Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management

Cardiac arrhythmias are frequently seen in patients with dilated cardiomyopathy (DCM) and can precipitate heart failure and death. In patients with non-ischaemic DCM, evidence for the benefit of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death has recently been questioned. Algorithms devised to identify high-risk individuals who might benefit most from ICD implantation have focussed on clinical criteria with little attention paid to the underlying aetiology of DCM. Malignant ventricular arrhythmias often occur as a nonspecific consequence of DCM but can also be a primary manifestation of disease in heritable forms of DCM and may precede DCM onset. We undertook a literature search and identified 11 genes that have been associated with DCM and ventricular arrhythmias in multiple kindreds. Many of these genes fall into a diagnostic grey zone between left-dominant arrhythmogenic right ventricular cardiomyopathy and arrhythmic DCM. Genes associated predominantly with arrhythmic DCM included LMNA and SCN5A, as well as the more recently-reported DCM disease genes, RBM20, FLNC, and TTN. Recognition of arrhythmic DCM genotypes is important, as this may impact on clinical management. In particular, prophylactic ICD implantation and early referral for heart transplantation may be indicated in genotype-positive individuals. Collectively, these findings argue in favour of including genetic testing in standard-of-care management of familial DCM. Further studies in genotyped patient cohorts are required to establish the long-term health and economic benefits of this strategy

Contemporary and Future Approaches to Precision Medicine in Inherited Cardiomyopathies: JACC Focus Seminar 3/5

Inherited cardiomyopathies are commonly occurring myocardial disorders that are associated with substantial morbidity and mortality. Clinical management strategies have focused on treatment of heart failure and arrhythmic complications in symptomatic patients according to standardized guidelines. Clinicians are now being urged to implement precision medicine, but what does this involve? Advances in understanding of the genetic underpinnings of inherited cardiomyopathies have brought new possibilities for interventions that are tailored to genes, specific variants, or downstream mechanisms. However, the phenotypic variability that can occur with any given pathogenic variant suggests that factors other than single driver gene mutations are often involved. This is propelling a new imperative to elucidate the nuanced ways in which individual combinations of genetic variation, comorbidities, and lifestyle may influence cardiomyopathy phenotypes. Here, Part 3 of a 5-part precision medicine Focus Seminar series reviews the current status and future opportunities for precision medicine in the inherited cardiomyopathies

Feasibility of TEE-guided stroke risk assessment in atrial fibrillation—background, aims, design and baseline data of the TIARA pilot study

Contains fulltext : 97916.pdf (publisher's version ) (Open Access)BACKGROUND: Antithrombotic management in atrial fibrillation (AF) is currently based on clinical characteristics, despite evidence of potential fine-tuning with transoesophageal echocardiography (TEE). This open, randomised, multicentre study addresses the hypothesis that a comprehensive strategy of TEE-based aspirin treatment in AF patients is feasible and safe. METHODS: Between 2005 and 2009, ten large hospitals in the Netherlands enrolled AF patients with a moderate risk of stroke. Patients without thrombogenic TEE characteristics were randomised to aspirin or vitamin K antagonists (VKA). The primary objective is to show that TEE-based aspirin treatment is safe compared with VKA therapy. The secondary objective tests feasibility of TEE as a tool to detect echocardiographic features of high stroke risk. This report compares randomised to non-randomised patients and describes the feasibility of a TEE-based approach. RESULTS: In total, 310 patients were included. Sixty-nine patients were not randomised because of non-visualisation (n = 6) or TEE risk factors (n = 63). Compared with non-randomised patients, randomised patients (n = 241) were younger (65 +/- 11 vs. 69 +/- 9 years, p = 0.004), had less coronary artery disease (9 vs. 20%, p = 0.018), previous TIA (1.7 vs. 7.2%, p = 0.029), AF during TEE (25 vs. 54%, p < 0.001), mitral incompetence (55 vs. 70%, p = 0.038), VKA use (69 vs. 82%, p = 0.032), had a lower mean CHADS(2) score (1.2 +/- 0.6 vs. 1.6 +/- 1.0, p = 0.004), and left ventricular ejection fraction (59 +/- 8 vs. 56 +/- 8%, p = 0.016). CONCLUSIONS: This study shows that a TEE-based approach for fine-tuning stroke risk in AF patients with a moderate risk for stroke is feasible. Follow-up data will address the safety of this TEE-based approach

СОФТ-ФАКТОРЫ МЕНЕДЖМЕНТА В ОТРАСЛЯХ ПРОМЫШЛЕННОСТИ

No proper attention is given in existing management theories and concepts to systematization and analysis of non-material management factors, so-called «soft-factors». In industries, management soft-factors may be treated in a broader way. An example of a broader treatment of management soft-factors is given for the system of state regulation of foreign trade activities in industries along with specification, determination and rating of organizational and administrative management soft-factors.В современных теориях и концепциях менеджмента не уделяется должного внимания проблеме систематизации и анализа нематериальных ресурсов менеджмента, так называемых «мягких факторов» или софт-факторов. Софт-факторы менеджмента в отраслях промышленности можно трактовать расширительно. Рассмотрен пример расширительной трактовки софт-факторов менеджмента в системе государственного регулирования внешнеторговой деятельности в отраслях промышленности. Выделены и определены организационно-управленческие софт-факторы с установлением их рейтинговой оценки

Chapter 3: Pathophysiology

The hallmark pathophysiologic feature of dilated cardiomyopathy is systolic dysfunction. Several pathogenetic mechanisms appear to be operative. These include increased hemodynamic overload, ventricular remodeling, excessive neurohumoral stimulation, abnormal myocyte calcium cycling, excessive or inadequate proliferation of the extracellular matrix, accelerated apoptosis, and genetic mutations. Although beneficial in the early stages of heart failure, these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Genetic causes account for 30\u201340% of DCM and involve genes that encode a heterogeneous group of molecules that participate in force generation, force transmission, sarcomere integrity, cytoskeletal and nuclear architecture, electrolyte homeostasis, mitochondrial function, and transcription. Additional research will improve our understanding of the complex and longitudinal molecular changes that lead from gene mutation to clinical expressio

Echocardiographic assessment of mitral valve morphology after Percutaneous Transvenous Mitral Commissurotomy (PTMC)

<p>Abstract</p> <p>Aims</p> <p>PTMC produces significant changes in mitral valve morphology as improvement in leaflets mobility. The determinants of such improvement have not been assessed before.</p> <p>Methods and results</p> <p>The study included 291 symptomatic patients with mitral stenosis undergoing PTMC. Post-PTMC subvalvular splitting area was a determinant of post-PTMC excursion in both the anterior (B 0.16, 95% CI 0.03 to 0.30, p < 0.05) and the posterior (B 0.12, 95% CI 0.01 to 0.24, p < 0.05) leaflets. Another determinant was the post-PTMC transmitral pressure gradient for anterior (B -0.02, 95% CI -0.04 to -0.005, p < 0.01) and posterior (B -0.01, 95% CI -0.04 to -0.005, p < 0.05) leaflets excursion. The relationship between post-PTMC MVA and leaflet excursion was non-linear "S curve". There was a steep increase of both anterior (p, 0.02) and posterior (p, 0.03) leaflets excursion with increased MVA till the MVA reached a value of about 1.5 cm²; after which both linear and S curves became nearly parallel.</p> <p>Conclusion</p> <p>The improvement in leaflets excursion after PTMC is determined by several morphologic and hemodynamic changes produced in the valve. The increase in MVA improves mobility within limit; after which any further increase in MVA is not associated by a significant improvement in mobility in both leaflets.</p

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene

BACKGROUND: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. METHODS: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). RESULTS: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). CONCLUSIONS: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions

A Locus on Chromosome 5 Is Associated with Dilated Cardiomyopathy in Doberman Pinschers

Dilated cardiomyopathy (DCM) is a heterogeneous group of heart diseases with a strong genetic background. Currently, many human DCM cases exist where no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 cases and 70 controls collected in Germany we identified a genome-wide significant association to DCM on chromosome 5. We validated the association in an independent cohort collected in the United Kingdom. There is no known DCM candidate gene under the association signal. Therefore, DCM in Doberman Pinschers offers the chance of identifying a novel DCM gene that might also be relevant for human health

Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management