Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih(-/-)) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk(-/-)) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk(-/-) embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk(s11) variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.
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PMID:Early myocardial function affects endocardial cushion development in zebrafish. 1513 99

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic cardiac disorder with various genotypic and phenotypic manifestations, and is often a diagnostic challenge. Although more than forty years have passed since the first description of HCM, a variety of mutations in genes encoding sarcomeric proteins, that cause the disease have been defined by laboratory and clinical studies over the past few years. The fact that HCM is the most common cause of sudden death in young competitive athletes and that, it is actually an important cause of morbidity and mortality in people of all ages, has made the researchers to concentrate more on the molecular basis and treatment strategies of the disease. This study aims to summarize both pathological features and rapidly evolving molecular genetics of HCM, and so to understand this not infrequently seen, complex disorder better.
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PMID:Hypertrophic cardiomyopathy: pathological features and molecular pathogenesis. 1575 11

Hypertrophic Cardiomyopathy (HCM) is a relatively common primary cardiac disorder defined as the presence of a hypertrophied left ventricle in the absence of any other diagnosed etiology. HCM is the most common cause of sudden cardiac death in young people which often occurs without precedent symptoms. The overall clinical phenotype of patients with HCM is broad, ranging from a complete lack of cardiovascular symptoms to exertional dyspnea, chest pain, and sudden death, often due to arrhythmias. To date, 270 independent mutations in nine sarcomeric protein genes have been linked to Familial Hypertrophic Cardiomyopathy (FHC), thus the clinical variability is matched by significant genetic heterogeneity. While the final clinical phenotype in patients with FHC is a result of multiple factors including modifier genes, environmental influences and genotype, initial screening studies had suggested that individual gene mutations could be linked to specific prognoses. Given that the sarcomeric genes linked to FHC encode proteins with known functions, a vast array of biochemical, biophysical and physiologic experimental approaches have been applied to elucidate the molecular mechanisms that underlie the pathogenesis of this complex cardiovascular disorder. In this review, to illustrate the basic relationship between protein dysfunction and disease pathogenesis we focus on representative gene mutations from each of the major structural components of the cardiac sarcomere: the thick filament (beta MyHC), the thin filament (cTnT and Tm) and associated proteins (MyBP-C). The results of these studies will lead to a better understanding of FHC and eventually identify targets for therapeutic intervention.
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PMID:Sarcomeric proteins and familial hypertrophic cardiomyopathy: linking mutations in structural proteins to complex cardiovascular phenotypes. 1641 46

Hypertrophic cardiomyopathy (HCM) is a complex and relatively common genetic heart disease. HCM is caused by mutations of genes encoding sarcomeric contractile proteins and it is characterized by heterogeneous pattern of left ventricular hypertrophy with dynamic obstruction of left ventricular outflow tract. HCM is associated with both impaired left ventricular contractility and diastolic function. Using Doppler echocardiography, we are able to assess left ventricular diastolic function and measure left ventricular outflow gradient. Tissue Doppler imaging of mitral annulus is able to discriminate genotype-positive patients which allows us to improve diagnostic sensitivity of echocardiography. The Tei index is a new Doppler index, combining systolic and diastolic time intervals as an expression of global myocardial performance ("index of myocardial performance"). Non-pharmacologic treatment of obstructive HCM (alcohol septal ablation) is associated with improvement of Tei index. Doppler echocardiography is an indispensable tool in the management of HCM.
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PMID:[Role of Doppler echocardiography in the diagnostics and therapy of hypertrophic cardiomyopathy]. 1663 27

Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark of a rare familial or sporadic unclassified heart disease of heterogeneous origin. NVM results presumably from a congenital developmental error and has been traced back to single point mutations in various genes. The objective of this study was to determine the underlying genetic defect in a large German family suffering from NVM. Twenty four family members were clinically assessed using advanced imaging techniques. For molecular characterization, a genome-wide linkage analysis was undertaken and the disease locus was mapped to chromosome 14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 (encoding the alpha- and beta-myosin heavy chain, respectively) were sequenced, leading to the identification of a previously unknown de novo missense mutation, c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid in the myosin subfragment-1 (R281T). In silico simulations suggest that the mutation R281T prevents the formation of a salt bridge between residues R281 and D325, thereby destabilizing the myosin head. The mutation was exclusively present in morphologically affected family members. A few members of the family displayed NVM in combination with other heart defects, such as dislocation of the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A high degree of clinical variability was observed, ranging from the absence of symptoms in childhood to cardiac death in the third decade of life. The data presented in this report provide first evidence that a mutation in a sarcomeric protein can cause noncompaction of the ventricular myocardium.
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PMID:Noncompaction of the ventricular myocardium is associated with a de novo mutation in the beta-myosin heavy chain gene. 1815 45

Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy, is the most common inherited cardiac disorder. This condition is the major cause of sudden death in the young (<30 years of age) and in athletes. The clinical phenotype is heterogeneous, and mutations in a number of sarcomeric contractile-protein genes are responsible for causing the disease in approximately 60% of individuals with HCM. Other inherited syndromes, as well as metabolic and mitochondrial disorders, can present as clinical phenocopies and can be distinguished by their associated cardiac and noncardiac features and on the basis of their unique molecular genetics. The mode of inheritance, natural history and treatment of phenocopies can differ from those of HCM caused by mutations in sarcomere genes. Detailed clinical evaluation and mutation analysis are, therefore, important in providing an accurate diagnosis in order to enable genetic counseling, prognostic evaluation and appropriate clinical management. This Review summarizes current knowledge on the genetics, disease mechanisms, and correlations between phenotype and genotype in patients with HCM, and discusses the implications of genetic testing in routine clinical practice.
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PMID:Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. 1822 14

Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to this report, cTnC had not been classified as a HCM-susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients enrolled over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric-HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. This study may help to further define TNNC1 as an HCM-susceptibility gene, a classification that has already been established for the other members of the troponin complex.
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PMID:Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. 1857 89

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.
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PMID:Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. 1865 46

Although bone marrow-derived mesenchymal stromal cells (MSCs) may be beneficial in treating heart disease, their ability to transdifferentiate into functional cardiomyocytes remains unclear. Here, bone marrow-derived MSCs from adult female transgenic mice expressing green fluorescent protein (GFP) under the control of the cardiac-specific alpha-myosin heavy chain promoter were cocultured with male rat embryonic cardiomyocytes (rCMs) for 5-15 days. After 5 days in coculture, 6.3% of MSCs became GFP(+) and stained positively for the sarcomeric proteins troponin I and alpha-actinin. The mRNA expression for selected cardiac-specific genes (atrial natriuretic factor, Nkx2.5, and alpha-cardiac actin) in MSCs peaked after 5 days in coculture and declined thereafter. Despite clear evidence for the expression of cardiac genes, GFP(+) MSCs did not generate action potentials or display ionic currents typical of cardiomyocytes, suggesting retention of a stromal cell phenotype. Detailed immunophenotyping of GFP(+) MSCs demonstrated expression of all antigens used to characterize MSCs, as well as the acquisition of additional markers of cardiomyocytes with the phenotype CD45(-)-CD34(+)-CD73(+)-CD105(+)-CD90(+)-CD44(+)-SDF1(+)-CD134L(+)-collagen type IV(+)-vimentin(+)-troponin T(+)-troponin I(+)-alpha-actinin(+)-connexin 43(+). Although cell fusion between rCMs and MSCs was detectable, the very low frequency (0.7%) could not account for the phenotype of the GFP(+) MSCs. In conclusion, we have identified an MSC population displaying plasticity toward the cardiomyocyte lineage while retaining mesenchymal stromal cell properties, including a nonexcitable electrophysiological phenotype. The demonstration of an MSC population coexpressing cardiac and stromal cell markers may explain conflicting results in the literature and indicates the need to better understand the effects of MSCs on myocardial injury. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro. 1868 94

The heart is a highly plastic organ capable of remodeling in response to changes in physiological or pathological demand. For example, when workload increases, compensatory hypertrophic growth of individual cardiomyocytes occurs to increase cardiac output. Sustained stress, however, such as that occurring with hypertension or following myocardial infarction, triggers changes in energy metabolism and sarcomeric protein composition, loss of cardiomyocytes, ventricular dilation, reduced pump function, and ultimately heart failure. It has been known for some time that autophagy is active in cardiomyocytes, occurring at increased levels in disease. Now, with recent advances in our understanding of molecular mechanisms governing autophagy, the potential contributions of cardiomyocyte autophagy to ventricular remodeling and disease pathogenesis are being explored. As part of this work, several recent studies have focused on autophagy in heart disease elicited by changes in hemodynamic load. Pressure overload stress elicits a robust autophagic response in cardiomyocytes that is maladaptive, contributing to disease progression. In this context, load-induced aggregation of intracellular proteins is a proximal event triggering autophagic clearance mechanisms. These findings in the setting of pressure overload contrast with protein aggregation occurring in a model of protein chaperone malfunction, where activation of autophagy is beneficial, antagonizing disease progression. Here, we review recent studies of cardiomyocyte autophagy in load-induced disease and address molecular mechanisms and unanswered questions.
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PMID:Autophagy in load-induced heart disease. 1905 38


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