Summary Direct cardiac reprogramming holds great potential for regenerative medicine. However, it remains inefficient, and induced cardiomyocytes (iCMs) generated in vitro are less mature than those in vivo , suggesting that undefined extrinsic factors may regulate cardiac reprogramming. Previous in vitro studies mainly used hard polystyrene dishes, yet the effect of substrate rigidity on cardiac reprogramming remains unclear. Thus, we developed a Matrigel-based hydrogel culture system to determine the roles of matrix stiffness and mechanotransduction in cardiac reprogramming. We found that soft matrix comparable with native myocardium promoted the efficiency and quality of cardiac reprogramming. Mechanistically, soft matrix enhanced cardiac reprogramming via inhibition of integrin, Rho/ROCK, actomyosin, and YAP/TAZ signaling and suppression of fibroblast programs, which were activated on rigid substrates. Soft substrate further enhanced cardiac reprogramming with Sendai virus vectors via YAP/TAZ suppression, increasing the reprogramming efficiency up to ∼15%. Thus, mechanotransduction could provide new targets for improving cardiac reprogramming.
The aim of the present study was to clarify the age-related changes in 13 clinical parameters and their associations with common complex diseases. Study subjects comprised 6,027 community-dwelling individuals who were recruited to a population-based longitudinal genetic epidemiological study. Bonferroni's correction was applied to compensate for multiple comparisons of association and P<0.0011 was considered statistically significant. Body mass index and waist circumference increased with age up to ~50 years and decreased thereafter in men, whereas the two parameters increased linearly with age in women. The prevalence of obesity was highest (41.1%) in men aged 40–49 years, after which it decreased with age. The prevalence of obesity in women increased with age to ≤32.2% in those aged ≥70 years. Systolic and mean blood pressure (BP), as well as pulse pressure, increased linearly with age in all subjects, whereas diastolic BP increased with age up to ~60 years and subsequently decreased. The prevalence of hypertension increased with age to ≤69.9 or 68.5% at age ≥70 years in men and women, respectively. The fasting plasma glucose level, blood hemoglobin A1c content and the prevalence of type 2 diabetes mellitus increased gradually with age in men and women. The serum triglyceride concentration increased with age up to ~50 years and decreased thereafter in men, whereas it increased linearly with age in women. The prevalence of hypertriglyceridemia increased to a peak of 56.8% at age 50–59 years and subsequently decreased in men, whereas in women it increased with age to ≤34.9% at ≥70 years. The serum high-density lipoprotein (HDL)-cholesterol concentration increased with age up to ~50 years and decreased thereafter in women. The prevalence of hypo-HDL-cholesterolemia increased gradually with age in women. The serum concentration of low-density lipoprotein (LDL)-cholesterol increased with age up to ~50 years and subsequently declined in men, whereas it increased linearly with age in women. The prevalence of hyper-LDL-cholesterolemia increased with age to ≤53.4% at 50–59 years in men and ≤63.9% at 60–69 years in women and it decreased thereafter in the two genders. The serum creatinine concentration and the estimated glomerular filtration rate increased or decreased linearly with age, respectively. The prevalence of chronic kidney disease (CKD) increased with age to ≤45.1 or 39.6% at ≥70 years in men and women, respectively. Therefore, these results indicate that 13 clinical parameters, as well as the prevalence of obesity, hypertension, type 2 diabetes mellitus, dyslipidemia and CKD, were significantly associated with age. They may therefore prove informative for the prevention of these diseases and contribute to the achievement of a healthy long life and successful aging.
Background: Immune checkpoint inhibitor (ICI)-related myositis with myocarditis is a rare but potentially fatal immune-related adverse event. However, its clinical features, response to immunosuppressive treatment, and prognosis remain poorly understood. Here, we describe the clinical course of patients with ICI-related myositis overlapping with myocarditis treated at our institution and a systematic review focusing on the response to immunosuppressive therapy.Methods: We identified patients who developed ICI-induced myositis with myocarditis and were treated at our hospital using a retrospective chart review of electronic medical records. For the systematic review, studies reporting ICI-induced myositis with myocarditis were identified using the Cochrane Library and PubMed databases.Results: Of the 625 patients treated with ICIs, four developed myositis with concurrent myocarditis. All the patients received immunosuppressive therapy. We assessed the activity of myocarditis and myositis based on temporal changes in troponin and creatine kinase (CK) levels. In all patients, peak troponin values appeared later than the peak CK values (median, 17 days). The median time from the start of ICI therapy to the peak of troponin and CK levels was 42.5 and 28 days, respectively. In all patients, CK levels decreased rapidly and steadily after the initiation of immunosuppressants. However, troponin levels were unstable and increased. In all patients, CK levels normalized within one month (range, 12–27 days), but troponin levels took several months to normalize (range, 84–161 days). Fourteen cases of ICI-related myositis with myocarditis were included in the systematic review. Of the 14 cases, 12 (86%) had their CK level decreased after the initial steroid treatment, but the troponin level increased and was higher than that before the start of treatment. In addition, the peak troponin values appeared later than the peak CK values (a median of 6.5 days). Eight (89%) of 9 long-term follow-up patients had troponin levels above the normal range even after CK normalization.Conclusion: In most cases of ICI-related myositis with myocarditis, troponin levels increased after the initial steroid treatment despite decreased CK levels, and exceeded pre-steroid levels. In addition, troponin remained elevated for several months after CK normalized.
Abstract. The C→T polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 (BTN2A1) gene has been previously identified as a susceptibility locus for myocardial infarction by a genome-wide association study. As hypertension is a major risk factor for myocardial infarction, the association between the BTN2A1 polymorphism, rs6929846, and myocardial infarction may be partly due to its effect on hypertension susceptibility. The aim of the present study was to examine the possible association of rs6929846 with hypertension. The study subjects comprised 5,959 community-dwelling individuals (2,183 subjects with hypertension and 3,776 controls) who were recruited to a population-based cohort study. The rs6929846 genotype was determined by a method that combined polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons between the genotype distributions (P= 0.0090) and allele frequencies (P= 0.0051) by the χ 2 test revealed that rs6929846 was significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs6929846 was significantly associated with hypertension (P=0.0008; odds ratio, 1.29; dominant model), with the minor T allele representing a risk factor for this condition. Among all the individuals, systolic, diastolic and mean blood pressure was significantly higher in the combined group of individuals with the CT or TT genotypes compared to the CC genotype group. BTN2A1 may thus be a susceptibility gene for hypertension. Therefore, determining the genotype for this polymorphism may provide genetic risk assessment information for hypertension.
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