Hypertrophic cardiomyopathy (HCM) is defined as the presence of a hypertrophied, nondilated left ventricle in the absence of another causative disease (1). It is estimated to affect 1 in 500 persons, with highly variable clinical and pathologic presentations and penetrance (2,3). The severity of disease varies from a lifelong asymptomatic course to a sentinel event of sudden cardiac death (SCD) at a young age. A growing realization that the implanted cardioverter defibrillator (ICD) is effective in the primary and secondary prevention of SCD has provided an added impetus to discover new approaches for the identification and risk stratification of susceptible individuals in whom the prophylactic implantation of an ICD might be life saving (4).. In addition to this phenotypic variability, there is profound heterogeneity in the genetic substrate for HCM. To date, nine genes encoding various components of the cardiac sarcomere have been implicated in HCM: cardiac beta-myosin heavy chain (MYH7) ...
Thyroid hormone exerts marked effects on cardiovascular function. Expression of cardiac alpha- and beta-myosin heavy chain (MHC) isoforms can be altered in response to thyroid hormone as well as by hemodynamic changes imposed on the heart. The molecular mechanisms that mediate these changes are not …
While docking in Marseille yesterday, the Costa Pacifica came in contact with a buoy structure that formed a gash around 26 feet long just above the waterline. Luckily, no one was injured when the collision occurred, but it did keep ...
Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in 9 sarcomeric protein genes. The most commonly affected is beta-myosin heavy chain (MYH7), where missense mutations cluster in the head and neck regions and directly affect motor function. Comparable mutations have not been described in the light meromyosin (LMM) region of the myosin rod, nor would these be expected to directly affect motor function. We studied 82 probands with HCM in whom no mutations had been found in MYH7 exons encoding the head and neck regions of myosin nor in the other frequently implicated disease genes. Primers were designed to amplify exons 24 to 40 of MYH7. These amplimers were subjected to temperature modulated heteroduplex analysis by denaturing high-performance liquid chromatography. An Ala1379Thr missense mutation in exon 30 segregated with disease in three families and was not present in 200 normal chromosomes. The mutation occurred on two haplotypes, indicating that it was not a polymorphism linked with
A form of Ventricular Myosin that contains two alpha-Myosin Heavy Chains. It has a higher ATPase activity and Contracts at a faster rate than Myosins containing beta-Myosin Heavy Chains ...
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Hypertrophic cardiomyopathy is a primary myocardial disorder with an autosomal pattern of inheritance, characterized by asymmetric left ventricular hypertrophy with myocyte and myofibrillar disarray. Approximately 30% to 50% of all cases are accounted for by mutations in the beta-cardiac myosin heavy chain gene on chromosome 14q1. Recent linkage analysis led to the association of the disease with additional loci on chromosomes 1q3, 11p13-q13, and 15q2, but the underlying gene defects are as yet unidentified. To date, about 34 mutations of the beta-cardiac myosin heavy chain gene have been described and shown to have important prognostic implications. Definite genotype-phenotype correlations have been described; however, wide diversity in cardiac morphology, pathophysiologic features, and clinical manifestations is still evident, even within the same family. The disease has an annual mortality of approximately 3%, related to both progressive heart failure and sudden cardiac death. Not o
Backgrounds: Left ventricular (LV) adverse remodeling is enhanced by inflammatory cytokines. Pentraxin 3 (PTX3), which is one of the pentraxin superfamily same as C-reactive protein, is rapidly produced in response to inflammatory signals, and plasma PTX3 levels are increased in patients with heart failure. Previously we reported that PTX3 deficient mice demonstrated the suppression of hypertrophic cardiac remodeling after pressure overload. This study aimed to examine the cardiac specific influence of PTX3 on LV hypertrophy and dysfunction in response to pressure overload.. Methods and Results: We created transgenic (TG) mice with cardiac-specific overexpression of PTX3 using alpha-myosin heavy chain promoter. We performed transverse aortic constriction (TAC) or sham operation on TG and wild type (WT) littermate mice. Expression of PTX3 was increased after TAC in WT mice, and immunohistochemistry proved that PTX3 was produced mainly from the interstitial tissue of the heart and infiltrating ...
Familial hypertrophic cardiomyopathy 12 information including symptoms, diagnosis, misdiagnosis, treatment, causes, patient stories, videos, forums, prevention, and prognosis.
Animal models have been used to examine the development of the classic phenotypic findings of LVH, myocyte disarray and interstitial fibrosis. In a transgenic rabbit model of HCM (β-MyHC-Q403), myocyte disarray occurred before cellular hypertrophy and fibrosis (10). The transgenic rabbit model is interesting because beta-myosin heavy chain is the predominant protein, as in humans; this is unlike in mice, in which alpha-myosin heavy chain is the predominant protein. With respect to imaging findings, a reduction in septal and lateral systolic and diastolic mitral annulus velocities was the earliest observation when transgenic mutant animals were compared with nontransgenic or wild-type animals (11). Interestingly, myocardial velocities were not related to disarray, hypertrophy, or collagen volume fraction. Conversely, reduced calcium sensitivity of myofibrillar ATPase activity was detected in these animals at the same time abnormal myocardial function was observed by imaging. With disease ...
HCM - MedHelps HCM Center for Information, Symptoms, Resources, Treatments and Tools for HCM. Find HCM information, treatments for HCM and HCM symptoms.
Familial hypertrophic cardiomyopathy, also known as FHC or HCM, is a rare condition best known publicly for its association with sudden death among young athletes. It is estimated that about 1 in 500 people have HCM and the associated thickening of the heart muscle (hypertrophy). An irregular heartbeat (arrhythmia) may lead to collapse and death during or after an athletic competition. There are usually no symptoms of a heart condition before the sudden collapse, which is also called sudden cardiac death or SCD. Fortunately, SCD occurs to a very small fraction of those carrying HCM mutations. Ordinary screening does not pick up this condition. A family history of sudden death before age 50 may be the only clue that a child or teenager needs a closer medical check before starting a sport. Most HCM appears to be inherited in a dominant fashion. Family members who carry the same genes may not have cardiac hypertrophy; those who do have hypertrophy can be treated clinically, and they will ...
In the studies reported in the American Journal of Pathology, Dr. Charles Murry and his colleagues at the University of Washington, in collaboration with scientists at Geron Corporation, produced cardiomyocytes from hESCs and injected the cells into the left ventricular wall of normal healthy rats. The transplant was examined one and four weeks after injection and human cells were detected in the rat myocardium at both timepoints. At the four week timepoint, the grafted human cardiomyocytes were identified using characteristic markers including sarcomeric actin, alpha and beta-myosin heavy chain, and myosin light chain 2v. Approximately 10% of the cardiomyocytes at the four week timepoint retained proliferative capacity, thereby potentially enhancing engraftment. Both host and graft derived angiogenesis (new blood vessel formation) was observed, critical to sustaining the viability of the graft. No evidence of tumor formation was seen ...
Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease with protean clinical manifestations, ranging from asymptomatic to that of severe heart failure or sudden death. There ist no known parameter in individuals with hypertrophic cardiomyopathy (HCM) that predicts a specific clinical event. This is particularly troublesome for premature sudden death that frequently occurs in young athletes without prior symptoms. Recent identifications of mutations in the beta-myosin heavy chain (betaMHC) gene that co-segregate with the inheritance of the disease provides an opportunity to determine whether certain mutations are more likely to induce a particular clinical event. In this study we analyzed the genotype and phenotype of individuals from two unrelated families with HCM in which the affected individuals have the same missense mutation in exon 13 (G1208A) of the coding sequence for betaMHC. Results: We studied 54 individuals from the two families, 21 were affected with HCM of ...
Skinned fibers from the normal human heart with the beta-myosin heavy chain (ventricular fibers) revealed both a higher force generation per cross section and a higher Ca2+ sensitivity than skinned fibers with the alpha-myosin heavy chain (atrial fibers). The relation between isometric ATPase activity and isometric tension of atrial fibers was higher than that of ventricular fibers. Since the ATPase-tension relation equals the rate constant for the transition from force-generating into non-force-generating crossbridge states (g(app)), myosin heavy chain isoenzymes seem to have different crossbridge turnover kinetics. Modulation of g(app) by myosin heavy chain isoenzymes could explain the different contractile behavior of atrial and ventricular fibers. g(app) was independent of Ca2+. ...
Many of cTnT mutations linked to cardiomyopathies fall the TNT1 domain/N terminal tail region of unresolved high definition structure. This region (∼94-170) of cTnT is critical to Tm binding and contraction regulation. Here, the impact of the E163R mutation in cTnT-TNT1 on contractile function and tension cost was investigated using intact and skinned preparations from WT and transgenic mouse hearts. Methods: Left and right ventricular trabeculae were dissected from non-transgenic wild type (WT) and heterozygous (E163R or R92Q) mouse hearts and mounted isometrically to record twitch tension or, when skinned, Ca2+ activated force. Myofibrillar ATPase activity was measured by fluorimetric enzyme coupled assay (de Tombe and Stienen, 1995). In this thesis we aimed to assess the primary alterations of the contractile function and of tension cost caused by E163R cTnT-TNT1domain mutation, using skinned preparations or single myofibrils from WT and transgenic mouse hearts. Than we aimed to ...
The literature shows that genetic testing could stimulate solidarity among family members, but also lead to major conflicts. To prevent negative effects, clinical geneticists and ethicists have stressed the importance of good communication within families. In this qualitative study, we followed six extended families in the southern and eastern Netherlands involved in genetic testing for familial hypertrophic cardiomyopathy for three and a half years. In total 57 members of these families were interviewed in depth, most more than once. Our analysis shows that genetic testing does affect families, but that families perform a lot of balancing work in order to prevent genetic testing from becoming too all-encompassing. There is much more continuity in family life than is often thought. Moreover, as these families demonstrate different styles of family work, establishing a single norm of good communication in clinical genetics might in fact be more harmful for family life than genetic testing ...
Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the alpha-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction
MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genoty …
pFN21AE3371 8011 bp TCAATATTGGCCATTAGCCATATTATTCATTGGTTATATAGCATAAATCAATATTGGCTA TTGGCCATTGCATACGTTGTATCTATATCATAATATGTACATTTATATTGGCTCATGTCC AATATGACCGCCATGTTGGCATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGG GTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCC GCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCAT AGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGC CCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTCCGCCCCCTATTGACGTCAATGA CGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTACGGGACTTTCCTACTTG GCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACAC CAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGT CAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAATAACCC CGCCCCGTTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGC TGGTTTAGTGAACCGTCAGATCACTAGAAGCTTTATTGCGGTAGTTTATCACAGTTAAAT TGCTAACGCAGTCAGTGCTTCTGACACAACAGTCTCGAACTTAAGCTGCAGAAGTTGGTC GTGAGGCACTGGGCAGGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAA ACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTAC ...
pFN21AE2508 6067 bp TCAATATTGGCCATTAGCCATATTATTCATTGGTTATATAGCATAAATCAATATTGGCTA TTGGCCATTGCATACGTTGTATCTATATCATAATATGTACATTTATATTGGCTCATGTCC AATATGACCGCCATGTTGGCATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGG GTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCC GCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCAT AGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGC CCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTCCGCCCCCTATTGACGTCAATGA CGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTACGGGACTTTCCTACTTG GCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACAC CAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGT CAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAATAACCC CGCCCCGTTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGC TGGTTTAGTGAACCGTCAGATCACTAGAAGCTTTATTGCGGTAGTTTATCACAGTTAAAT TGCTAACGCAGTCAGTGCTTCTGACACAACAGTCTCGAACTTAAGCTGCAGAAGTTGGTC GTGAGGCACTGGGCAGGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAA ACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTAC ...
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Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease with variable clinical features that is inherited as autosomal dominant with variable penetrance. Recent developments in genetics of hereditary cardiomyopathy have not only enlightened many points about pathogenesis, but have also provided great benefit to diagnostic approaches of clinicians. Heterozygous mutation of c3691-3692insTTCA in MYBPC3 gene was identified in a pediatric patient with diagnosis of hypertrophic cardiomyopathy at clinic. Hypertrophy was observed in sister and father of the patient in echocardiography screening, and it was subsequently determined that they also had same mutation. This mutation has not previously been defined and reported previously in the literature as cause of hypertrophic cardiomyopathy.. Keywords: Echocardiography, hypertrophic cardiomyopathy, molecular genetics, MYBPC ...
The last 2 decades have borne witness to a rapid and vigorous expansion of our understanding of the genetic basis underlying many cardiovascular diseases. As fellows-in-training, this marks an exciting time with a rapid tempo of discovery that keeps us in constant motion, which challenges us to keep up with current developments to provide optimal cardiovascular care to our patients. Since the discovery in 1990 that a mutation in the β cardiac myosin heavy chain, a component of the sarcomere, caused familial hypertrophic cardiomyopathy (1,2), investigators in the field of cardiovascular genetics have developed an increasingly complex understanding of the pathophysiologic basis of inherited cardiac diseases (3). Genetic testing for these heritable diseases has rapidly advanced from basic scientific discovery to clinical application, and commercially targeted gene testing and comprehensive disease panels have entered mainstream cardiology practice in the past several years (4). Clinical screening ...
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Expression in the adult heart of a number of cardiac genes, including the two genes comprising the cardiac myosin heavy chain locus (Myh), is controlled by thyroid hormone (T3) levels, but there is minimal information concerning the epigenetic status of the genes when their expressions change. We fed mice normal chow or a propyl thio uracil (PTU, an inhibitor of T3 production) diet for 6 weeks, or the PTU diet for 6 weeks followed by normal chow for a further 2 weeks. Heart ventricles from these groups were then used for ChIP-seq analyses with an antibody to H3K4me3, a well-documented epigenetic marker of gene activation. The resulting data show that, at the Myh7 locus, H3K4me3 modifications are induced primarily at 5′ transcribed region in parallel with increased expression of beta myosin heavy chain (MHC). At the Myh6 locus, decreases in H3K4me3 modifications occurred at the promoter and 5′ transcribed region. Extensive H3K4me3 modifications also occurred at the intergenic region between ...
Wolff-Parkinson-White pattern Familial hypertrophic cardiomyopathy 6 not provided Primary familial hypertrophic cardiomyopathy Glycogen storage disease of heart, lethal congenital ...