Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

News in diagnostics and treament of cardiomyopathies.

Cardiomyopathies are defined as myocardial disorders in which the heart muscle is structurally and functionaly abnormal in the absence of a disease sufficient to cause this abnormality such as coronary artery disease, hypertension, valvular or congenital heart disease. According to the phenotype expresion cardiomyopathies are divided into dilated, hypertrophic, restrictive, arrhytmogenic and unclassified cardiomyopathies (noncompaction and tako-tsubo cardiomyopathy). The same phenotypic expression may include etiologically different forms of the disease, and at the same time phenotypic expression may change in many cardiomyopathies in the course of illness. For each type of cardiomyopathy, we further distinguish the familial (genetic) form and the acquired form. The clinical manifestation of the disease includes symptoms of heart failure, with reduced, mildly reduced or preserved ejection fraction, symptoms resulting from a number of arrhythmias and extracardiac symptoms, but in some cases symptoms may not be presented for a relatively long time. The disease can lead to significant morbidity and mortality if not detected and treated early, especially in young people who are frequently affected. Significant developments in diagnostic and treatment methods have led to an improvement in the prognosis of patients with cardiomyopathies in recent years.

Role of genetics in the development of cardiac allograft vasculopathy.

BACKGROUND: The association between genetic polymorphisms and early cardiac allograft vasculopathy (CAV) development is relatively unexplored. Identification of genes involved in the CAV process may offer new insights into pathophysiology and lead to a wider range of therapeutic options. METHODS: This prospective study of 109 patients investigated 44 single nucleotide polymorphisms (SNPs) within the susceptibility loci potentially related to coronary artery disease, carotid artery intima-media thickness (cIMT), and in nitric oxide synthase gene. Genotyping was done by the Fluidigm SNP Type assays and Fluidigm 48.48 Dynamic Array IFC. The intima thickness progression (IT) was evaluated by coronary optical coherence tomography performed 1 month and 12 months after heart transplantation (HTx). RESULTS: During the first post-HTx year, the mean intima thickness (IT) increased by 24.0 ± 34.2 µm (p < 0.001) and lumen area decreased by ‒0.9 ± 1.8 mm2 (p < 0.001). The rs1570360 (A/G) SNP of the vascular endothelial growth factor A (VEGFA) gene showed the strongest association with intima thickness progression, even in the presence of the traditional CAV risk factors. SNPs previously related to carotid artery intima-media thickness rs11785239 (PRAG1), rs6584389 (PAX2), rs13225723 (LINC02577) and rs17477177 (CCDC71L), were among the five most significantly associated with IT progression but lost their significance once traditional CAV risk factors had been added. CONCLUSION: Results of this study suggest that genetic variability may play an important role in CAV development. The vascular endothelial growth factor A gene SNP rs1570360 showed the strongest association with intima thickness (IT) progression measured by OCT, even in the presence of the traditional CAV risk factors (Tab. 3, Fig. 3, Ref. 36). Text in PDF www.elis.sk Keywords: cardiac allograft vasculopathy, optical coherence tomography, vascular endothelial growth factor A, intimal thickening, genetic polymorphism.

Cardiac magnetic resonance in patients with ARVC and family members: the potential role of native T1 mapping.

Left ventricular (LV) involvement in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is not evaluated in the revised Task Force Criteria, possibly leading to underdiagnosis. This study explored the diagnostic role of myocardial native T1 mapping in patients with ARVC and their first-degree relatives. Thirty ARVC patients (47% males, mean age 45 ± 27 years) and 59 first-degree relatives not meeting diagnostic criteria underwent CMR with native T1 mapping. C MR was abnormal in 26 (87%) patients with ARVC. The right ventricle was affected in isolation in 13 (43%) patients. Prior to T1 mapping assessment, 2 (7%) patients exhibited isolated LV involvement and 11 (36%) patients showed features of biventricular disease. Left ventricular involvement was manifest as detectable LV late gadolinium enhancement (LGE) in 12 out of 13 cases. According to pre-specified inter-ventricular septal (IVS) T1 mapping thresholds, 11 (37%) patients revealed raised native T1 values including 5 out of the 17 patients who would otherwise have been classified as exhibiting a normal LV by conventional imaging parameters. Native septal T1 values were elevated in 22 (37%) of the 59 first-degree relatives included. Biventricular involvement is commonly observed in ARVC; native myocardial T1 values are raised in more than one third of patients, including a significant proportion of cases that would have been otherwise classified as exhibiting a normal LV using conventional CMR techniques. The significance of abnormal T1 values in first-degree relatives at risk will need validation through longitudinal studies.

Danon disease is an underdiagnosed cause of advanced heart failure in young female patients: a LAMP2 flow cytometric study.

AIMS: Danon disease (DD) is a rare X-linked disorder caused by mutations in the lysosomal-associated membrane protein type 2 gene (LAMP2). DD is difficult to distinguish from other causes of dilated or hypertrophic cardiomyopathy (HCM) in female patients. As DD female patients regularly progress into advanced heart failure (AHF) aged 20-40 years, their early identification is critical to improve patient survival and facilitate genetic counselling. In this study, we evaluated the prevalence of DD among female patients with non-ischemic cardiomyopathy, who reached AHF and were younger than 40 years. METHODS AND RESULTS: The study cohort comprised 60 female patients: 47 (78%) heart transplant recipients, 2 (3%) patients treated with ventricular assist device, and 11 (18%) patients undergoing pre-transplant assessment. Aetiology of the cardiomyopathy was known in 15 patients (including two DD patients). LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients. Whole exome sequencing was used as an alternative independent testing method to FC. Five additional female DD patients (two with different novel LAMP2 mutations) were identified by FC. The total prevalence of DD in this cohort was 12%. HCM phenotype (57% vs. 9%, * P = 0.022) and delta waves identified by electrocardiography (43% vs. 0%, ** P = 0.002) were significantly more frequent in DD female patients. CONCLUSIONS: Danon disease is an underdiagnosed cause of AHF in young female patients. LAMP2 expression testing in peripheral WBCs by FC can be used as an effective screening/diagnostic tool to identify DD in this patient population.

Genetic architecture of recent-onset dilated cardiomyopathy in Moravian region assessed by whole-exome sequencing and its clinical correlates.

AIMS: Recent-onset dilated cardiomyopathy (RODCM) is a disease of heterogeneous aetiology and clinical outcome. In this pilot study, we aimed to assess its genetic architecture and correlate genotype with left ventricular reverse remodelling (LVRR). PATIENTS AND METHODS: In this multi-centre prospective observational study, we enrolled 83 Moravian patients with RODCM and a history of symptoms of less than 6 months, for whole-exome sequencing (WES). All patients underwent 12-month clinical and echocardiographic follow-up. LVRR was defined as an absolute increase in left ventricular ejection fraction > 10% accompanied by a relative decrease of left ventricular end-diastolic diameter > 10% at 12 months. RESULTS: WES identified at least one disease-related variant in 45 patients (54%). LVRR occurred in 28 patients (34%), most often in carriers of isolated titin truncated variants, followed by individuals with a negative, or inconclusive WES and carriers of other disease-related variants (56% vs. 42% vs. 19%, P=0.041). CONCLUSION: A substantial proportion of RODCM cases have a monogenic or oligogenic genetic background. Carriers of non-titin disease-related variants are less likely to reach LVRR at 12- months than other individuals. Genetic testing could contribute to better prognosis prediction and individualized treatment of RODCM.