Cause Of Heart Transplantation Research Articles

Heart Failure: From Protein to Phenotype37MicroRNA-494 reduces ATF3 expression and promotes heart failure in cardiac hypertrophic remodeling in vivo38A novel recessive plakophilin-2 gene mutation causes severe arrhythmogenic dilated cardiomyopathy and sudden cardiac death at young age39Investigation of titin expression in explanted hearts with familial dilated cardiomyopathy and TTN truncating variants

Heart Failure: From Protein to Phenotype37MicroRNA-494 reduces ATF3 expression and promotes heart failure in cardiac hypertrophic remodeling in vivo38A novel recessive plakophilin-2 gene mutation causes severe arrhythmogenic dilated cardiomyopathy and sudden cardiac death at young age39Investigation of titin expression in explanted hearts with familial dilated cardiomyopathy and TTN truncating variants

Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation

Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting. Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies. Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as non-pathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%). The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases.

Lessons learned from the Pediatric Cardiomyopathy Registry (PCMR) Study Group.

Cardiomyopathy is a rare disorder of the heart muscle, affecting 1.13 cases per 100,000 children, from birth to 18 years of age. Cardiomyopathy is the leading cause of heart transplantation in children over the age of 1. The Pediatric Cardiomyopathy Registry funded in 1994 by the National Heart, Lung, and Blood Institute was established to examine the epidemiology of the disease in children below 18 years of age. More than 3500 children across the United States and Canada have been enrolled in the Pediatric Cardiomyopathy Registry, which has followed-up these patients until death, heart transplantation, or loss to follow-up. The Pediatric Cardiomyopathy Registry has provided the most in-depth illustration of this disease regarding its aetiology, clinical course, associated risk factors, and patient outcomes. Data from the registry have helped in guiding the clinical management of cardiomyopathy in children under 18 years of age; however, questions still remain regarding the most clinically effective diagnostic and treatment approaches for these patients. Future directions of the registry include the use of next-generation whole-exome sequencing and cardiac biomarkers to identify aetiology-specific treatments and improve diagnostic strategies. This article provides a brief synopsis of the work carried out by the Pediatric Cardiomyopathy Registry since its inception, including the current knowledge on the aetiologies, outcomes, and treatments of cardiomyopathy in children.

Mouse models of autoimmune diseases - autoimmune myocarditis.

Cardiovascular diseases are the leading cause of death in industrialized nations worldwide. Of all deaths resulting from cardiovascular diseases, 2% are caused by inflammatory heart disease; specifically, myocarditis. The etiology causing myocarditis still remains unclear. Both infectious and non-infectious factors are capable of triggering myocarditis. Acute myocarditis manifests itself in a variety of ways ranging from subclinical disease to sudden heart failure, as well as the occurrence of chest pain, palpitations, and syncope. Myocarditis can lead to dilated cardiomyopathy, this being the most frequent cause for heart transplantation. Since the underlying mechanism and the pathways behind the disease initiation and progression still need to be elucidated, the need for mouse models simulating the human disease is evident. Various mouse models are frequently used to study myocarditis. Inflammation of the myocardium as a result of infectious agents can be investigated with a widely used animal model where mice are infected with coxsackievirus B3. For autoimmune (non-viral) myocarditis, several mouse models (including induction with myosin or troponin I) have been established to better understand the role of autoantibodies and their influence on disease progression. With these different models, various phases of the disease can be investigated and these findings are used to develop more specific therapies that can be translated into the clinic as a "bench-to-bedside" approach.

Paediatric dilated cardiomyopathy: clinical profile and outcome. The experience of a tertiary centre for paediatric cardiology

Dilated cardiomyopathy is the most common form of cardiomyopathy in the paediatric population and an important cause of heart transplantation in children. The clinical profile and course of dilated cardiomyopathy in children have been poorly characterised. A retrospective review of 61 patients (37 female; 24 male) diagnosed with dilated cardiomyopathy from January, 2005 to June, 2012 at a single institution was performed. The median age at diagnosis was 15 months. Heart failure was present in 83.6% of patients and 44.3% required intensive care. The most prevalent causes were idiopathic (47.5%), viral myocarditis (18.0%) and inherited metabolic diseases (11.5%). In viral myocarditis, Parvovirus B19 was the most common identified agent, in concurrence with the increasing incidence documented recently. Inherited metabolic diseases were responsible for 11.5% of dilated cardiomyopathy cases compared with the 4-6% described in the literature, which reinforces the importance of considering this aetiology in differential diagnosis of paediatric dilated cardiomyopathy. The overall mortality rate was 16.1% and five patients underwent heart transplantation. In our series, age at diagnosis and aetiology were the most important prognosis factors. We report no mortality in the five patients who underwent heart transplantation, after 2 years of follow-up.

Correlational study of CD226 gene single nucleotide polymorphism and dilated cardiomyopathy in the Chinese Han population

Objectives Background and objective: Dilated cardiomyopathy (DCM) is a group of heterogenic cardiomyopathy characterised by ventricular dilation and dysfunction. It is the third main culprit leading to heart failure and the most common cause of heart transplantation. Autoimmunity is one of the most important pathogenic mechanisms of DCM. Recent studies have reported two single nucleotide polymorphism (SNP) rs763361 and rs727088 within the last exon of CD226 gene were associated with multiple autoimmune diseases. However, it is still unknown whether these SNPs also affect patients9 susceptibility to DCM. In this study, we aim to investigate whether the SNPs rs763361 and rs727088 in CD226 gene are associated with DCM. Methods Totally 308 DCM patients and 389 control subjects were recruited in this study. PCR-restriction fragment length polymorphism (PCR-RFLP) was used to genotype all the SNPs. Results The frequency of T allele for SNP rs763361 was found to be significantly increased in the DCM group compared with the control group (44.8% vs 36.2%, OR=0.700, 95% CI 0.564 to 0.869, p=0.00120). Also, the frequency of TT genotype of SNP rs763361 in DCM patients compared with healthy controls were significantly different (14.9% vs 11.3%, p=0.00076). Meanwhile, the frequency of G allele of SNP rs727088 was found to be significantly higher in the DCM group than the control group (33.3% vs 23.7%, OR=0.621, 95% CI 0.491 to 0.786, p Conclusions Our results indicate that the association of the CD226 gene SNPs with human DCM, and the allele T at SNP rs763361 and allele G at SNP rs727088 in CD226 gene may increase the risk of DCM.

CORRELATIONAL STUDY OF CD226 GENE SINGLE NUCLEOTIDE POLYMORPHISM AND DILATED CARDIOMYOPATHY IN THE CHINESE HAN POPULATION

ObjectivesBackground and objective: Dilated cardiomyopathy (DCM) is a group of heterogenic cardiomyopathy characterised by ventricular dilation and dysfunction. It is the third main culprit leading to heart failure and the...

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT(R141W) and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of α-myosin heavy chain (MHC)-cTnT(R141W)×CYP2E1-silence double-transgenic mice when compared with the cTnT(R141W) transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome c, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT(R141W) transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT(R141W) or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.

628 A Single-Dose Recombinant Glutathione s-Transferase P1-1 Improves Cardiac Function Post Myocardial Infarction in Rats

Myocardial infarction (MI) and its subsequent heart failure (HF) are the main leading causes of heart transplantation. MI is associated with inflammatory cascades that go on to harm cardiomyocytes. Cellular tumor necrosis factor (TNF)-α signaling occurs via TNF-α receptor-associated factor 2 (TRAF2)-dependent activation of the mitogen-activated protein kinase (MAPK) cascade. Glutathione S-transferase P1-1 (GSTP1-1) has been implicated in the prevention of TNF-α-associated apoptosis through interaction with TRAF2, and ameliorating inflammation by suppressing MAPK activity.

Changes in etiology, cause of death, survival, and mortality rates in cardiac transplant patients from 1998 to 2011

We retrospectively analyzed changes in heart failure etiology, causes of death, mortality and survival rates in cardiac transplant patients from 1998 to 2011. A total of 144 patients (112 men, 32 women; mean age 40.2±14.3 years) underwent cardiac transplantation between February 1998 and January 2011. The patients were divided into two groups; hence, 63 patients (group 1; mean age 42.5±12.6 years) receiving transplantation up to January 2006, and 81 patients (group 2; mean age 38.4±15.3 years) receiving transplantation from 2006 to 2011. In the latter period, a ventricular assist device was used in 17 patients before transplantation. Dilated cardiomyopathy was the main cause of heart transplantation in both groups (71.4% vs. 74.1%). Overall mortality, in-hospital mortality (<30 days), and late mortality (≥30 days) rates were 39.6% (n=57), 13.9% (n=20), and 25.7% (n=37), respectively. Survival rates for 1, 2, 5, and 10 years were 76%, 69%, 59%, and 46%, respectively. The second group had significantly lower rates of overall mortality and late mortality compared to group 1 (29.6% vs. 52.4%, p=0.005; 16.0% vs. 38.1%, p=0.002, respectively), whereas early mortality rates were similar. Survival rates were also higher in the second group, but these differences did not reach significance (1-year, 76.1% vs. 74.6%; 2-year, 73.0% vs. 65.1%; 5-year, 63.8% vs. 55.6%; log rank 0.33). In both groups, infections (30.3% vs. 33.3%), right ventricular failure (12.1% vs. 29.2%), and sudden cardiac death (15.2% vs. 16.7%) were the leading causes of death. Our data show that overall and late mortality rates show significant decreases in cardiac transplant patients from 1998 to 2011.

Polymorphisms of presenilin-1 gene associate with dilated cardiomyopathy susceptibility

Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. It is the third leading causes of heart failure and the most common cause of heart transplantation due to its ventricular dilatation and contractile dysfunction. Currently, four hypothesized pathogenic mechanisms have been proposed: genetic predisposition, persistent cardiotropic viral infection, autoimmunity, and cell apoptosis. Presenilin-1 gene has been previously found to be associated with cell apoptosis and cardiac development. To assess the role of presenilin-1 in DCM, we examined two single nucleotide polymorphisms (SNPs) in presenilin-1 gene, namely, rs1800844 and rs177415. A total of 282 DCM patients and 306 controls were included in the study, and all SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Compared with controls, the frequency of AA and AC genotypes and the A allele at SNP rs177415 were significantly increased in DCM patients. No difference of the SNP genotype and allele frequencies at SNP rs1800844 was detected between DCM and control groups. Unconditional logistic regression adjusting for type 2 diabetes, hyperlipidemia, cigarette smoking, and gender, confirmed the association between that SNP rs177415 of the presenilin-1 gene and the susceptibility of DCM (adjusted OR 1.300, 95% CI 1.013-1.669; P=0.039). Our data indicate, for the first time, the association of the presenilin-1 gene SNPs with human DCM and the allele A at SNP rs177415 in presenilin-1 gene may increase the risk of DCM.

Genome-wide Studies of Copy Number Variation and Exome Sequencing Identify Rare Variants in BAG3 as a Cause of Dilated Cardiomyopathy

Dilated cardiomyopathy commonly causes heart failure and is the most frequent precipitating cause of heart transplantation. Familial dilated cardiomyopathy has been shown to be caused by rare variant mutations in more than 30 genes but only ~35% of its genetic cause has been identified, principally by using linkage-based or candidate gene discovery approaches. In a multigenerational family with autosomal dominant transmission, we employed whole-exome sequencing in a proband and three of his affected family members, and genome-wide copy number variation in the proband and his affected father and unaffected mother. Exome sequencing identified 428 single point variants resulting in missense, nonsense, or splice site changes. Genome-wide copy number analysis identified 51 insertion deletions and 440 copy number variants > 1 kb. Of these, a 8733 bp deletion, encompassing exon 4 of the heat shock protein cochaperone BCL2-associated athanogene 3 (BAG3), was found in seven affected family members and was absent in 355 controls. To establish the relevance of variants in this protein class in genetic DCM, we sequenced the coding exons in BAG3 in 311 other unrelated DCM probands and identified one frameshift, two nonsense, and four missense rare variants absent in 355 control DNAs, four of which were familial and segregated with disease. Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure. We conclude that new comprehensive genomic approaches have identified rare variants in BAG3 as causative of DCM.

The Pediatric Cardiomyopathy Registry and Heart Failure: Key Results from the First 15 Years

Cardiomyopathy is a serious disorder of the heart muscle and, although rare, is a common cause of heart failure in children and the most common cause for heart transplantation in children older than 1 year of age. Funded by the National Heart Lung and Blood Institute since 1994, the Pediatric Cardiomyopathy Registry (PCMR) has followed more than 3500 North American children with cardiomyopathy. Early analyses determined estimates for the incidence of pediatric cardiomyopathy (1.13 cases per 100,000 children per year), risk factors for cardiomyopathy (age <1 year, male sex, black race, and living in New England as opposed to the central southwestern states), the prevalence of heart failure at diagnosis (6%-84% depending on cause), and 10-year survival (29%-94% depending on cause). More recent analyses explored cause-specific functional status, survival and transplant outcomes, and risk factors in greater detail. For many topics these analyses are based on the largest and best-documented samples of children with disease such as the muscular dystrophies, mitochondrial disorders, and Noonan syndrome. Data from the PCMR continue to provide valuable information that guides clinical management and the use of life-saving therapies, such as cardiac transplantation and approaches to treating heart failure, and prepares children, their families, and their caregivers to deal with this serious condition.

Presence of Borrelia burgdorferi in endomyocardial biopsies in patients with new-onset unexplained dilated cardiomyopathy

Dilated cardiomyopathy (DCM) represents the third most common cause of heart failure and the most frequent cause of heart transplantation. Infectious, mostly viral, and autoimmune mechanisms, together with genetic abnormalities, have been reported as three major causes of DCM. We hypothesized that Lyme disease (LD), caused by spirochete Borrelia burgdorferi (Bb), might be an important cause of new-onset unexplained DCM in patients living in a highly endemic area for LD such as the Czech Republic. We performed endomyocardial biopsy (EMB) in 39 consecutive patients presenting with symptomatic unexplained left ventricular (LV) systolic dysfunction lasting no more than 12 months. In eight subjects (21%), Bb was detected in the EMB sample by polymerase chain reaction or by electron microscopy. None of these patients exhibited any form of atrioventricular block or other extracardiac manifestation of Bb infection. Serological testing identified IgG antibodies against Bb in only two cases and IgM antibodies in none. All affected patients were treated with intravenous ceftriaxone for 3 weeks. At 6 months follow-up, LV morphology and function as well as functional status of these patients significantly improved. In conclusion, Bb infection may represent an important cause of new-onset unexplained DCM in patients living in endemic regions such as the Czech Republic. Because the antibiotic treatment appears to be markedly effective and serological examination does not provide a tool for diagnosing the disease, EMB focused on the detection of Bb should be performed in all patients from endemic areas with new-onset unexplained DCM not responding to conventional therapy.

Parasitic Infections in Solid Organ Transplant Recipients

Parasitic Infections in Solid Organ Transplant Recipients

Remodeling of dystrophin and sarcomeric Z-band occurs in pediatric cardiomyopathies: a unifying mechanism for force transmission defect

Cardiomyopathies (CMPs) lead to associated systolic dysfunction and are the major causes of congestive heart failure and a leading cause for heart transplantation. Although the precise mechanism leading to systolic dysfunction is still elusive, chronic mechanical loading, along with altered calcium (Ca) cellular homeostasis, is believed to impair force transmission and induce cardiac morphological and structural changes, namely cardiac remodeling. Interestingly, dystrophin remodeling has been previously reported to occur in adults with end-stage CMP irrespective of the underlying cause. In order to determine the structural culprit associated with pediatric dilated cardiomyopathy (DCM) due to various causes, we investigated the structural continuum connecting dystrophin and the dystrophin-associated glycoprotein complex to the contractile apparatus in heart samples from four children with idiopathic dilated CMP: one with myocarditis, one sporadic DCM child previously identified with a delta-sarcoglycan deletion mutation, and one child with X-linked CMP with a reported splicing site mutation in the dystrophin-coded DYS gene. Immunohistochemical analysis of cytoskeletal proteins connecting the dystrophin-associated glycoprotein complex to the sarcomere identified that myocarditis, idiopathic, and genetic-based DCM are characterized by disruption of the dystrophin connection to the sarcomere and perturbation of the Z-band. Our data suggest that both dystrophin remodeling and sarcomeric Z-band/disk derangements may occur in the myocardium of children with DCM irrespective of the cause. This suggests that genetic mutations in the dystrophin-associated glycoprotein complex or any of its partners could result in sarcomere-sarcolemma connection alteration and associated Z-band disturbance, thus leading to force transmission dysfunction.

Predictor factors for the development of arterial hypertension following heart transplantation

Up to 95% of the patients with heart transplantation (HT) suffer from arterial hypertension (AHT). The development of de novo AHT after HT has not been greatly studied. To identify the predictor variables for the development of de novo AHT after HT. We retrospectively studied 253 patients with HT and who did not previously have AHT. We excluded cases of early mortality, re-transplants and combined transplants. We considered AHT as the constant need to take anti-hypertensive drugs to maintain blood pressure < 140/90 mmHg. We studied all the variables relating to recipient, donor, surgical procedure, immunosuppression and follow-up. The statistics used were the Student's t-test, chi-square statistic and a logistic regression analysis. Of the 253 patients, 109 (43%) developed AHT. The variables associated with more prevalent AHT were male recipient/donor, idiopathic dilated cardiomyopathy (IDCM) as cause of HT, having been a smoker as well as renal deterioration (RD) and hypercholesterolemia after HT. The multivariate analysis found smoking prior to the HT and hypercholesterolemia during follow-up as independent risk factors and urgent HT as a protective variable. AHT after HT is frequent. The variables associated in our population were smoking before HT, male recipient/donor, IDCM prior to HT and hypercholesterolemia and RD after HT.

Follow-up Study on the Utility of von Willebrand Factor Levels in the Diagnosis of Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is the major cause of late death in patients undergoing heart transplantation (HT). The most validated method for its diagnosis is intravascular ultrasound (IVUS), and there are no sufficiently reliable non-invasive methods. von Willebrand factor (vWF) is a marker of endothelial dysfunction/activity that is rarely studied in the context of CAV. The purpose of this study was to determine whether patients with higher levels of vWF in the first year post-transplant will develop a greater degree of CAV. A prospective study of 113 consecutive cardiac transplant recipients was initiated in January 2002. vWF determinations were performed at 1, 2, 4, 6, 9 and 12 months post-transplant, at the same time as biopsies. Coronary arteriography and IVUS were performed on the first and last follow-up visits. Heart-lung transplants, retransplants and pediatric transplants were excluded from the study. Patients who died in the first month and those who refused consent were also excluded. The final analysis included 72 patients and 405 vWF determinations. CAV was defined as an intimal thickening of >or=0.5 mm on follow-up versus baseline IVUS. Patients with CAV (n = 41) and without CAV (n = 31) after 1 year of follow-up were compared. Patients who developed CAV had a higher prevalence of prior dyslipidemia, ischemic heart disease as the cause of HT, and rate of rejection, as well as higher vWF levels (321 +/- 122 vs 243 +/- 100%, p < 0.05). The receiver-operator characteristic (ROC) curve showed that vWF values of 150% provided a sensitivity of 91%, and values of 400% a specificity of 91% (p < 0.0001). The variables associated with CAV in the multivariate analysis were prior dyslipidemia, rejections and vWF, both linearly and by groups. vWF levels of 300% to 400% increased the probability of developing CAV by 390%, and levels >400% by 500%, versus levels <200%. vWF levels determined in the first year post-transplant help to distinguish a subgroup of patients with a higher incidence of CAV.

Discovering novel targets for autoantibodies in dilated cardiomyopathy

There is increasing evidence that a large proportion of dilated cardiomyopathy (DCM) cases are mediated by autoimmune processes. Since DCM is a fatal disorder with rapid aggravation and is the leading cause of heart transplantation, further insights into disease pathogenesis are needed. Recent studies have separated the pathogenic capacity of autoantibodies and initial clinical trials removing such autoantibodies via immunoadsorption have been promising. In order to elucidate the full autoantibody repertoire involved in DCM, we applied an autoantibody screening test using ventricular and atrial proteomes as autoantigenic sources and subsequently tested the autoantibody-binding patterns of sera from dogs with spontaneous DCM. With this method, we detected five potentially DCM-related autoantigens which were identified by MS as being: myosin heavy chain cardiac muscle alpha isoform, alpha cardiac actin, mitochondrial aconitate hydratase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and brain glycogen phosphorylase (GPBB). The recovery of two known DCM autoantigens (myosin heavy chain and alpha cardiac actin) and the discovery of three novel autoantigens (mitochondrial aconitate hydratase, GADPH, and GPBB) underscore the efficacy of this experimental method and the significance of the spontaneous canine DCM model.

Dilated Cardiomyopathy in Children

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and the leading cause of heart transplantation in children. Investigators examined the