Prognosis value of galectin-3 in patients with dilated cardiomyopathy: a meta-analysis.

Background: Accurate prediction and assessment of myocardial fibrosis (MF) and adverse cardiovascular events (MACEs) are crucial in patients with dilated cardiomyopathy (DCM). Several studies indicate that galectin-3 (gal-3) as a promising prognostic predictor in patients with DCM. Methods: A comprehensive search was conducted in PubMed, EMBASE, the Cochrane Library, and Web of Science for relevant studies up to August 2023. The hazard ratios (HRs) of gal-3 for MACEs in DCM patients, and for MACEs in LGE(+) versus LGE(-) groups, were evaluated. Statistical analysis was performed using STATA SE 14.0 software. Results: Seven studies, encompassing 945 patients, met the eligibility criteria. In DCM patients, abnormally elevated gal-3 levels were indicative of an increased MACEs risk (HR = 1.10, 95% CI [1.00-1.21], I2 = 65.7%, p = 0.008). Compared with the LGE(-) group, the level of gal-3 in LGE(+) group was higher (HR = 1.12, 95% CI [1.05-1.19], I2 = 31.4%, p = 0.233), and the combination of gal-3 and LGE significantly improved the prediction of MACEs. Sensitivity analysis confirmed the robustness of all results. Conclusions: This study's findings suggest that elevated gal-3 levels significantly correlate with increased MACE risk in DCM, highlighting its potential as a biomarker. However, significant heterogeneity among studies necessitates further research to ascertain gal-3's predictive and diagnostic value in DCM prognosis, particularly in conjunction with LGE. PROSPERO ID: CRD42023471199.

A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism.

Pediatric cardiomyopathies (CM) are rare and challenging to diagnose due to the complex and mixed phenotypes. With the advent of next-generation sequencing (NGS), variants in several genes associated with CM have been identified, such as Troponin C (TnC), encoded by the TNNC1 gene. De novo variants in TNNC1 have been associated with different types of CM, including dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The American College of Medical Genetics and Genomics recently added TNNC1 to their recommended list of genes for reporting secondary findings. In this study, we report a de novo variant, c.100G>C (p.Gly34Arg) in the TNNC1 gene identified in three siblings with a diagnosis of severe DCM causing infant death for one of the siblings and stillbirth in the other two pregnancies. The identification of the same de novo variant in all affected siblings is suggestive of germline mosaicism in this family.

Sex Differences in Dilated Cardiomyopathy Prognosis.

Dilated cardiomyopathy (DCM) is the most common type of cardiomyopathy, and it often has a poor outcome. Sex differences in the prognosis of patients with DCM remain controversial. The present meta-analysis aimed to investigate whether sex plays a role in the outcome of patients with DCM and to provide real-world information on these potential sex differences for physicians and patients.We searched the PubMed, Cochrane, and EMBASE databases for published cohort studies up to February 16, 2020 that reported sex-specific prognostic outcomes (e.g., all-cause mortality; sudden cardiac death (SCD) ) in patients with DCM.Finally, 5 clinical cohort studies with a total of 5,709 patients were included. The results showed that males with DCM had a higher risk of all-cause mortality than females (HR: 1.61, 95% CI: 1.36~1.90; P < 0.00001). Next, the included studies were divided into short-term (< 5 years) and long-term (≥ 5 years) outcome groups by follow-up duration. Males showed a higher risk of all-cause mortality in both subgroups (< 5 years, HR: 1.59, 95% CI: 1.13~2.23; P = 0.008; ≥ 5 years, HR: 1.65, 95% CI: 1.33~2.05; P < 0.00001). In addition, the risks of SCD (HR: 1.80, 95% CI: 1.63~2.61; P = 0.002) and cardiovascular mortality in males (HR: 1.67, 95% CI: 1.25~2.23; P = 0.0005) were higher than those in females.The evidence from the published studies suggested that compared with females, males with DCM had an increased risk of all-cause mortality, cardiovascular mortality, and SCD.

Outcomes after surgical ventricular restoration for ischemic cardiomyopathy.

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.

A machine-learning-based method to predict adverse events in patients with dilated cardiomyopathy and severely reduced ejection fractions.

OBJECTIVE: Patients with dilated cardiomyopathy (DCM) and severely reduced left ventricular ejection fractions (LVEFs) are at very high risks of experiencing adverse cardiac events. A machine learning (ML) method could enable more effective risk stratification for these high-risk patients by incorporating various types of data. The aim of this study was to build an ML model to predict adverse events including all-cause deaths and heart transplantation in DCM patients with severely impaired LV systolic function. METHODS: One hundred and eighteen patients with DCM and severely reduced LVEFs (<35%) were included. The baseline clinical characteristics, laboratory data, electrocardiographic, and cardiac magnetic resonance (CMR) features were collected. Various feature selection processes and classifiers were performed to select an ML model with the best performance. The predictive performance of tested ML models was evaluated using the area under the curve (AUC) of the receiver operating characteristic curve using 10-fold cross-validation. RESULTS: Twelve patients died, and 17 patients underwent heart transplantation during the median follow-up of 508 days. The ML model included systolic blood pressure, left ventricular end-systolic and end-diastolic volume indices, and late gadolinium enhancement (LGE) extents on CMR imaging, and a support vector machine was selected as a classifier. The model showed excellent performance in predicting adverse events in DCM patients with severely reduced LVEF (the AUC and accuracy values were 0.873 and 0.763, respectively). CONCLUSIONS: This ML technique could effectively predict adverse events in DCM patients with severely reduced LVEF. ADVANCES IN KNOWLEDGE: The ML method has superior ability in risk stratification in severe DCM patients.

Dilated ascending aorta in the fetus.

INTRODUCTION: Prenatal recognition of dilated aortic root is extremely rare and there are significant challenges in counselling these patients. The primary aim of this case series is to describe the prevalence, associations and outcome of dilated ascending aorta diagnosed during fetal life. METHODS: This is a retrospective cohort study from two tertiary fetal cardiology centres. Dilated ascending aorta was defined as gestation-specific standard deviation > 1.96 at some point during gestation. RESULTS: Sixteen infants were live born and underwent postnatal echocardiography. Prenatally suspected bicuspid aortic valve (BAV) (n = 6) was confirmed in 5 cases (83%) postnatally. Thirteen children have been followed up for a period of minimum one year. No connective tissue disease was found. CONCLUSIONS: Prenatal dilated ascending aorta is a rare finding (0.06%). It is associated with BAV in 37% of cases and extracardiac abnormalities in 15.7%. Nuchal translucency measurement was >3.5 in 13% of cases. Connective tissue disease was not diagnosed postnatally. This is the largest prenatal cohort with dilated ascending aorta and postnatal outcomes to date. We showed a postnatal persistence of ascending aortic dilatation in 43% of babies. In the absence of extra-cardiac abnormalities, medium term outcome appears good but postnatal surveillance of aortic dilation is required.

Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis.

BACKGROUND: Myocarditis is one of the most common causes leading to heart failure in children and a possible genetic background has been postulated. We sought to characterize the clinical and genetic characteristics in patients with myocarditis ≤18 years of age to predict outcome. METHODS: A cohort of 42 patients (Genetics in Pediatric Myocarditis) with biopsy-proven myocarditis underwent genetic testing with targeted panel sequencing of cardiomyopathy-associated genes. Genetics in Pediatric Myocarditis patients were divided into subgroups according to the phenotype of dilated cardiomyopathy (DCM) at presentation, resulting in 22 patients without DCM (myocarditis without phenotype of DCM) and 20 patients with DCM (myocarditis with phenotype of DCM). RESULTS: Myocarditis with phenotype of DCM patients (median age 1.4 years) were younger than myocarditis without phenotype of DCM patients (median age 16.1 years; P<0.001) and were corresponding to heart failure-like and coronary syndrome-like phenotypes, respectively. At least one likely pathogenic/pathogenic variant was identified in 9 out of 42 patients (22%), 8 of them were heterozygous, and 7 out of 9 were in myocarditis with phenotype of DCM. Likely pathogenic/pathogenic variants were found in genes validated for primary DCM (BAG3, DSP, LMNA, MYH7, TNNI3, TNNT2, and TTN). Rare variant enrichment analysis revealed significant accumulation of high-impact disease variants in myocarditis with phenotype of DCM versus healthy individuals (P=0.0003). Event-free survival was lower (P=0.008) in myocarditis with phenotype of DCM patients compared with myocarditis without phenotype of DCM and primary DCM. CONCLUSIONS: We report heterozygous likely pathogenic/pathogenic variants in biopsy-proven pediatric myocarditis. Myocarditis patients with DCM phenotype were characterized by early-onset heart failure, significant enrichment of likely pathogenic/pathogenic variants, and poor outcome. These phenotype-specific and age group-specific findings will be useful for personalized management of these patients. Genetic evaluation in children newly diagnosed with myocarditis and DCM phenotype is warranted.

Stem cell therapy for dilated cardiomyopathy.

BACKGROUND: Stem cell therapy (SCT) has been proposed as an alternative treatment for dilated cardiomyopathy (DCM), nonetheless its effectiveness remains debatable. OBJECTIVES: To assess the effectiveness and safety of SCT in adults with non-ischaemic DCM. SEARCH METHODS: We searched CENTRAL in the Cochrane Library, MEDLINE, and Embase for relevant trials in November 2020. We also searched two clinical trials registers in May 2020. SELECTION CRITERIA: Eligible studies were randomized controlled trials (RCT) comparing stem/progenitor cells with no cells in adults with non-ischaemic DCM. We included co-interventions such as the administration of stem cell mobilizing agents. Studies were classified and analysed into three categories according to the comparison intervention, which consisted of no intervention/placebo, cell mobilization with cytokines, or a different mode of SCT. The first two comparisons (no cells in the control group) served to assess the efficacy of SCT while the third (different mode of SCT) served to complement the review with information about safety and other information of potential utility for a better understanding of the effects of SCT. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all references for eligibility, assessed trial quality, and extracted data. We undertook a quantitative evaluation of data using random-effects meta-analyses. We evaluated heterogeneity using the I² statistic. We could not explore potential effect modifiers through subgroup analyses as they were deemed uninformative due to the scarce number of trials available. We assessed the certainty of the evidence using the GRADE approach. We created summary of findings tables using GRADEpro GDT. We focused our summary of findings on all-cause mortality, safety, health-related quality of life (HRQoL), performance status, and major adverse cardiovascular events. MAIN RESULTS: We included 13 RCTs involving 762 participants (452 cell therapy and 310 controls). Only one study was at low risk of bias in all domains. There were many shortcomings in the publications that did not allow a precise assessment of the risk of bias in many domains. Due to the nature of the intervention, the main source of potential bias was lack of blinding of participants (performance bias). Frequently, the format of the continuous data available was not ideal for use in the meta-analysis and forced us to seek strategies for transforming data in a usable format. We are uncertain whether SCT reduces all-cause mortality in people with DCM compared to no intervention/placebo (mean follow-up 12 months) (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.54 to 1.31; I² = 0%; studies = 7, participants = 361; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection in people with DCM (data could not be pooled; studies = 7; participants = 361; very low-certainty evidence). We are uncertain whether SCT improves HRQoL (standardized mean difference (SMD) 0.62, 95% CI 0.01 to 1.23; I² = 72%; studies = 5, participants = 272; very low-certainty evidence) and functional capacity (6-minute walk test) (mean difference (MD) 70.12 m, 95% CI -5.28 to 145.51; I² = 87%; studies = 5, participants = 230; very low-certainty evidence). SCT may result in a slight functional class (New York Heart Association) improvement (data could not be pooled; studies = 6, participants = 398; low-certainty evidence). None of the included studies reported major adverse cardiovascular events as defined in our protocol. SCT may not increase the risk of ventricular arrhythmia (data could not be pooled; studies = 8, participants = 504; low-certainty evidence). When comparing SCT to cell mobilization with granulocyte-colony stimulating factor (G-CSF), we are uncertain whether SCT reduces all-cause mortality (RR 0.46, 95% CI 0.16 to 1.31; I² = 39%; studies = 3, participants = 195; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection (studies = 1, participants = 60; very low-certainty evidence). SCT may not improve HRQoL (MD 4.61 points, 95% CI -5.62 to 14.83; studies = 1, participants = 22; low-certainty evidence). SCT may improve functional capacity (6-minute walk test) (MD 140.14 m, 95% CI 119.51 to 160.77; I² = 0%; studies = 2, participants = 155; low-certainty evidence). None of the included studies reported MACE as defined in our protocol or ventricular arrhythmia. The most commonly reported outcomes across studies were based on physiological measures of cardiac function where there were some beneficial effects suggesting potential benefits of SCT in people with non-ischaemic DCM. However, it is unclear if this intermediate effects translates into clinical benefits for these patients. With regard to specific aspects related to the modality of cell therapy and its delivery, uncertainties remain as subgroup analyses could not be performed as planned, making it necessary to wait for the publication of several studies that are currently in progress before any firm conclusion can be reached. AUTHORS' CONCLUSIONS: We are uncertain whether SCT in people with DCM reduces the risk of all-cause mortality and procedural complications, improves HRQoL, and performance status (exercise capacity). SCT may improve functional class (NYHA), compared to usual care (no cells). Similarly, when compared to G-CSF, we are also uncertain whether SCT in people with DCM reduces the risk of all-cause mortality although some studies within this comparison observed a favourable effect that should be interpreted with caution. SCT may not improve HRQoL but may improve to some extent performance status (exercise capacity). Very low-quality evidence reflects uncertainty regarding procedural complications. These suggested beneficial effects of SCT, although uncertain due to the very low certainty of the evidence, are accompanied by favourable effects on some physiological measures of cardiac function. Presently, the most effective mode of administration of SCT and the population that could benefit the most is unclear. Therefore, it seems reasonable that use of SCT in people with DCM is limited to clinical research settings. Results of ongoing studies are likely to modify these conclusions.

HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy.

Background Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experiments in vivo and in vitro. Methods and Results We measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group (P<0.0001). Echocardiography showed that left ventricular end-diastolic diameter tends to decrease over time (58±7.3 to 51±6.6 mm; P<0.0001) in the low HE4 group (<59.65 pmol/L [median value]). HE4 was significantly associated with risk reduction of mortality and cardiovascular hospitalization in multivariate Cox model. In vivo, HE4 was highly expressed in kidney and lung tissue of mouse, and scarcely expressed in heart. In genetically induced DCM mouse model, HE4 expression increased in kidney but not in heart and lung. In vitro, supernatant from HE4-transfected human embryonic kidney 293T cells enhanced transdifferentiation of rat neonatal fibroblasts and increased expression of fibrosis-related genes, and this was accompanied by the activation of extracellular signal-regulated kinase signaling in cardiac fibroblasts. Treatment with an inhibitor of upstream signal of extracellular signal-regulated kinase or a neutralizing HE4 antibody canceled the profibrotic properties of HE4. Conclusions HE4 functions as a secretory factor, activating cardiac fibroblasts, thereby inducing cardiac interstitial fibrosis. HE4 could be a promising biomarker for assessing ongoing fibrosis and a novel therapeutic target in DCM. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr; Unique identifier: UMIN000043062.

Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis.

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

Temporal trends in outcome and patient characteristics in dilated cardiomyopathy, data from the Swedish Heart Failure Registry 2003-2015.

BACKGROUND: Temporal trends in clinical composition and outcome in dilated cardiomyopathy (DCM) are largely unknown, despite considerable advances in heart failure management. We set out to study clinical characteristics and prognosis over time in DCM in Sweden during 2003-2015. METHODS: DCM patients (n = 7873) from the Swedish Heart Failure Registry were divided into three calendar periods of inclusion, 2003-2007 (Period 1, n = 2029), 2008-2011 (Period 2, n = 3363), 2012-2015 (Period 3, n = 2481). The primary outcome was the composite of all-cause death, transplantation and hospitalization during 1 year after inclusion into the registry. RESULTS: Over the three calendar periods patients were older (p = 0.022), the proportion of females increased (mean 22.5%, 26.4%, 27.6%, p = 0.0001), left ventricular ejection fraction was higher (p = 0.0014), and symptoms by New York Heart Association less severe (p < 0.0001). Device (implantable cardioverter defibrillator and/or cardiac resynchronization) therapy increased by 30% over time (mean 11.6%, 12.3%, 15.1%, p < 0.0001). The event rates for mortality, and hospitalization were consistently decreasing over calendar periods (p < 0.0001 for all), whereas transplantation rate was stable. More advanced physical symptoms correlated with an increased risk of a composite outcome over time (p = 0.0043). CONCLUSIONS: From 2003 until 2015, we observed declining mortality and hospitalizations in DCM, paralleled by a continuous change in both demographic profile and therapy in the DCM population in Sweden, towards a less affected phenotype.

Improved Risk Stratification for Ventricular Arrhythmias and Sudden Death in Patients With Nonischemic Dilated Cardiomyopathy.

BACKGROUND: Risk stratification for ventricular arrhythmias (VA) and sudden death in nonischemic dilated cardiomyopathy (DCM) remains suboptimal. OBJECTIVES: The goal of this study was to provide an improved risk stratification algorithm for VA and sudden death in DCM. METHODS: This was a retrospective cohort study of consecutive patients with DCM who underwent cardiac magnetic resonance with late gadolinium enhancement (LGE) at 2 tertiary referral centers. The combined arrhythmic endpoint included appropriate implantable cardioverter-defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest, and sudden death. RESULTS: In 1,165 patients with a median follow-up of 36 months, LGE was an independent and strong predictor of the arrhythmic endpoint (hazard ratio: 9.7; p < 0.001). This association was consistent across all strata of left ventricular ejection fraction (LVEF). Epicardial LGE, transmural LGE, and combined septal and free-wall LGE were all associated with heightened risk. A simple algorithm combining LGE and 3 LVEF strata (i.e., ≤20%, 21% to 35%, >35%) was significantly superior to LVEF with the 35% cutoff (Harrell's C statistic: 0.8 vs. 0.69; area under the curve: 0.82 vs. 0.7; p < 0.001) and reclassified the arrhythmic risk of 34% of patients with DCM. LGE-negative patients with LVEF 21% to 35% had low risk (annual event rate 0.7%), whereas those with high-risk LGE distributions and LVEF >35% had significantly higher risk (annual event rate 3%; p = 0.007). CONCLUSIONS: In a large cohort of patients with DCM, LGE was found to be a significant, consistent, and strong predictor of VA or sudden death. Specific high-risk LGE distributions were identified. A new clinical algorithm integrating LGE and LVEF significantly improved the risk stratification for VA and sudden death, with relevant implications for implantable cardioverter-defibrillator allocation.

Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure.

Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia. Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). Design, Setting, and Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. Main Outcomes and Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). Conclusions and Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas' disease and idiopathic dilated cardiomyopathy.

Chagas' disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.

Strain parameters for predicting the prognosis of non-ischemic dilated cardiomyopathy using cardiovascular magnetic resonance tissue feature tracking.

BACKGROUND: A considerable number of non-ischemic dilated cardiomyopathy (NDCM) patients had been found to have normalized left ventricular (LV) size and systolic function with tailored medical treatments. Accordingly, we aimed to evaluate if strain parameters assessed by cardiovascular magnetic resonance (CMR) feature tracking (FT) analysis could predict the NDCM recovery. METHODS: 79 newly diagnosed NDCM patients who underwent baseline and follow-up CMR scans were enrolled. Recovery was defined as a current normalized LV size and systolic function evaluated by CMR. RESULTS: Among 79 patients, 21 (27%) were confirmed recovered at a median follow-up of 36 months. Recovered patients presented with faster heart rates (HR) and larger body surface area (BSA) at baseline (P < 0.05). Compared to unrecovered patients, recovered pateints had a higher LV apical radial strain divided by basal radial strain (RSapi/bas) and a lower standard deviation of time to peak radial strain in 16 segments of the LV (SD16-TTPRS). According to a multivariate logistic regression model, RSapi/bas (P = 0.035) and SD16-TTPRS (P = 0.012) resulted as significant predictors for differentiation of recovered from unrecovered patients. The sensitivity and specificity of RSapi/bas and SD16-TTPRS for predicting recovered conditions were 76%, 67%, and 91%, 59%, with the area under the curve of 0.75 and 0.76, respectively. Further, Kaplan Meier survival analysis showed that patients with RSapi/bas ≥ 0.95% and SD16-FTPRS ≤ 111 ms had the highest recovery rate (65%, P = 0.027). CONCLUSIONS: RSapi/bas and CMR SD16-TTPRS may be used as non-invasive parameters for predicting LV recovery in NDCM. This finding may be beneficial for subsequent treatments and prognosis of NDCM patients. Registration number: ChiCTR-POC-17012586.

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Clinical Implications of Fragmented QRS Complex as an Outcome Predictor in Children with Idiopathic Dilated Cardiomyopathy.

Fragmented QRS (fQRS) is an easily evaluated noninvasive parameter in electrocardiograms (ECGs) for predicting cardiac adverse events. Our study aimed to evaluate whether fQRS could be used as a risk factor to predict a major adverse cardiac event (MACE) in children with idiopathic dilated cardiomyopathy (DCM). Our retrospective study enrolled 63 patients aged ≤ 19 years who were newly diagnosed with idiopathic DCM at Samsung Medical Center from 2003 to 2014, and followed up until December 2018. Demographic data, ECGs, and echocardiography were reviewed and analyzed for their possible links with adverse outcomes. The median age was 14.0 months and the median length of follow-up was 65.0 months. Age, QRS duration, and ejection fraction in M-mode at diagnosis were significantly different between the fQRS and non-fQRS groups (P = 0.026; P = 0.001; and P = 0.020). Significant difference between the fQRS and non-fQRS groups was found in patients with a MACE (P = 0.016, odd ratio 3.643) or any arrhythmias (P = 0.008, odd ratio 6.563). The MACE-free survival rate showed a significant difference in terms of fQRS (P = 0.003; P = 0.007; and P = 0.027). In univariate analyses, age, QRS duration, corrected QT, positive fQRS, and the number of leads with fQRS were significant predictors of MACEs. Among the above factors, positive fQRS at diagnosis was a strongly significant predictor of adverse outcomes in multivariate analyses (hazards ratio 94.529, P = 0.001). Fragmented QRS complex at diagnosis could be used as a strong predictor for cardiac adverse outcomes in pediatric patients with idiopathic DCM.

Longitudinal Prediction of Transplant-Free Survival by Echocardiography in Pediatric Dilated Cardiomyopathy.

BACKGROUND: The prognostic significance of serial echocardiography and its rate of change in children with dilated cardiomyopathy (DCM) is incompletely defined. METHODS: We retrospectively analysed up to 4 serial echocardiograms. Associations between mortality/transplant and echocardiographic parameters over time and between outcomes and the rate of change of echocardiographic parameters were analysed. Estimation of patient-specific intercepts and slopes was done using linear regression models. RESULTS: Fifty-seven DCM children were studied (50% male; median age, 0.6 year; average follow-up, 2.1 ± 2.4 years). The median time to transplant or death was 2.0 years. Increased left ventricular (LV) diastolic (LVEDD) and systolic (LVESD) dimensions and myocardial performance index (MPI) were associated with increased mortality and transplant risk. Increased LV ejection fraction, mitral E-deceleration time, right ventricular (RV) fractional area change, and tricuspid annular plane systolic excursion were associated with reduced mortality and transplant risk. Transplant/mortality likelihood increased by 41.6% and 19.8% for each unit increase in LVEDD and LVESD z scores, respectively (LVEDD: hazard ratio [HR], 1.416; 95% confidence interval [CI], 1.285-1.560; P < 0.001; LVESD: HR, 1.198; 95% CI, 1.147-1.251; P < 0.001). A higher monthly change in LVESD z score increased transplant/mortality likelihood by 85.6% (HR, 1.856; 95% CI, 1.572-2.191; P = 0.015). Greater changes in mitral E/e' (HR, 0.707; 95% CI, 0.636-0.786; P < 0.001) and RV MPI (HR, 0.412; 95% CI, 0.277-0.613; P < 0.001) were associated with reduced mortality and transplant risk. CONCLUSIONS: LV and RV systolic and diastolic dimensions and function over time and their rate of change are associated with risk for transplant and mortality in childhood DCM. Serial changes in these parameters may be useful to predict clinical outcomes.

Clinical and Genetic Investigations of 109 Index Patients With Dilated Cardiomyopathy and 445 of Their Relatives.

BACKGROUND: It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center. METHODS: Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives (P<0.001). RESULTS: Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing. CONCLUSIONS: A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.

The role of atrial fibrillation as a prognostic factor in doberman pinschers with dilated cardiomyopathy and congestive heart failure.

Atrial fibrillation (AF) in congestive heart failure (CHF) is associated with a high risk of mortality and shorter survival times in human and veterinary medicine. A retrospective review of medical records was performed to evaluate the impact of AF on survival times in Doberman Pinschers with dilated cardiomyopathy (DCM). Time of first onset of CHF and its role as a prognostic factor were also determined, as were predictors of AF development. Forty-eight client-owned purebred Doberman Pinschers with DCM and CHF were included; 23 dogs presented with AF and 25 dogs did not develop AF until immediately before cardiac-related death. Dogs with AF survived for significantly shorter times than those without AF (P = 0.043). For dogs with AF, mean and median survival times were 88.2 days and 22 days, respectively (range, 42.1-134.4 days); mean and median survival times for dogs without AF were 150.7 days and 98 days, respectively (range, 98.5-203 days). AF increased the risk of cardiac-related death (hazard ratio [HR], 2.371; 95% confidence intervals [CI], 1.14-4.95; P = 0.021). Biventricular and right atrial dilation was only present in dogs with AF and right atrial enlargement was the only significant predictor of AF after multivariate analysis (P < 0.001). Dogs with AF had significantly higher mean heart rates than dogs without AF (201 beats per min [bpm] vs. 132 bpm; P < 0.001). In conclusion, AF in Doberman Pinschers with DCM and CHF increased the risk of cardiac-related death and reduced survival time.