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Background: To examine influence of COVID-19 pandemic on cardiovascular system in general population, ECG changes during the COVID-19 pandemic period were compared with those before the pandemic period. Methods: Incidence of newly appeared ECG abnormalities (T wave abnormalities and ST-segment depression including minor changes, and abnormal Q wave) was evaluated in subjects 40 to 74 years of age who had 12-lead ECG recording in annual health checkup offered to adult citizens of Moriguchi city, Osaka, Japan in 2019 and 2020. The incidence was compared with that of those who received ECG recording in 2018 and 2019 as the control value before the COVID-19 pandemic. Those with history of cardiovascular disease, any T wave abnormality, any ST-segment depression, abnormal Q wave, left bundle brunch block, or pace-maker rhythm at baseline ECG were excluded. Multivariate logistic regression analyses were performed adjusted for age, sex, hypertension, current smoking, diabetes, drinking habit and hypercholesterolemia. Results: There were 5,221 (mean age 63±10, men 40%) subjects who received ECG recording in 2018 and 2019 and 4,100 (mean age 63±10, men 41%) subjects who received ECG recording in 2019 and 2020. The incidence of newly appeared T wave abnormalities was 5.2 %, ST-segment depression was 2.8 % and abnormal Q wave was 1.1 % from 2018 to 2019, whereas the incidence of newly appeared T wave abnormalities was 5.8 %, ST-segment depression was 4.3 % and abnormal Q wave was 1.7 % from 2019 to 2020. The incidence of ST-segment depression (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.27 to 1.98, p Conclusions: Increased incidence of ST-segment depression and abnormal Q wave was observed during the COVID-19 pandemic period.

Background: To examine influence of COVID-19 pandemic on cardiovascular risk factors in general population, incidence of newly diagnosed hypertension, diabetes mellitus, hypercholesterolemia and excess body weight during the COVID-19 pandemic period was compared with that of those before the pandemic period. Methods: Annual incidence of hypertension, diabetes mellitus, hypercholesterolemia and excess body weight was evaluated in subjects who had annual health checkup offered to adult citizens of Moriguchi city, Osaka, Japan in 2019 and 2020. Those with history of cardiovascular disease were excluded. The incidence was compared with that of those who received the checkup in 2018 and 2019 as the control value. The incidence of each risk factor was evaluated in separate models in which subjects with the risk factor of interest at baseline were excluded. Multivariate logistic regression analyses were performed adjusted for clinical valuables including age, sex, hypertension, diabetes, current smoking, drinking habit and excess body weight in each model. Results: Characteristics of the subjects at baseline and incidence of the risk factor next year in each model were presented in the table. The incidence of hypertension (odds ratio (OR)=1.45, 95% confidence interval (CI)=1.29 to 1.64, p Conclusions: Increased incidence of hypertension, hypercholesterolemia, and excess body weight was observed during the COVID-19 pandemic period.

Background: Health checkup results, even if 12-lead ECG and chest X-ray are included, usually do not reflect risk of smoking and it may lead smokers to continue smoking. Therefore, to show specific risk amount of smoking, 10-year cardiovascular (CV) risks were calculated with and without smoking at the same level of other risk factors and the information was sent to the smokers. Smoking cessation rate was compared between smokers with and without the information. Methods: In subjects who had the annual health checkup offered to adult citizens of Moriguchi city, Osaka, Japan in 2018, the brochure which included the 2 values of 10-year CV risks calculated by the Framingham risk score (2008) based on the results of the health checkup was sent to male smokers aged 40 between 74 with no history of CV disease and the 10-year CV risk between 10% and 40%. Male smokers with the same condition were extracted from subjects who had the annual health checkup in 2017 as the control subjects. Smoking cessation was evaluated at the health checkup next year. Results: The brochure was sent to 499 smokers in 2018 and 344 of those received the health checkup in 2019. The 10-year CV risk of smokers was 1.80±0.05 times higher than that of non-smokers at the same level of other risk factors. As the control subjects, 568 smokers were extracted from 2017 checkup and 407 of those received the health checkup in 2018. Clinical characteristics of the 2018 checkup (n=344) and the 2017 checkup (n=407) groups were similar in terms of age, clinical risk factors, duration of smoking and number of cigarettes smoked per day. Smoking cessation rate of the 2018 checkup group next year was 7.0% while that of the 2017 checkup group was 7.1%. By the logistic regression analysis adjusted for age, duration of smoking and number of cigarettes smoked per day, smoking cessation rate of the 2018 checkup group was not higher than that of the 2017 checkup group (odds ratio=0.97, 95% confidence interval=0.55 to 1.71, p=0.9131). Conclusions: Showing specific amount of risk by smoking was not helpful for smoking cessation. Most smokers seem to be aware of the risk. To promote smoking cessation, interventions such as increased price of cigarette and/or limitation of smoking area may be more practical than emphasizing health hazards of smoking.

Aging is associated with various heart diseases, and this may be attributable, in part, to the prolonged exposure of the heart to cardiovascular risk factors. However, aging is also associated with heart disorders such as diastolic dysfunction that are not necessarily linked to the risk factors for cardiovascular diseases. Recent studies have demonstrated a mechanistic link between Wnt signaling and premature aging or aging-related phenotypes. As a part of the review series on Wnt signaling and the cardiovascular system, we discuss here the possible involvement of Wnt signaling in aging-associated heart diseases or heart disorders.

Rationale : The number of patients with coronary heart disease, including myocardial infarction, is increasing and novel therapeutic strategy is awaited. Tumor suppressor protein p53 accumulates in the myocardium after myocardial infarction, causes apoptosis of cardiomyocytes, and plays an important role in the progression into heart failure. Objectives : We investigated the molecular mechanisms of p53 accumulation in the heart after myocardial infarction and tested whether anti-p53 approach would be effective against myocardial infarction. Methods and Results : Through expression screening, we found that CHIP (carboxyl terminus of Hsp70-interacting protein) is an endogenous p53 antagonist in the heart. CHIP suppressed p53 level by ubiquitinating and inducing proteasomal degradation. CHIP transcription was downregulated after hypoxic stress and restoration of CHIP protein level prevented p53 accumulation after hypoxic stress. CHIP overexpression in vivo prevented p53 accumulation and cardiomyocyte apoptosis after myocardial infarction. Promotion of CHIP function by heat shock protein (Hsp)90 inhibitor, 17-allylamino-17-demethoxy geldanamycin (17-AAG), also prevented p53 accumulation and cardiomyocyte apoptosis both in vitro and in vivo. CHIP-mediated p53 degradation was at least one of the cardioprotective effects of 17-AAG. Conclusions : We found that downregulation of CHIP level by hypoxia was responsible for p53 accumulation in the heart after myocardial infarction. Decreasing the amount of p53 prevented myocardial apoptosis and ameliorated ventricular remodeling after myocardial infarction. We conclude that anti-p53 approach would be effective to treat myocardial infarction.

Background: Physical activity reduces body weight and incidence of diabetes mellitus (DM). We examined associations of commuting mode with prevalence of excess body weight, hypertension and DM. Methods: We studied 16,397 subjects who had the annual health checkup offered to adult citizens of Moriguchi city, Osaka, Japan in 2012. The subjects were asked about their work (Is your work physically active, sedentary or "cannot say"?) and commuting mode (walking or cycling / bus or train / car driving). Odds ratios (OR) of prevalence of excess body weight (body mass index >25.0 kg/m 2 ), hypertension, and DM with 95% confidence intervals (CI) relative to the car driving group were calculated using logistic regression analyses adjusted for clinical variables. Results: There were 5,908 eligible workers. Characteristics of the subjects according to commuting mode are presented in the table. Compared to the car driving group, logistic regression analyses showed that the public transportation group had a significantly lower prevalence of excess body weight (OR=0.56, 95% CI=0.45 to 0.69, p Conclusions: The use of public transportation was associated with lower prevalence of excess body weight, hypertension, and DM.

Backgound: Left atrial (LA) enlargement has been proposed as a barometer of diastolic dysfunction and a predictor of congestive heart failure (CHF) in patients with sinus rhythm. Whether LA volume predicts CHF in patients with atrial fibrillation (AF) is not well known. Methods: To determine the clinical importance of LA volume in the prediction of CHF in patients with AF, AF patients referred for clinically-indicated echocardiogram, without a history of significant mitral valve disease, congenital heart disease, pacemaker, or cardiac surgery, in 2007-2008 were prospectively included and followed forward them up to September 2014. LA volume was measured using the biplane area-length formula. CHF was ascertained using the Framingham criteria. Cox proportional hazards modeling was used to assess the risk factors of CHF development. Results: Of 456 AF patients who met all study criteria (mean 70 ± 10 year-old, 67% men, 62% hypertension, 26% diabetes, LV ejection fraction 68 ± 13%, LA volume 52 ± 24 mL/m 2 ), 46 (10%) developed CHF events during a mean follow-up of 44 ± 31 months. CHF events were significantly increased with advancing age (HR 1.4, 95%CI 1.0-2.0, P2 ; HR 1.2, 95% CI 1.1-1.3, P Conclusions: In our cohort with AF, LA volume predicted CHF developments, independent of LV systolic function and other cardiovascular comorbidities, which appears to be clinically useful information for risk stratification.

In 1996, the late Jeffrey Isner proposed the use of vascular endothelial growth factor (VEGF) gene delivery in patients undergoing percutaneous transluminal angioplasty as a strategy to limit the risk of restenosis.1VEGF promotes endothelial cell function and is a potent stimulator of endothelial cell migration and survival. Because normal endothelium inhibits smooth muscle cell proliferation, it was hypothesized that accelerating the reendothelialization of the balloon-injured site would diminish the severity of restenosis. Indeed, reports in animal models demonstrate that local administration of VEGF-A or VEGF-C leads to accelerated reendothelialization and a reduction in intimal thickening.2–5 However, the utility of VEGF or other proangiogenic factors for the treatment of restenosis is questioned by reports that have documented extensive vascular networks in atherosclerotic plaques6 and balloon-injured coronary arteries.7 Thus, the delivery of proangiogenic agents might exacerbate the growth of vascular lesions, analogous to the concept that angiogenesis contributes to tumor growth. These concerns are supported by studies showing that treatment of apolipoprotein E (ApoE)-deficient mice with an angiogenesis inhibitor reduced intimal neovascularization and plaque growth,8 and administration of VEGF enhanced atherosclerotic plaque progression, which was associated with increased capillary density.9 See pp 2424, 2430, 2436, 2444 This controversy has been rekindled by 3 articles appearing in the present issue of Circulation .10–12 Although many of the previous studies focused on the effects of exogenously administered angiogenic growth factors on vascular lesions, these new studies analyze the role of endogenous angiogenic growth factor signaling in neointima formation after acute vascular injury. Specifically, these studies tested whether VEGF-Traps (Figure), inhibitors of endogenous VEGF signaling, have a positive or negative effect on the process of intimal hyperplasia. On the basis of these new studies, we can conclude that VEGF inhibits restenosis,10 VEGF promotes restenosis,12 …

Background: Although smoking cessation reduces mortality, weight gain is concerned because it may weaken the benefit of quitting. All-cause mortality of quitters according to weight change after smoking cessation was compared to that of smokers. Methods: Among subjects who received annual health checkups from 1997 through 2013 in Moriguchi City, Osaka, Japan, 5,204 subjects were extracted who were smokers at the first time they received the checkup and had 3 consecutive annual checkups. Of those, smokers were defined who reported smoking at all 3 consecutive checkups. Quitters were defined who reported smoking at the first checkup but not smoking at the second and the third checkups of a 3 consecutive checkups. Smokers who reported not smoking and quitters who reported smoking at any checkups after the 3 consecutive checkups used for the definition were excluded. The oldest 3 consecutive checkups were used as clinical and follow-up data of smokers. The 3 consecutive checkups in which a subject met the criteria of quitters were used as clinical and follow-up data of quitters. Weight change was assessed between the first and the second checkups of the 3 consecutive checkups. According to weight change, quitters were divided into 3 groups; no weight gain (n=362), weight gain no more than 2 kg (n=458) and weight gain more than 2 kg (n=485). All-cause mortality of 3 groups was compared to smokers using multivariate proportional hazards regression analysis adjusted for age, sex, hypertension, diabetes and hyperlipidemia. Results: There were 2803 smokers and 1,305 quitters. Mean age was 54±15 years with 65% of men. There were 449 deaths during 9.7±4.7 years (median 9.8 years) follow-up. Mean weight was 59.9±11.0 kg and mean number of checkups the subjects received was 8.0±4.3 times. Compared to smokers, quitters of no weight gain group (relative risk (RR)=0.66, 95% confidence interval (CI)=0.47-0.93, p=0.0164), weight gain no more than 2 kg group (RR=0.51, 95%CI=0.36-0.71, p Conclusions: Quitters had significantly lower mortality than smokers regardless of weight change after smoking cessation.

Abstract —Although smooth muscle cells (SMCs) are critical components of the circulatory system, the regulatory mechanisms of SMC differentiation remain largely unknown. In the present study, we examined the mechanism of SMC differentiation by using Xenopus laevis SM22α (XSM22α) as an SMC-specific marker. XSM22α cDNA contained a 600-bp open reading frame, and the predicted amino acid sequences were highly conserved in evolution. XSM22α transcripts were first detected in heart anlage, head mesenchyme, and the dorsal side of the lateral plate mesoderm at the tail-bud stage, possibly representing the precursors of muscle lineage. At the tadpole stage, XSM22α transcripts were restricted to the vascular and visceral SMCs. XSM22α was strongly induced by basic fibroblast growth factor (FGF) in animal caps. Although expressions of Xenopus cardiac actin were not affected by the expression of a dominant-negative FGF receptor, its injection dramatically suppressed the XSM22α expression. These results suggest that XSM22α is a useful molecular marker for the SMC lineage in Xenopus and that FGF signaling plays an important role in the induction of XSM22α and in the differentiation of SMCs.

Abstract —Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and fibroblasts, we examined signal transduction pathways leading to activation of extracellular signal–regulated kinases (ERKs). Ang II–induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the G βγ subunit–binding domain of the β-adrenergic receptor kinase 1 in cardiac fibroblasts but not in cardiac myocytes. Inhibition of protein kinase C strongly inhibited activation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyrosine kinases but not of protein kinase C abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of C-terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapidly induced phosphorylation of Shc and association of Shc with Grb2. Cotransfection of the dominant-negative mutant of Ras or Raf-1 kinase abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of Csk or the dominant-negative mutant of Ras had no effects on Ang II–induced ERK activation in cardiac myocytes. These findings suggest that Ang II–evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, Ang II activates ERKs through a pathway including the G βγ subunit of G i protein, tyrosine kinases including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf-1 kinase, whereas G q and protein kinase C are important in cardiac myocytes.

Many lines of evidence have suggested that angiotensin II (Ang II) plays an important role in cardiac hypertrophy. Ang II not only increases protein synthesis but also induces the reprogramming of gene expression in cultured cardiac myocytes. In the present study, to elucidate the mechanism by which Ang II regulates gene expression in cardiac myocytes, we examined whether Ang II activates c-Jun NH 2 -terminal kinase (JNK), which is a member of the mitogen-activated protein kinase family and activates the transcription factor, activator protein-1 (AP-1). The activity of JNK increased 5 minutes after the addition of Ang II, peaked at 20 minutes, and gradually decreased thereafter. Examination of the Ang II dose-response relation revealed detectable JNK activation at 10 −9 mol/L and maximal activation at 10 −6 mol/L. Ang II activated JNK through the AT 1 receptor, and the activation was attenuated by the downregulation of protein kinase C or the chelation of intracellular Ca 2+ . Although the addition of either Ca 2+ ionophore or phorbol ester resulted in little or no activation of JNK, simultaneous addition of both Ca 2+ ionophore and phorbol ester markedly activated JNK. Slight expressions of the c- jun gene were observed in unstimulated cardiac myocytes, and Ang II increased expressions of the c- jun gene as well as the c- fos gene. Ang II increased transcription of the endothelin-1 gene through the AP-1 binding site. In conclusion, Ang II may activate JNK in cultured cardiac myocytes through an increase in intracellular Ca 2+ and activation of protein kinase C, and the activated JNK may regulate gene expression by activating AP-1 during Ang II–induced cardiac hypertrophy.

See related article, pages 663–673 Research on myocardial regeneration is an exciting and promising area, which challenges the dogma that the heart is a nonregenerating organ. Recently, several methods of stem cell therapy have been developed. One method is to transplant cells into the infarcted area of the myocardium. Currently, clinical trials of autologous skeletal myoblast transplantation into the failed heart are underway and have been reported to improve the cardiac function.1 However, the mechanism of its efficacy is unknown, and there are some questions about the safety because myoblasts do not transdifferentiate into cardiomyocytes and may induce lethal arrhythmia.1 In this point, embryonic stem (ES) cells that can differentiate into cardiomyocytes are thought to be more promising.2 For patients experiencing extensive myocardial infarction or dilated cardiomyopathy, however, the effectiveness of cell transplantation is questionable. Bone marrow-derived cells have been reported to transdifferentiate into various types of cells in situ. Indeed, bone marrow-derived stem cells were reported to prevent left ventricular remodeling after myocardial infarction and improve cardiac function by their differentiation into cardiomyocytes.3 However, recent accumulating evidence has indicated that very few bone marrow cells, if any, transdifferentiate into cardiomyocytes.4–6 Cytokine therapy using G-CSF strongly prevents ventricular remodeling after myocardial infarction by antiapoptotic and angiogenic effects, but not by recruitment of bone marrow cells.7 Over the past few years, adult hearts have been reported to contain the cardiac stem/progenitor cells such as c-kit+,8 Sca-1+,9,10 isl-1+,11 and side population cells.12 Because these cells have the ability to proliferate and …

BACKGROUND Previous studies have demonstrated that angiotensin II (Ang II) acts as a growth-promoting factor directly on cardiac myocytes and that angiotensin-converting enzyme inhibitor induces regression of hypertrophied hearts both in experimental animals and in humans. These results suggest that the renin-angiotensin system (RAS) is involved in the formation of left ventricular hypertrophy (LVH). To elucidate the role of RAS in the progression of cardiac hypertrophy, we evaluated the effect of an Ang II receptor antagonist on LVH in spontaneously hypertensive rats (SHRs) and investigated the molecular mechanisms by which antagonizing Ang II receptors reduces cell hypertrophy of myocytes using the in vitro model of mechanical stretch. METHODS AND RESULTS In the in vivo study, we treated SHRs with the nonpeptide Ang II receptor antagonist TCV-116 (0.1, 1, or 10 mg/kg per day) or hydralazine (10 mg/kg per day). Blood pressure was measured by the tail-cuff method, and wall thickness of left ventricle was serially monitored using M-mode echocardiography. Rats were killed at the age of 13, 17, 21, or 25 weeks, and left ventricular (LV) weight, transverse diameter of cardiomyocytes, relative amount of V3 myosin heavy chain (MHC), and degree of interstitial collagen accumulation were examined. Untreated SHRs progressively developed severe hypertension, but treatment with TCV-116 or hydralazine inhibited the increase in blood pressure. Treatment with TCV-116 reduced LV weight, LV wall thickness, transverse diameter of myocytes, relative amount of V3 MHC, and interstitial fibrosis, whereas treatment with hydralazine slightly prevented an increase in LV wall thickness but did not exert significant reduction in other parameters. In the in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes and mechanically stretched with or without pretreatment of CV-11974 (an active metabolite of TCV-116), and [3H]phenylalanine incorporation, activity of mitogen-activated protein (MAP) kinase, and c-fos mRNA expression were analyzed. Pretreatment of cultured cardiomyocytes with 10(-7) mol/L CV-11974 inhibited an increase in [3H]phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by stretch of cardiomyocytes. CONCLUSIONS The Ang II receptor antagonist TCV-116 induced regression of cardiac hypertrophy and had cardioprotective effects on hypertrophied myocardium in vivo, and antagonizing Ang II receptors inhibited intracellular signaling of stretch-mediated cardiomyocyte hypertrophy in vitro. These results suggest a crucial role of the cardiac RAS in the development of LVH produced by pressure overload.

Insulin-like growth factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). Although some of the effects of IGFBPs appear to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown. In this study we demonstrate that IGFBP-4 is a novel cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation of P19CL6 embryonal carcinoma cells and embryonic stem (ES) cells in vitro. Conversely, siRNA-mediated knockdown of IGFBP-4 in P19CL6 cells or ES cells attenuated cardiomyocyte differentiation, and morpholino-mediated knockdown of IGFBP-4 in Xenopus embryos resulted in severe cardiac defects and complete absence of the heart in extreme cases. We also demonstrate that the cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signaling. IGFBP-4 physically interacted with a Wnt receptor Frizzled 8 (Frz8) and a Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Moreover, the cardiogenic defects induced by IGFBP-4 knockdown both in vitro and in vivo was rescued by simultaneous inhibition of canonical Wnt signaling. Thus, IGFBP-4 is an inhibitor of the canonical Wnt signaling, and Wnt inhibition by IGFBP-4 is required for cardiogenesis. The present study provides a molecular link between IGF signaling and Wnt signaling, and suggests that IGFBP-4 may be a novel therapeutic target for heart diseases.