Search

The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssyn-chrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymp-tomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spi-ronolactone or the usual care for approximately 9 months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by -2.8, 95% confi-dence interval -4.6 to -1.0 ms, p = 0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection frac-tion, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9 months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF.(c) 2022 Elsev-ier Inc. All rights reserved. (Am J Cardiol 2023;191:39-42)

Dilated cardiomyopathy (DCM) has a genetic cause in up to 40% of cases, with differences in disease penetrance and clinical presentation, due to different exogeneous triggers and implicated genes. Cardiac inflammation can be the consequence of an exogeneous trigger, subsequently unveiling a phenotype. The study aimed to determine cardiac inflammation in a cohort of genetic DCM patients and investigate whether it associated with a younger disease onset. The study included 113 DCM patients with a genetic etiology, of which 17 had cardiac inflammation as diagnosed in an endomyocardial biopsy. They had a significant increased cardiac infiltration of white blood, cytotoxic T, and T-helper cells (p < 0.05). Disease expression was at a younger age in those patients with cardiac inflammation, compared to those without inflammation (p = 0.015; 50 years (interquartile range (IQR) 42–53) versus 53 years (IQR 46–61). However, cardiac inflammation was not associated with a higher incidence of all-cause mortality, heart failure hospitalization, or life-threatening arrhythmias (hazard ratio 0.85 [0.35–2.07], p = 0.74). Cardiac inflammation is associated with an earlier disease onset in patients with genetic DCM. This might indicate that myocarditis is an exogeneous trigger unveiling a phenotype at a younger age in patients with a genetic susceptibility, or that cardiac inflammation resembles a ‘hot-phase’ of early-onset disease.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:79 issue:22 pages:2219-2232 ispartof: location:United States status: published

AIMS: Heart failure (HF) is common in both men and women, yet disease pathophysiology, presentation, and progression differ between sexes. Studies addressing whether biomarkers predict new onset HF sex-specifically are scarce. This study therefore aims to test the sex-specificity of 252 protein biomarkers for new-onset HF. METHODS AND RESULTS: A matched case-control design in patients selected from cohorts within the HOMAGE consortium was used. Cases (new-onset HF, n = 562) and controls (n = 780) were matched for cohort (PREDICTOR, HEALTH-ABC, & PROSPER), follow-up time (defined as time from entry to incident HF), and age. Incident HF was defined as first hospitalization for HF. Targeted plasma proteins (n = 252) were measured using Proximity Extension Assay technology from O-link. To look for sex differences for new onset HF, we adjusted for cohort, age, and baseline clinical parameters. At baseline, women had a biomarker profile reflecting activated metabolism and immune responses. However, none of the biomarkers had a significant interaction with sex in predicting new onset HF, but four biomarkers had a trend towards sex-specificity (P

Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with

OBJECTIVES This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.BACKGROUND In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.METHODS Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledgebased network analysis. RESULTS A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).CONCLUSIONS Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450) (C) 2021 by the American College of Cardiology Foundation.

AIMS: Previous uncontrolled studies suggested a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)-related dilated cardiomyopathy (DCM). This randomized, double-blind, placebo-controlled, single-centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence. METHODS AND RESULTS: Fifty patients (39 men; mean age 54 ± 11 years) with idiopathic chronic (>6 months) DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) 200 copies/µg DNA were blindly randomized to either IVIg (n = 26, 2 g/kg over 4 days) or placebo (n = 24). The primary outcome was change in LVEF at 6 months after randomization. Secondary outcomes were change in functional capacity assessed by 6-min walk test (6MWT), quality of life [Minnesota Living with Heart Failure Questionnaire (MLHFQ)], left ventricular end-diastolic volume (LVEDV), and EMB B19V load at 6 months after randomization. LVEF significantly improved in both IVIg and placebo groups (absolute mean increase 5 ± 9%, P = 0.011 and 6 ± 10%, P = 0.008, respectively), without a significant difference between groups (P = 0.609). Additionally, change in 6MWT [median (interquartile range) IVIg 36 (13;82) vs. placebo 32 (5;80) m; P = 0.573], MLHFQ [IVIg 0 (-7;5) vs. placebo -2 (-6;6), P = 0.904] and LVEDV (IVIg -16 ± 49 mL/m2 vs. placebo -29 ± 40 mL/m2 ; P = 0.334) did not significantly differ between groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups. CONCLUSION: Intravenous immunoglobulin therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT00892112. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:23 issue:2 pages:302-309 ispartof: location:England status: published

Aims The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups. Methods and results We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping. Conclusion The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach., Graphical Abstract

BACKGROUND: Adipose tissue influences the expression and degradation of circulating biomarkers. We aimed to identify the biomarker profile and biological meaning of biomarkers associated with obesity to assess the effect of spironolactone on the circulating biomarkers and to explore whether obesity might modify the effect of spironolactone. METHODS AND RESULTS: Protein biomarkers (n = 276) from the Olink Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline, 1 month and 9 months from the HOMAGE randomized controlled trial participants. Of the 510 participants, 299 had obesity defined as an increased waist circumference (≥102 cm in men and ≥88 cm in women). Biomarkers at baseline reflected adipogenesis, increased vascularization, decreased fibrinolysis, and glucose intolerance in patients with obesity at baseline. Treatment with spironolactone had only minor effects on this proteomic profile. Obesity modified the effect of spironolactone on systolic blood pressure (Pinteraction = 0.001), showing a stronger decrease of blood pressure in obese patients (-14.8 mm Hg 95% confidence interval -18.45 to -11.12) compared with nonobese patients (-3.6 mm Hg 95% confidence interval -7.82 to 0.66). CONCLUSIONS: Among patients at risk for heart failure, those with obesity have a characteristic proteomic profile reflecting adipogenesis and glucose intolerance. Spironolactone had only minor effects on this obesity-related proteomic profile, but obesity significantly modified the effect of spironolactone on systolic blood pressure. ispartof: JOURNAL OF CARDIAC FAILURE vol:28 issue:5 pages:778-786 ispartof: location:United States status: published

OBJECTIVES This study sought to investigate the prevalence of systolic dysfunction using global longitudinal strain (GLS) and its prognostic value in relatives of dilated cardiomyopathy (DCM) patients that had normal left ventricular ejection fraction (LVEF).BACKGROUND DCM relatives are advised to undergo cardiac assessment including echocardiography, irrespective of the genetic status of the index patient. Even though LVEF is normal, the question remains whether this indicates absence of disease or simply normal cardiac volumes. GLS may provide additional information regarding (sub)clinical cardiac abnormalities and thus allow earlier disease detection.METHODS A total of 251 DCM relatives and 251 control subjects with a normal LVEF (>= 55%) were screened. Automated software measured the GLS on echocardiographic 2-, 3-, and 4-chamber views. The cutoff value for abnormal strain was >-21.5. Median follow-up was 40 months (interquartite range: 5 to 80 months). Primary outcome was the combination of death and cardiac hospitalization.RESULTS A total of 120 relatives and 83 control subjects showed abnormal GLS (48% vs. 33%, respectively; p CONCLUSIONS Relatives of DCM patients had a significantly higher prevalence of systolic dysfunction detected by GLS despite normal LVEF compared with control subjects, independent of age, sex, comorbidities, and genotype. Abnormal GLS was associated with LVEF deterioration, cardiac hospitalization, and death. (C) 2020 by the American College of Cardiology Foundation.

Contains fulltext : 284809.pdf (Publisher’s version ) (Open Access)

Aims The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial.Methods and results Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean difference(sspiro/control): -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m(2); interaction p(across-tertiles) = 0.005; interaction p(third tertile) = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differences(spiro/control): -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction p(across-tertiles) = 0.09; interaction p(third tertile) < 0.001].Conclusions These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).[GRAPHICS]Patients at risk of heart failure from the HOMAGE clinical trial were classified according to the baseline degree of myocardial collagen cross-linking, non-invasively assessed by the serum collagen type I C-terminal telopeptide (CITP) to matrix metalloproteinase-1 (MMP-1) ratio (CITP:MMP-1). As highly cross-linked collagen fibres are more resistant to degradation and CITP is a cross-linked peptide, for a given MMP-1 quantity less CITP will be released and, subsequently, serum CITP:MMP-1 will be lower. Whereas patients with low collagen cross-linking (high CITP:MMP-1) benefit from the cardioprotective effects of treatment with spironolactone on left atrial remodelling [i.e. a decrease in left atrial volume index (LAVI)] and on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, these beneficial effects are not found in patients with higher collagen cross-linking (low CITP:MMP-1).

Aims Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone’s effect. Methods and results HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25–50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25–75) age was 73 (69–79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by −10.3 (−13.0 to −7.5) mmHg and DBP by −3.2 (−4.8 to −1.7) mmHg (P Conclusion Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

Background: Acute myocarditis is a complex inflammatory disease increasingly associated with dilated cardiomyopathy (DCM) and arrhythmogenic ventricular cardiomyopathy (ACM), but its underlying genetic basis is unknown. We sought to determine if there is a genetic overlap between myocarditis and inherited forms of cardiomyopathy. Methods: Population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA-sequencing for well-characterised cardiomyopathy-associated genes with comparison to healthy controls (n=1053). Case ascertainment was assessed against national admission data. Findings: Variants of known or likely pathogenicity were identified in 6% of cases compared to

Aims To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients. Methods and results We quantified fibrosis in 209 DCM patients at three levels: (i) non‐invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino‐terminal propeptide of procollagen type III (PIIINP) and carboxy‐terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life‐threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90–6.60; P, Multilevel assessment of myocardial fibrosis demonstrates significant correlations between histology, non‐invasive imaging, and blood markers. A combined multi‐parametric approach with carboxy‐terminal propeptide of procollagen type I (PICP) and late gadolinium enhancement (LGE) allows the best risk stratification of idiopathic dilated cardiomyopathy (DCM) patients, accompanied with a profile of high expression of combined pro‐inflammatory and pro‐fibrotic genes, indicating a potential marker for disease activity.

Contains fulltext : 225426.pdf (Publisher’s version ) (Open Access)

AIM: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). METHODS AND RESULTS: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. CONCLUSION: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:22 issue:9 pages:1586-1597 ispartof: location:England status: published

Background Mutations in dystrophin gene (DMD) can cause skeletal myopathy and dilated cardiomyopathy (DCM) independently or in combination. Natural history of DMD mutation carriers and dystrophin-associated DCM is poorly understood. Objectives This study sought to describe phenotype and prognosis of DMD mutations in a large multicenter cohort of Non-Duchenne DMD mutations carriers. Methods The study cohort comprised 223 individuals with a DMD mutation (83% males, 33±15 years at first evaluation) followed at 26 European centers. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, heart transplant, LVAD implantation, aborted SCD or appropriate ICD shock. Results At initial evaluation, 85 patients (38%) had DCM (52 in combination with muscular disease) and 92 (41%) had isolated muscular disease. After a median follow-up of 96 months, 112 individuals (53%) had DCM and 20% of the individuals who had normal cardiac function at baseline developed DCM. DCM penetrance by age 30 was 56%. DCM onset was associated with male sex and was independent of the type of mutation, the presence of skeletal myopathy or serum creatine kinase levels. MACE occurred in 11% and 22% individuals from the entire cohort and with DCM respectively, and were more frequent in DCM patients without muscular disease than in those with skeletal myopathy (35.5% vs 17.7%; p=0.04). Among patients with DCM, 18% developed end-stage heart failure and 9% a major arrhythmic event (SCD/aborted SCD/ICD shock/VT). There were not differences in survival between patients with isolated DCM and those with DCM and muscular phenotype. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Atrial fibrillation and neurological events were also frequent. Prognosis of individuals who did not develop DCM was good with 96% survival during follow-up. Conclusions DCM caused by mutations in DMD is characterized by moderate penetrance but a high risk of MACE, progression to end-stage heart failure and ventricular arrythmias. DCM onset is the major determinant of prognosis in DMD mutation carriers with similar survival irrespectively of the presence of concomitant muscular disease. Survival free of MACE analysis Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III. Contratos i-PFIS: Doctorados IIS-empresa en Ciencias y Tecnologías de la Salud

Background: Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome. Methods: This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias. Results: A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block ( P P =0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM ( P Conclusions: One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.

Background: Cardiac resynchronization therapy (CRT) is an established therapy in patients with dilated cardiomyopathy (DCM) and conduction disorders. Still, one-third of the patients with DCM do not respond to CRT. This study aims to depict the underlying cardiac pathophysiological processes of nonresponse to CRT in patients with DCM using endomyocardial biopsies. Methods: Within the Maastricht and Innsbruck registries of patients with DCM, 99 patients underwent endomyocardial biopsies before CRT implantation, with histological quantification of fibrosis and inflammation, where inflammation was defined as >14 infiltrating cells/mm 2 . Echocardiographic left ventricular end-systolic volume reduction ≥15% after 6 months was defined as response to CRT. RNA was isolated from cardiac biopsies of a representative subset of responders and nonresponders. Results: Sixty-seven patients responded (68%), whereas 32 (32%) did not respond to CRT. Cardiac inflammation before implantation was negatively associated with response to CRT (25% of responders, 47% of nonresponders; odds ratio 0.3 [0.12–0.76]; P =0.01). Endomyocardial biopsies fibrosis did not relate to CRT response. Cardiac inflammation improved the robustness of prediction beyond well-known clinical predictors of CRT response (likelihood ratio test P COL1A1, COL1A2, COL3A1, COL5A1, POSTN, CTGF, LOX, TGFβ1, PDGFRA, TNC, BGN , and TSP2 were significantly higher expressed in the hearts of nonresponders. Conclusions: Cardiac inflammation along with a transcriptomic profile of high expression of combined proinflammatory and profibrotic genes are associated with a poor response to CRT in patients with DCM.

Background A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM. Methods We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole‐exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression. Results PDLIM5 was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating TTN‐variant. The PDLIM5 loss‐of‐function (LoF) variant affected all cardiac‐specific isoforms of PDLIM5 and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of PDLIM5 and its direct interactors (MYOT, LDB3, and MYOZ2) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The PDLIM5 variant cosegregated with the TTN‐variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10 kb‐deletion of exon 2 in PDLIM5 resulting in early‐onset cardiac disease, showing the importance of PDLIM5 in cardiac function. Conclusions Heterozygous PDLIM5 variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early‐onset cardiac disease. Other environmental and/or genetic factors are probably necessary to unveil the cardiac phenotype in PDLIM5 mutation carriers., A computational ranking‐based method performed in whole exome sequencing data of dilated cardiomyopathy patient put PDLIM5 forward as novel gene implicated in this cardiac disease.

Contains fulltext : 190758.pdf (Publisher’s version ) (Open Access) Aims: Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). We aim to study clinical parameters and long-term outcomes related to the TTNtv genotype and determine the related molecular changes at tissue level in TTNtv DCM patients. Methods and results: A total of 303 consecutive and extensively phenotyped DCM patients (including cardiac imaging, Holter monitoring, and endomyocardial biopsy) underwent DNA sequencing of 47 cardiomyopathy-associated genes including TTN, yielding 38 TTNtv positive (13%) patients. At long-term follow-up (median of 45 months, up to 12 years), TTNtv DCM patients had increased ventricular arrhythmias compared to other DCM, but a similar survival. Arrhythmias are especially prominent in TTNtv patients with an additional environmental trigger (i.e. virus infection, cardiac inflammation, systemic disease, toxic exposure). Importantly, cardiac mass is reduced in TTNtv patients, despite similar cardiac function and dimensions at cardiac magnetic resonance. These enhanced life-threatening arrhythmias and decreased cardiac mass in TTNtv DCM patients go along with significant cardiac energetic and matrix alterations. All components of the mitochondrial electron transport chain are significantly upregulated in TTNtv hearts at RNA-sequencing. Also, interstitial fibrosis was augmented in TTNtv patients at histological and transcript level. Conclusion: Truncating titin variants lead to pronounced cardiac alterations in mitochondrial function, with increased interstitial fibrosis and reduced hypertrophy. Those structural and metabolic alterations in TTNtv hearts go along with increased ventricular arrhythmias at long-term follow-up, with a similar survival and overall cardiac function.

Contains fulltext : 182645.pdf (Publisher’s version ) (Open Access) Dilated cardiomyopathy (DCM) is extremely heterogeneous with a large proportion due to dominantly inherited disease-causing variants in sarcomeric genes. Recessive metabolic diseases may cause DCM, usually with onset in childhood, and in the context of systemic disease. Whether metabolic defects can also cause adult-onset DCM is currently unknown. Therefore, we performed an extensive metabolic screening in 36 consecutive adult-onset DCM patients. Diagnoses were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Measurement of propionyl-CoA carboxylase (PCC) activity was done in fibroblasts. Whole exome sequencing (WES) data of 157 additional DCM patients were analyzed for genetic defects. We found a metabolic profile characteristic for propionic acidemia in a patient with severe DCM from 55 years of age. Genetic analysis demonstrated compound heterozygous variants in PCCA. Enzymatic activity of PCC in fibroblasts was markedly reduced. A targeted analysis of the PCCA and PCCB genes using available WES data from 157 further DCM patients subsequently identified another patient with propionic acidemia. This patient had compound heterozygous variants in PCCB, and developed severe DCM from 42 years of age. Adult-onset DCM can be caused by propionic acidemia, an autosomal recessive inheritable metabolic disorder usually presenting as neonatal or childhood disease. Current guidelines advise a low-protein diet to ameliorate or prevent detrimental aspects of the disease. Long-term follow-up of a larger group of patients may show whether this diet would also ameliorate DCM. Our results suggest that diagnostic metabolic screening to identify propionic acidemia and related disorders in DCM patients is justified.

ispartof: JOURNAL OF THE AMERICAN HEART ASSOCIATION vol:8 issue:11 ispartof: location:England status: published

Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.

Background Haloperidol at high dosage is associated with QTc prolongation and polymorphic ventricular arrhythmia but the effects of low-dose haloperidol remain unknown. Objective To evaluate the effects of low-dose haloperidol on QTc-duration in frail hospitalized elderly patients with delirium. Methods A prospective observational study including hospitalized patients aged ≥70 years with Groningen Frailty Index-score > 3. We included 150 patients who received haloperidol and 150 age- and frailty-matched control patients. Serial ECG recordings were performed at hospital admission and during hospitalization. QT-interval was corrected according to Framingham (QTc). Patients were grouped according to baseline QTc in normal (nQTc), borderline (bQTc) or abnormal (aQTc). Primary outcome was change in QTc-duration between first and second ECG. Potentially dangerous QTc was defined as QTc >500 ms or an increase of >50 ms. Results Patients in the haloperidol group (48% male, mean age 85y, nQT n = 98, bQT n = 31, aQT n = 20) received an average dose of 1.5 mg haloperidol per 24 hours. QTc decreased in patients with borderline (mean − 15 ± 29 ms, P Conclusion A trend to QTc shortening was seen, especially in patients with borderline or abnormal QTc at baseline, regardless of haloperidol use. These findings suggest that ECG monitoring of frail elderly patients who receive low-dose haloperidol, may not be necessary.

Over the last decade, parvovirus B19 (B19V) has frequently been linked to the pathogenesis of myocarditis (MC) and its progression towards dilated cardiomyopathy (DCM). The exact role of the presence of B19V and its load remains controversial, as this virus is also found in the heart of healthy subjects. Moreover, the prognostic relevance of B19V prevalence in endomyocardial biopsies still remains unclear. As a result, it is unclear whether the presence of B19V should be treated. This review provides an overview of recent literature investigating the presence of B19V and its pathophysiological relevance in MC and DCM, as well as in normal hearts. In brief, no difference in B19V prevalence is observed between MC/DCM and healthy control hearts. Therefore, the question remains open whether and how cardiac B19V may be of pathogenetic importance. Findings suggest that B19V is aetiologically relevant either in the presence of other cardiotropic viruses, or when B19V load is high and/or actively replicating, which both may maintain myocardial (low-grade) inflammation. Therefore, future studies should focus on the prognostic relevance of the viral load, replicative status and virus co-infections. In addition, the immunogenetic background of MC/DCM patients that makes them susceptible to develop heart failure upon presence of B19V should be more thoroughly investigated.

Background: Improvement of left ventricular function (also called left ventricular reverse remodeling [LVRR]) is an important treatment goal in patients with dilated cardiomyopathy (DCM) and hypokinetic non-DCM (HNDC) and is prognostically favorable. We tested whether genetic DCM mutations impact LVRR independent from clinical parameters. Methods and Results: Patients with DCM and hypokinetic non-DCM (n=346; mean left ventricular ejection fraction, 30%) underwent genotyping for 47 DCM-associated genes in addition to extensive phenotyping. LVRR was defined as improvement of left ventricular ejection fraction >50% or ≥10% absolute increase, with cardiac dimensions (left ventricular end diastolic diameter) ≤33 mm/m 2 or ≥10% relative decrease. LVRR occurred in 180 (52%) patients after a median follow-up of 12-month optimal medical treatment. Low baseline left ventricular ejection fraction, a hypokinetic non-DCM phenotype, high systolic blood pressure, absence of a family history of DCM, female sex, absence of atrioventricular block, and treatment with β-blockers were all independent positive clinical predictors of LVRR. With the exception of TTN , genetic mutations were strongly associated with a lower rate of LVRR (odds ratio, 0.19 [0.09–0.42]; P TTN and LMNA were independently associated with LVRR (odds ratio, 2.49 [1.09–6.20]; P =0.038 and 0.11 [0.01–0.99]; P =0.049, respectively). Adding mutation status significantly improved discrimination (C statistics) and reclassification (integrated discrimination improvement/net reclassification index) of the clinical model predicting LVRR. Furthermore, the risk for heart failure hospitalization and cardiovascular death is lower in the LVRR patients on the long term (hazard ratio, 0.47 [0.24–0.91]; P =0.009 and 0.18 [0.04–0.82]; P =0.007, respectively), and LVRR is an independent predictor for event-free survival. Conclusions: The genetic substrate is associated with the clinical course and long-term prognosis of patients with DCM/hypokinetic non-DCM.

Background The multifactorial pathogenesis leading to dilated cardiomyopathy (DCM) makes stratification difficult. The recent MOGE(S) (morphofunctional, organ involvement, genetic or familial, etiology, stage) classification addresses this issue. Objectives The purpose of this study was to investigate the applicability and prognostic relevance of the MOGE(S) classification in patients with DCM. Methods This study used patients from the Maastricht Cardiomyopathy Registry in the Netherlands and excluded patients with ischemic, valvular, hypertensive, and congenital heart disease. All other patients underwent a complete diagnostic work-up, including genetic evaluation and endomyocardial biopsy. Results A total of 213 consecutive patients with DCM were included: organ involvement was demonstrated in 35 (16%) and genetic or familial DCM in 70 (33%) patients, including 16 (8%) patients with a pathogenic mutation. At least 1 cause was found in 155 (73%) patients, of whom 48 (23%) had more than 1 possible cause. Left ventricular reverse remodeling was more common in patients with nongenetic or nonfamilial DCM than in patients with genetic or familial DCM (40% vs. 25%; p = 0.04). After a median follow-up of 47 months, organ involvement and higher New York Heart Association functional class were associated with adverse outcome (p Conclusions The MOGE(S) classification in DCM is applicable, and each attribute or the gene-environment interaction is associated with outcome. Importantly, the presence of multiple attributes was a strong predictor of adverse outcome. Finally, adaptation of the MOGE(S) involving multiple possible etiologies is recommended.

Background: Genetic evaluation is recommended in patients with unexplained dilated cardiomyopathy (DCM), but its diagnostic yield and prognostic relevance in unexplained isolated left ventricular dysfunction (LVdys) is unknown. Methods and Results: A total of 127 LVdys and 262 DCM patients underwent genetic screening. Long-term outcome consisted of a combined end point of life-threatening arrhythmia, heart transplantation, and death. At baseline, LVdys patients were younger and had less frequently New York Heart Association class ≥3 when compared with DCM (55±13 versus 58±12; P =0.019 and 21% versus 36%; P =0.003, respectively). The prevalence of familial disease and pathogenic mutations was similar in LVdys and DCM (45% versus 40%; P =0.37 and 19% versus 17%; P =0.61, respectively). After a follow-up of 56 (31–82) months, outcome did not differ in LVdys compared with DCM patients (hazard ratio, 0.83; 95% confidence interval, 0.47–1.45; P =0.51). Overall, outcome was less favorable in patients with a genetic mutation or familial disease when compared with those without (hazard ratio, 2.7; 95% confidence interval, 1.07–7.7; P =0.048 and hazard ratio, 2.2; 95% confidence interval, 1.2–4.2; P =0.013, respectively). Thus, the diagnostic yield of genetic testing in LVdys and DCM is similarly high. The presence of a gene mutation or familial predisposition results in an equally worse prognosis. Conclusions: Genetic evaluation is advised in LVdys patients and should not merely be restricted to DCM.

Antineutrophil cytoplasmic antibodies (ANCA) associated systemic vasculitis (AAV) is a grouping of systemic small-vessel vasculitides, autoimmune diseases wherein patients have pathogenic autoantibodies reacting to myeloperoxidase (MPO) or proteinase 3 (PR3). AAV comprises three disease types: microscopic polyangiiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg–Strauss Syndrome), and granulomatosis with polyangiitis (GPA; formerly known as Wegener's granulomatosis). With current therapy, AAV has become a chronic relapsing rather than a fatal condition. With this prolonged survival, patients may experience long-term sequelae as a result of vasculitis or its treatment. Large-scale evidence shows that patients with AAV have an increased mortality rate as a consequence of cardiovascular disease. Moreover, several studies have shown that cardiac involvement in these patients is an independent predictor of mortality. More importantly, both symptomatic and asymptomatic patients have demonstrated cardiac involvement that was associated with worse outcome. Despite this overwhelming evidence, current guidelines do not recommend cardiac screening in AAV patients. Finally, the impact of glucocorticoids and/or additional immunosuppressive regimens is poorly defined and it remains largely unknown whether these treatment strategies can prevent or reverse cardiac damage. Herein, we review all published data on cardiac involvement and its prognostic relevance in AAV and the current therapeutic evidence to prevent or treat these abnormalities.

Dilated cardiomyopathy is a heart disease that causes a sudden weakening of the heart muscle in adults aged thirty to fifty years in particular. This condition may lead to heart failure, arrhythmias and even sudden cardiac death. Dilated cardiomyopathy is associated with a poor prognosis, as there is no specific treatment for it. However, a recent doctoral research project may provide new insights. During this project, cardiac biopsies, genetic material, ECGs and other diagnostic tests were gathered and analysed for years. The study results show that an important predictor of this heart muscle disease is a combination of factors. By characterising patients on the basis of these individual features physicians can offer them a more specific treatment and even prevent this heart muscle disease.

Myocarditis is a challenging diagnosis due to the extreme diversity of clinical manifestations. The actual incidence of myocarditis is also difficult to determine as endomyocardial biopsy (EMB), the diagnostic gold standard, is used infrequently. Nevertheless, in up to 30 % of patients with biopsy-proven myocarditis, progression to dilated cardiomyopathy (DCM) can occur and is associated with a poor prognosis. Recent position statements of the European Society of Cardiology (ESC) and the American Heart Association vary widely with regard to indications for performing an EMB in these patients. This makes decision-making, in particular for general practitioners (GPs) and regional hospitals, difficult and unclear. Therefore, we will present a short summary of the ESC Working Group on Myocardial and Pericardial Diseases statement and our suggestions for GPs and regional hospitals for the diagnostic approach in patients with suspected myocarditis.

Recently, the term heart failure (HF) with recovered ejection fraction (HFrecovEF) was introduced for patients with a normalization of the left ventricular ejection fraction (LVEF) [(1)][1]. The question remains whether this means true recovery of systolic left ventricular function or simply

Aims Familial hypertrophic cardiomyopathy (HCM), frequently caused by sarcomeric gene mutations, is characterized by cellular dysfunction and asymmetric left-ventricular (LV) hypertrophy. We studied whether cellular dysfunction is due to an intrinsic sarcomere defect or cardiomyocyte remodelling. Methods and results Cardiac samples from 43 sarcomere mutation-positive patients (HCMmut: mutations in thick ( MYBPC3 , MYH7 ) and thin ( TPM1 , TNNI3 , TNNT2 ) myofilament genes) were compared with 14 sarcomere mutation-negative patients (HCMsmn), eight patients with secondary LV hypertrophy due to aortic stenosis (LVHao) and 13 donors. Force measurements in single membrane-permeabilized cardiomyocytes revealed significantly lower maximal force generating capacity (Fmax) in HCMmut (21 ± 1 kN/m2) and HCMsmn (26 ± 3 kN/m2) compared with donor (36 ± 2 kN/m2). Cardiomyocyte remodelling was more severe in HCMmut compared with HCMsmn based on significantly lower myofibril density (49 ± 2 vs. 63 ± 5%) and significantly higher cardiomyocyte area (915 ± 15 vs. 612 ± 11 μm2). Low Fmax in MYBPC3 mut, TNNI3 mut, HCMsmn, and LVHao was normalized to donor values after correction for myofibril density. However, Fmax was significantly lower in MYH7 mut, TPM1 mut, and TNNT2 mut even after correction for myofibril density. In accordance, measurements in single myofibrils showed very low Fmax in MYH7 mut, TPM1 mut, and TNNT2 mut compared with donor (respectively, 73 ± 3, 70 ± 7, 83 ± 6, and 113 ± 5 kN/m2). In addition, force was lower in MYH7 mut cardiomyocytes compared with MYBPC3 mut, HCMsmn, and donor at submaximal [Ca2+]. Conclusion Low cardiomyocyte Fmax in HCM patients is largely explained by hypertrophy and reduced myofibril density. MYH7 mutations reduce force generating capacity of sarcomeres at maximal and submaximal [Ca2+]. These hypocontractile sarcomeres may represent the primary abnormality in patients with MYH7 mutations.

Background— Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of microRNA-155 manipulation in hypertensive heart disease. Methods and Results— Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into microRNA-155 knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a microRNA-155 -dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Conclusions— Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.