart transplantation, and rehospitalization. Prognostic value was evaluated by the Kaplan-Meier method and Cox regression.During a median follow-up of 31 months, 44 patients experienced MACEs, including 9 deaths, 1 heart transplantation, and 34 rehospitalizations due to heart failure. Univariate and multivariate Cox analyses showed that cardiac function and myocardial strain indexes were not associated with the prognosis of IDCM (all p0.05). NT-proBNP (HR 1.5, 95%CI: 1.053 to 2.137), Late‑gadolinium enhancement(LGE) mass (HR 1.022, 95%CI: 1.005 to 1.038), and LGE mass/left ventricle mass were significant predictors (HR 1.027, 95%CI: 1.007 to 1.046) for MACEs, all p 0.05. Besides, poorest prognosis was observed in IDCM patients with positive LGE combined with NT-proBNP (log-rank = 27.261, p ≤ 0.001).NT-proBNP and extent of LGE were reliable predictors in IDCM patients with reduced LVEF. Additionally, presence of LGE combined with NT-proBNP showed the strongest prognostic value in IDCM with reduced LVEF. Myocardial strain parameters seemed to have no prognostic value in IDCM patients with reduced LVEF.

We present the case of a 28-year-old man with a history of unexplained syncope, frequent ventricular arrhythmias, familial LMNA-related dilated cardiomyopathy (DCM), and mitral annular disjunction (MAD). We provide the first association of a novel truncating LMNA variant serving as a potential vulnerable substrate for arrhythmogenic MAD syndrome. This could suggest a possible synergistic role between concealed genetic variants (resulting in fibrosis as a "substrate" for arrhythmogenesis) and the presence of mitral annular disjunction (the "trigger" with mechanical stretch initiating ventricular arrhythmias), which may provide a link between mitral valve prolapse and sudden cardiac death.

We applied various methods to investigate how mutations S283D and S61D that mimic phosphorylation of tropomyosin (Tpm) affect structural and functional properties of cardiac Tpm carrying cardiomyopathy-associated mutations in different parts of its molecule. Using differential scanning calorimetry and molecular dynamics, we have shown that the S61D mutation (but not the S283 mutation) causes significant destabilization of the N-terminal part of the Tpm molecule independently of the absence or presence of cardiomyopathy-associated mutations. Our results obtained by cosedimentation of Tpm with F-actin demonstrated that both S283D and S61D mutations can reduce or even eliminate undesirable changes in Tpm affinity for F-actin caused by some cardiomyopathy-associated mutations. The results indicate that Tpm pseudo-phosphorylation by mutations S283D or S61D can rescue the effects of mutations in the TPM1 gene encoding a cardiac isoform of Tpm that lead to the development of such severe inherited heart diseases as hypertrophic or dilated cardiomyopathies.

Genetic factors play an important role in nonischemic dilated cardiomyopathy (NIDC). However, prime opportunities remain for genetic discovery and prognostic understanding. TITIN gene truncating variant mutations (TTNtv) are of interest because of their frequent appearance in NIDC series. We sought to discover known and novel TTNtv mutations in a NIDC cohort and assess 5-year outcomes. Patients with NIDC entered into the INSPIRE Registry with ≥3 years of follow-up were studied. Whole exome sequencing (WES) was performed using an Illumina Novaseq platform. Genetic analysis used Sentieon software and the GRCh38 human reference genome. Variant calls were annotated with ClinVar. Five-year outcomes were determined by functional assessment and ejection fraction (EF) as recovered (EF ≥50%), persistent (EF 21% to 49%), or progressive (left ventricular assist device, transplant, heart failure [HF] or arrhythmic death, or EF ≤20%). The study comprised 229 NIDC patients (age = 50 ± 15 years, 58% men). TTNtv's were discovered in 27 patients with 22 unique mutations; (7 known, 15 novel). TTNtv+ patients more frequently presented with severe NIDC (EF ≤20%) (p = 0.032). By 5-year, outcomes were worse in TTNtv+ patients (p = 0.027), and patients less often recovered (11% vs. 30%). Prognosis was similar with known and novel mutations. Nongenetic (e.g., environmental) cocausal risk factors for HF were frequently present, and these factors frequently appeared to act in concert with genetic variants to precipitate clinical HF. In conclusion, our study expands the library of likely pathogenic TTN mutations and increases our understanding of their clinical impact in association with other HF risk factors.

The objective of immunosuppressive drugs used in solid organ transplantation is to achieve acceptable rejection rates, minimize infections, and prolong graft and patient survival. Cardiovascular disease is a major cause of death in kidney transplant recipients. The drugs commonly used to prevent rejection (calcineurin inhibitors [CNIs] and steroids) contribute to cardiac disease seen in transplant patients by increasing the risk of hypertension and diabetes. Direct cardiac toxicity of chemotherapeutic drugs such as doxorubicin is well-known but potential direct effect of CNIs on myocardium is less explored and understood. Cardiac toxicity a rare but serious adverse effect of tacrolimus, has been observed in patients receiving solid organ transplants such as liver, bowel and kidney. In this report, we describe a case of new onset severe dilated cardiomyopathy after kidney transplantation. Reversal of heart failure occurred after tacrolimus discontinuation and the switch to a mammalian target of rapamycin (mTOR) inhibitor: sirolimus.

Background: The role of calcineurin (protein phosphatase 2B (PP2B)) in the pathogenesis of human dilated cardiomyopathy (DCM) has not been fully elucidated. We determined the potential involvement of calcineurin in the pathogenesis of DCM caused by mutations in CnB1, a subunit of calcineurin. Methods: By whole-exome sequencing, we identified a new CnB1 variant in a Han Chinese proband with cardiomyopathy from a 3-generation family with 2 normal individuals and 3 individuals with familial dilated cardiomyopathy. The potential pathogenic variant was validated by Sanger sequencing. We performed functional and mechanistic experiments in a CnB1-knockin (KI) mouse model and at the cellular level. Results: We detected a rare heterozygous CnB1 variant (p.D102A) in a proband with dilated cardiomyopathy. This variant was localized to the EF hand 3 region of CnB1, where no variants have been previously reported. KI mice harboring the p.D102A variant exhibited decreased cardiac function and cardiac dilatation. Immunoblotting, RT-PCR and immunofluorescence results showed decreased cardiomyocyte size and heart failure-related protein expression. A calcineurin activity assay demonstrated decreased calcineurin activity in the KI mice, accompanied by the decreased ability of CnB1 to bind CnA. Conclusions: CnB1 p.D102A is a disease-associated variant that confers susceptibility to cardiac dilatation. This variant is associated with impaired calcineurin activity and a subsequent decrease in the ability of CnB1 to bind CnA.