Hypertrophic cardiomyopathy (HCM) is the most common monogenic inherited myocardial disease in children, and mutations in sarcomere genes (such as MYH7 and MYBPC3) are the most common genetic etiology of HCM, among which mutations in the MYH7 gene are the most common and account for 30%-50%. MYH7 gene mutations have the characteristics of being affected by environmental factors, coexisting with multiple genetic variations, and age-dependent penetrance, which leads to different or overlapping clinical phenotypes in children, including various cardiomyopathies and skeletal myopathies. At present, the pathogenesis, course, and prognosis of HCM caused by MYH7 gene mutations in children remain unclear. This article summarizes the possible pathogenesis, clinical phenotype, and treatment of HCM caused by MYH7 gene mutations, in order to facilitate the accurate prognostic evaluation and individualized management and treatment of the children with this disorder.
Child ; Humans ; Cardiomyopathy, Hypertrophic/therapy* ; Phenotype ; Troponin T/genetics* ; Mutation ; Carrier Proteins/genetics* ; Myosin Heavy Chains/genetics* ; Cardiac Myosins/genetics*

Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.
Animals ; C-Reactive Protein ; genetics ; immunology ; Cecum ; surgery ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Female ; Heart ; drug effects ; physiopathology ; Humans ; Interleukin-6 ; genetics ; immunology ; Ligation ; adverse effects ; Male ; Myocardium ; immunology ; Phenanthrenes ; administration & dosage ; chemistry ; Punctures ; adverse effects ; Rats ; Salvia miltiorrhiza ; chemistry ; Sepsis ; drug therapy ; etiology ; immunology ; physiopathology ; Troponin T ; genetics ; immunology ; Tumor Necrosis Factor-alpha ; genetics ; immunology

Cardiac troponin T (cTnT) serves as a structural protein of myocardial fiber, and participates in heart excitation-contraction coupling process. Here, we generated tnnt2a (cTnT-coding gene) deletion mutant zebrafish via CRISPR/Cas9 technique, and performed phenotypic analysis of the identified tnnt2a mutants. We observed that there was no significant difference between heterozygous mutant and wild type zebrafish, and the homozygous mutants displayed significant malformations in heart, including cardiac arrest, atrium and ventricle enlargement, pericardium effusion, and the individuals usually died before 7 day post fertilization (dpf). We further analyzed the expression alternations of heart sarcomere genes (tnnt2a, actc1a, tpm4a, myl7, vmhc) at transcriptional level in tnnt2a(Δ2) zebrafish by performing real time RT-PCR, and found that the RNA expression level of tnnt2a in tnnt2azebrafish decreased constantly at each time point of developmental stages, and actc1a, tpm4a, myl7 and vmhc all showed higher expressions at early developmental stages and lower expressions at late developmental stages, in comparison with those of wild type zebrafish. Lastly, electron microscopy on cardiac tissues suggested that there were significant changes of the thick or thin filament structures in tnnt2a(Δ2) zebrafish, which was further confirmed by F-actin and Tpm4 immunofluorescence staining. The tnnt2azebrafish generated by CRISPR/Cas9 bears the most common symptoms of patients with dilated cardiomyopathy, and therefore can be used as a tool to study TNNT2-deficiency related cardiomyopathy.
Animals ; CRISPR-Cas Systems ; Disease Models, Animal ; Gene Knockout Techniques ; Myocardium ; pathology ; Sequence Deletion ; Troponin T ; genetics ; Zebrafish ; Zebrafish Proteins ; genetics

OBJECTIVETo investigate the expression of Junctophilin 1 (JP1) in cardiogenesis of mammalian.

METHODSCardiac differentiation of embryonic stem cells (ESCs) was generated by hanging drop method. Fetal heart was obtained from the rats aged d 14-20 of gestation. The expression of JP1 and JP2 during cardiogenesis of ESCs and rat embryos was analyzed by RT-PCR or Western blotting. Immunofluorescence staining was employed to reveal the distribution of JP1 and JP2 in embryoid body (EB), probing for merging of JP1 and JP2 and cardiac sarcomeric α-Actinin or Troponin-T. Percentage of JP1 and JP2-positive staining cells was analyzed quantitatively by FCS on d17.

RESULTSJP1 mRNA was up-regulated at the early stage (d 5-11) and then decreased. The expression of JP1 protein was up-regulated at the early stage (d 7-9), then decreased gradually and disappeared after d 15. While JP2 gene and protein expression increased in a time-dependent manner during cardiogenesis of rat embryos. The results of immunofluorescence staining showed that there was a parallel co-localization of JP2 with Troponin-T or α-Actinin on d17, while JP1 failed to express in the sarcomeric positive area at the same time point. Furthermore, FCS analysis showed that about 16.59% of cells were JP2-positive, while no cells were stained positively for JP1 in d17 EBs.

CONCLUSIONJP1 gene is expressed during the whole process of cardiogenesis, while JP1 protein only appears on the early stage. The expression of JP1 in cardiogenesis of ESCs is consistent with that of rat embryos.

Actinin ; genetics ; metabolism ; Animals ; Cell Differentiation ; Cell Line ; Embryonic Stem Cells ; cytology ; metabolism ; Heart ; embryology ; Membrane Proteins ; genetics ; metabolism ; Mice ; Mice, Inbred ICR ; Myocytes, Cardiac ; cytology ; metabolism ; RNA, Messenger ; genetics ; Rats ; Troponin T ; genetics ; metabolism

OBJECTIVETo study cardiac troponin T (TNNT2) gene mutations in Chinese patients with hypertrophic cardiomyopathy (HCM) and analyze the correlation between the genotype and phenotype.

METHODSNinety-five unrelated Chinese patients with HCM and 120 control individuals were screened for TNNT2 gene mutations. Seven exons (8, 9, 10, 11, 14, 15, and 16) in the functional regions of TNNT2 gene were amplified using PCR and the products were sequenced. The patients with positive results underwent further family screening.

RESULTS AND CONCLUSIONThis study did not find any HCM-caused mutations in TNNT2 gene, a result different from the reported rates of TNNT2 gene mutation ranging from 10% to 20% in other nations, suggesting that TNNT2 gene is not a susceptible gene for HCM in Chinese population.

Asian Continental Ancestry Group ; genetics ; Cardiomyopathy, Hypertrophic ; genetics ; Case-Control Studies ; Humans ; Mutation ; Troponin T ; genetics

OBJECTIVETo investigate the role of homeobox gene Nkx2-5 in cardiac myogenesis.

METHODSTwo P19 cell lines, namely cells transfected with exogenous expression of Nkx2-5 gene and non-transfected cells, were cultured in suspension for 4 days to induce cell aggregation, and the cell aggregates were transferred to the Petri dish for further adherent culture. On days 4, 8, 12 and 16 of adherent culture, the expressions of α-sarcomeric actin (α-SA) and cardiac troponin T (cTnT) protein were detected by immunocytochemistry, and the mRNA expressions of GATA-4, α-myosin heavy chain (α-MHC) and atrial natriuretic factor (ANF) genes by RT-PCR.

RESULTSIn the transfected cells, α-SA and cTnT protein expressions were detected on days 8, 12 and 16 of adhere culture, and their expressions increased gradually with time. α-SA and cTnT expression was significantly higher on day 16 than on day 8 of culture (P<0.01). RT-PCR analysis of the transfected cell showed the presence of GATA-4 expression on day 4 of adherent culture, and the expression increased on days 8 and 12 but decreased on day 16. ANF and α-MHC expressions were found on days 8, 12, and 16, increasing gradually over time and showing significant differences from those on day 4 (P<0.05 or P<0.01). The expression of α-MHC was significantly higher on days 12 and 16 than on day 8 (P<0.05 or P<0.01), and ANF expression was significantly higher on day 16 than on days 8 and 12 (P<0.01). The non-transfected cells were negative for the expressions of all these genes.

CONCLUSIONExogenous expression of Nkx2-5 gene can induce P19 cells to express cardiac markers in vitro.

Actins ; metabolism ; Animals ; Atrial Natriuretic Factor ; metabolism ; Cell Culture Techniques ; Cell Differentiation ; Cell Line ; GATA4 Transcription Factor ; metabolism ; Gene Expression ; Homeobox Protein Nkx-2.5 ; Homeodomain Proteins ; genetics ; metabolism ; Mice ; Myocytes, Cardiac ; cytology ; metabolism ; Myosin Heavy Chains ; metabolism ; Transcription Factors ; genetics ; metabolism ; Transfection ; Troponin T ; metabolism

OBJECTIVETo evaluate the value of the myocardial biochemical markers including creatine kinase MB isoenzyme (CK-MB), cardiac isoform of Tropnin-T (cTnT) and N-termimal pro-brain natriuretic peptide (NT-proBNP) and electrocardiogram (ECG) in monitoring the cardiotoxicity of recombinant human endostatin (rh-endostatin) in cancer patients.

METHODSForty cancer patients were divided into two groups and received rh-endostatin in addition to chemotherapy (group A, n=24) or chemotherapy only (Group B, n=24). Serum CK-MB, cTnT levels and plasma NT-proBNP levels were measured and the ECG was recorded in all the patients before and after each of the two therapy cycles.

RESULTSIn group A, serum CK-MB, cTnT and plasma NT-proBNP levels were significantly increased after the treatment in comparison with the baseline levels (P<0.05), but such increment was not observed in group B (P>0.05). With comparable baseline levels of CK-MB, cTnT and NT-proBNP before the treatment (P>0.05), patients in group A showed significantly higher levels of the indices than those in group B after each therapy cycle (P<0.05). Increased ECG abnormality were observed after rh-endostatin treatment in Group A (P<0.05) at a rate significantly higher than that of Group B after the second treatment cycle (P<0.05).

CONCLUSIONRh-endostatin has definite cardiotoxicity, and detection of the myocardial biochemical markers of CK-MB, cTnT and NT-proBNP may help predict the occurrence of cardiotoxicity.

Adult ; Aged ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Biomarkers, Tumor ; blood ; Carcinoma, Non-Small-Cell Lung ; blood ; drug therapy ; Creatine Kinase, MB Form ; blood ; Endostatins ; adverse effects ; genetics ; therapeutic use ; Female ; Humans ; Lung Neoplasms ; blood ; drug therapy ; Male ; Middle Aged ; Natriuretic Peptide, Brain ; blood ; Ovarian Neoplasms ; blood ; drug therapy ; Peptide Fragments ; blood ; Recombinant Proteins ; adverse effects ; therapeutic use ; Risk Assessment ; Troponin T ; blood

AIMTo analyze the distribution of single nucleotide polymorphisms in Han ethnic population from Northern China.

METHODSAllele frequencies in a sample of healthy Chinese Hans (n = 204) were determined by polymerase chain reactions followed by restriction analyses with specific endonucleases.

RESULTSThe SNP 27916722 A/C in exon 11 from the NCBI database was not detected in this population. And there were significant differences between the allele frequencies of the SNPs (27930097 C/G and 27920978 C/T) in Han ethnic population from Northern China and those in the NCBI.

CONCLUSIONIt is suggested that the SNPs of sTnT are different in different ethnic populations.

Adolescent ; Adult ; Ethnic Groups ; genetics ; Exons ; Female ; Gene Frequency ; Genotype ; Humans ; Male ; Polymorphism, Single Nucleotide ; Troponin T ; classification ; genetics

OBJECTIVEThe aim of this study was to screen the disease-causing gene mutations and investigate the genotype-phenotype correlation in 10 Chinese pedigrees with familial hypertrophic cardiomyopathy (HCM).

METHODSThere are 91 family members from these 10 pedigrees and 5 members were normal mutated carriers, 23 members were HCM patients (14 male) aged from 1.5 to 73 years old. The functional regions of myosin heavy chain gene (MYH7), cardiac myosin-binding protein C (MYBPC3) and cardiac troponin T gene (TNNT2) were screened with PCR and direct sequencing technique. Clinical information from all patients was also evaluated in regard to the genotype.

RESULTSMutations were found in 5 out of 10 pedigrees. Mutations in MYH7 (Arg663His, Glu924Lys and Ile736Thr) were found in 3 pedigrees and 3 patients from these pedigrees suffered sudden death at age 20-48 years old during sport. Mutations in MYBPC3 were found in 2 pedigrees, 1 with complex mutation (Arg502Trp and splicing mutation IVS27 + 12C > T) and 1 with novel frame shift mutation (Gly347fs) and the latter pedigree has sudden death history. No mutation was identified in TNNT2.

CONCLUSIONSAlthough the Han Chinese is a relatively homogeneous ethnic group, different HCM gene mutations were responsible for familiar HCM suggesting the heterogeneity nature of the disease-causing genes and HCM MYH7 mutations are associated with a higher risk of sudden death in this cohort. Furthermore, identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of familiar HCM.

Adolescent ; Adult ; Aged ; Asian Continental Ancestry Group ; genetics ; Cardiac Myosins ; genetics ; Cardiomyopathy, Hypertrophic, Familial ; ethnology ; genetics ; Carrier Proteins ; genetics ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Middle Aged ; Mutation ; Myosin Heavy Chains ; genetics ; Pedigree ; Phenotype ; Troponin T ; genetics ; Young Adult

Cardiomyopathy, Hypertrophic ; epidemiology ; genetics ; China ; epidemiology ; Humans ; Mutation ; Prevalence ; Troponin T ; genetics