Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice.

Myosin-binding protein C (Mybpc3)-targeted knock-in mice (KI) recapitulate typical aspects of human hypertrophic cardiomyopathy. We evaluated whether these functional alterations can be reproduced in engineered heart tissue (EHT) and yield novel mechanistic information on the function of cMyBP-C. EHTs were generated from cardiac cells of neonatal KI, heterozygous (HET) or wild-type controls (WT) and developed without apparent morphological differences. KI had 70% and HET 20% lower total cMyBP-C levels than WT, accompanied by elevated fetal gene expression. Under standard culture conditions and spontaneous beating, KI EHTs showed more frequent burst beating than WT and occasional tetanic contractions (14/96). Under electrical stimulation (6Hz, 37°C) KI EHTs exhibited shorter contraction and relaxation times and a twofold higher sensitivity to external [Ca(2+)]. Accordingly, the sensitivity to verapamil was 4-fold lower and the response to isoprenaline or the Ca(2+) sensitizer EMD 57033 2- to 4-fold smaller. The loss of EMD effect was verified in 6-week-old KI mice in vivo. HET EHTs were apparently normal under basal conditions, but showed similarly altered contractile responses to [Ca(2+)], verapamil, isoprenaline and EMD. In contrast, drug-induced changes in intracellular Ca(2+) transients (Fura-2) were essentially normal. In conclusion, the present findings in auxotonically contracting EHTs support the idea that cMyBP-C's normal role is to suppress force generation at low intracellular Ca(2+) and stabilize the power-stroke step of the cross bridge cycle. Pharmacological testing in EHT unmasked a disease phenotype in HET. The altered drug response may be clinically relevant.

Autophagy-mediated degradation is necessary for regression of cardiac hypertrophy during ventricular unloading.

Cardiac hypertrophy occurs in response to a variety of stresses as a compensatory mechanism to maintain cardiac output and normalize wall stress. Prevention or regression of cardiac hypertrophy can be a major therapeutic target. Although regression of cardiac hypertrophy occurs after control of etiological factors, the molecular mechanisms remain to be clarified. In the present study, we investigated the role of autophagy in regression of cardiac hypertrophy. Wild-type mice showed cardiac hypertrophy after continuous infusion of angiotensin II for 14 days using osmotic minipumps, and regression of cardiac hypertrophy was observed 7 days after removal of the minipumps. Autophagy was induced during regression of cardiac hypertrophy, as evidenced by an increase in microtubule-associated protein 1 light chain 3 (LC3)-II protein level. Then, we subjected cardiac-specific Atg5-deficient (CKO) and control mice (CTL) to angiotensin II infusion for 14 days. CKO and CTL developed cardiac hypertrophy to a similar degree without contractile dysfunction. Seven days after removal of the minipumps, CKO showed significantly less regression of cardiac hypertrophy compared with CTL. Regression of pressure overload-induced cardiac hypertrophy after unloading was also attenuated in CKO. These results suggest that autophagy is necessary for regression of cardiac hypertrophy during unloading of neurohumoral and hemodynamic stress.

Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats.

Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure or mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity.

Nicotinamide Mononucleotide Alleviates Cardiomyopathy Phenotypes Caused by Short-Chain Enoyl-Coa Hydratase 1 Deficiency.

Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency plays a role in cardiomyopathy. Whether ECHS1 deficiency causes or is only associated with cardiomyopathy remains unclear. By using Echs1 heterogeneous knockout (Echs1 +/-) mice, we found that ECHS1 deficiency caused cardiac dysfunction, as evidenced by diffuse myocardial fibrosis and upregulated fibrosis-related genes. Mechanistically, ECHS1 interacts with the p300 nuclear localization sequence, preventing its nuclear translocation in fibroblasts. ECHS1 deficiency promotes p300 nuclear translocation, leading to increased H3K9 acetylation, a known risk factor for cardiomyopathy. Nicotinamide mononucleotide-mediated acetylation targeting suppressed ECHS1 deficiency-induced cardiomyopathy phenotypes in Echs1 +/- mice. Thus, enhancing p300-mediated H3K9ac is a potential interventional approach for preventing ECHS1 deficiency-induced cardiomyopathy.

MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B.

Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and ß-myosin heavy chain (ß-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3' untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.

Relatively Benign yet a Reversible Cause of Dilated Cardiomyopathy.

Arrhythmia-induced cardiomyopathy secondary to frequent ventricular premature contractions is a well-studied phenomenon; however, there is a paucity of data showing a similar association with frequent atrial premature contractions (APCs). Early recognition and successful APC ablation can reverse left ventricular dysfunction in these patients. (Level of Difficulty: Beginner.).

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression.

As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin (Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Dox-induced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor (30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.

Overweight during lactation and its implications for biometric, nutritional and cardiovascular parameters of young and adult male and female rats.

Litter size reduction can induce early overnourishment, being an attractive experimental model to study short- and long-term consequences of childhood obesity. Epidemiological data indicate sex differences regarding cardiometabolic disorders and hypertrophic cardiomyopathy. The present study aimed to describe biometric, nutritional and cardiovascular changes related to neonatal overweight promoted by litter size reduction in young and adult Wistar rats of both sexes. Litter adjustment to eight or four pups/mother (1:1 male-to-female ratio) gave, respectively, control and overweight groups. Body mass, food intake, haemodynamic and echocardiographic parameters and cardiorespiratory capacity were evaluated at postnatal days 30 and 150. Diminished litters were correlated with higher body mass and weight gain (12 %) during lactation, validating the experimental model of neonatal overweight. Soon after weaning male (16 %) and female (25 %) offspring of these litters presented a lower food intake than their respective control, without differences in body mass. Adult males from reduced litters presented higher abdominal circumference (7 %), systolic blood pressure (10 %), interventricular septum thickness (15 %) and relative wall thickness (15 %) compared with their respective control. Rats' performance on the maximal effort ergometer test was not affected by neonatal overweight. Data suggest the occurrence of catch-down growth and hypophagia in male and female rats submitted to neonatal overweight. However, only male rats presented haemodynamic and cardiac structural changes. These findings are crucial to personalised/gender medicine.

Cardiac Adverse Events in EGFR-Mutated Non-Small Cell Lung Cancer Treated With Osimertinib.

OBJECTIVES: The purpose of this study was to assess osimertinib-associated cardiac adverse events (AEs) in a real-world setting, using a retrospective single-center cohort study in Japan. BACKGROUND: Cases of osimertinib-associated cardiac AEs have been reported but remain poorly understood. METHODS: A total of 123 cases of advanced non-small cell lung cancer (NSCLC) with confirmed EGFR mutations who received osimertinib monotherapy from 2014 to 2019 at the Osaka International Cancer Institute (Osaka, Japan) were evaluated. Cardiac AEs were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Changes in left ventricular ejection fraction (LVEF) and rates of cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a ≥10 % absolute decline in LVEF from baseline to a value of <53%, were further assessed in 36 patients in whom serial measurements of LVEF were obtained before and during osimertinib treatment. RESULTS: Severe cardiac AEs (CTCAE grade 3 or higher) occurred in 6 patients (4.9%) after osimertinib administration. These AEs included acute myocardial infarction (n = 1), heart failure with reduced LVEF (n = 3), and valvular heart disease (n = 2). Five of the 6 patients had a history of cardiovascular risk factors or disease. Myocardial biopsies in 2 of the patients showed cardiomyocyte hypertrophy and lipofuscin deposition. In 36 patients assessed with serial LVEF, LVEF declined from 69.4 ± 4.2% to 63.4 ± 10.5% with osimertinib therapy (p < 0.001). CTRCD occurred in 4 patients with a nadir LVEF of 40.3 ± 9.1% with osimertinib. CONCLUSIONS: In this retrospective cohort analysis, the incidence of cardiac AEs in patients treated with osimertinib was 4.9%. Additional prospective data collected from patients with NSCLC treated with osimertinib will be important in understanding the incidence, pathophysiology, and management of cardiac AEs with osimertinib.

Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation.

The clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague-Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.

Correlations of GDF-15 with sST2, MMPs, and worsening functional capacity in idiopathic dilated cardiomyopathy: Can we gain new insights into the pathophysiology?

Growth and differentiation factor-15 (GDF-15) has been implicated in fibrosis, inflammation, and ventricular remodeling. The role of GDF-15 in the regulation of cardiac remodeling in idiopathic dilated cardiomyopathy (DCM) remains poorly defined. This study attempts to analyze the molecular interactions between GDF-15 and markers of fibrosis as well as its positive correlations with worsening functional capacity. The study population consisted of 24 DCM patients and 8 control subjects. All DCM patients had normal coronary angiographic studies. Plasma levels of GDF-15, matrix metalloproteinase-2 (MMP2), MMP3, MMP9, tissue inhibitor of MMP 1 (TIMP1), and soluble suppression of tumorigenicity-2 protein (sST2) were determined by enzyme-linked immunosorbent assays. Brain Natriuretic Peptide (BNP) was measured as per core laboratory protocol assay at Scott and White Memorial Hospital core laboratory. Correlation analysis was performed between GDF-15 and each of the MMPs-MMP2, MMP3, MMP9, and TIMP as well as New York Heart Association (NYHA) class and echocardiographic parameters (left ventricular ejection fraction (LVEF) and left ventricular internal dimension in diastole (LVIDd)). LVEF and LVIDd were obtained by two-dimensional echocardiography. The protocol was approved by Scott and White Memorial Hospital Institutional Review Board (S&W IRB). Correlation analysis of control versus all DCM patients showed a strong correlation of GDF-15 with TIMP1 (r = 0.83, p < 0.0001) and weaker correlation with MMP3 (r = 0.41, p = 0.011) and MMP2 (r = 0.47, p = 0.003). MMP9 showed poor correlation with GDF-15 (r = 0.3036, p = 0.046). GDF-15 correlated negatively with MMP2/TIMP1 ratio (r = -0.47, p = 0.006). sST2 correlated strongly with GDF-15 (r = 0.7, p < 0.0001). GDF-15 correlated negatively with LVEF (r = -0.49, p = 0.004) and positively with LVIDd (r = 0.58, p = 0.0006). GDF-15 showed significant positive correlation with NYHA functional class (r = 0.71, p < 0.00001) and BNP (r = 0.86, p < 0.00001). Significant associations of GDF-15 with MMPs, sST2, LVIDd, LVEF, and NYHA class reported here for the first time in nonischemic dilated hearts may open up new avenues of investigations to better understand molecular mechanisms controlling cardiac remodeling. This study is limited by its small size and needs validation in larger populations.

Regional annular geometry in patients with mitral regurgitation: implications for annuloplasty ring selection.

BACKGROUND: The saddle shape of the normal mitral annulus has been quantitatively described by several groups. There is strong evidence that this shape is important to valve function. A more complete understanding of regional annular geometry in diseased valves may provide a more educated approach to annuloplasty ring selection and design. We hypothesized that mitral annular shape is markedly distorted in patients with diseased valves. METHODS: Real-time 3-dimensional echocardiography was performed in 20 patients with normal mitral valves, 10 with ischemic mitral regurgitation, and 20 with myxomatous mitral regurgitation (MMR). Thirty-six annular points were defined to generate a 3-dimensional model of the annulus. Regional annular parameters were measured from these renderings. Left ventricular inner diameter was obtained from 2-dimensional echocardiographic images. RESULTS: Annular geometry was significantly different among the three groups. The annuli were larger in the MMR and in the ischemic mitral regurgitation groups. The annular enlargement was greater and more pervasive in the MMR group. Both diseases were associated with annular flattening, although though the regional distribution of that flattening was different between groups. Left ventricular inner diameter was increased in both groups. However, relative to the Left ventricular inner diameter, the annulus was disproportionately dilated in the MMR group. CONCLUSIONS: Patients with MMR and ischemic mitral regurgitation have enlarged and flattened annuli. In the case of MMR, annular distortions may be the driving factor leading to valve incompetence. These data suggest that the goal of annuloplasty should be the restoration of normal annular saddle shape and that the use of flexible, partial, and flat rings may be ill advised.

Preoperative left ventricular internal dimension in end-diastole as earlier identification of early patent ductus arteriosus operation and postoperative intensive care in very low birth weight infants.

Patent ductus arteriosus (PDA) is common in premature infants. In very low birth weight infants (VLBWI), PDA requires surgical therapy in many cases. It is unclear to know at-risk infants showing cardio-dysfunction after PDA surgery. The purpose of this study was to identify at-risk infants showing cardio-dysfunction after surgery for patent ductus arteriosus (PDA). We examined the relationship between left ventricular (LV) performance before and after PDA ligation in a retrospective observational cohort study. We studied 64 preterm neonates with symptomatic PDA before and after surgical ligation. Echocardiographic examinations were performed pre- and postoperatively. M-mode measurements included left ventricular internal dimension in end-diastole (LVIDd) and LV fractional shortening (FS). All cases showed decreased LVFS after PDA closure. Most cases (49/64, 77%) showed postoperative FS decreased to below normal (<28%). Preoperative relative LVIDd was significantly larger in abnormal FS infants (137 ± 18%) than in normal FS infants (118 ± 11%; p<0.01). A cut-off value of preoperative relative LVIDd (absolute LVIDd/normal value) for predicting postoperative cardio-dysfunction was 127.4% (sensitivity, 0.735; specificity, 0.933; area under curve, 0.817). Determination of preoperative LVIDd might facilitate earlier identification of infants needing early PDA surgery and postoperative intensive care.

4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation.

OBJECTIVES: This study sought to evaluate 4-year outcomes of percutaneous repair versus surgery for mitral regurgitation. BACKGROUND: Transcatheter therapies are being developed to treat valvular heart disease. In the EVEREST (Endovascular Valve Edge-to-Edge Repair Study) II trial, treatment of mitral valve regurgitation (MR) with a novel percutaneous device was compared with surgery and showed superior safety, but less reduction in MR at 1 year overall. We report the 4-year outcomes from the EVEREST II trial. METHODS: Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the MitraClip (Abbott, Menlo Park, California) device or conventional mitral valve surgery in a 2:1 ratio (184:95). Patients prospectively consented to 5 years of follow-up. RESULTS: At 4 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the intention-to-treat population was 39.8% versus 53.4% in the percutaneous repair group and surgical groups, respectively (p = 0.070). Rates of death were 17.4% versus 17.8% (p = 0.914), and 3+ or 4+ MR was present in 21.7% versus 24.7% (p = 0.745) at 4 years of follow-up, respectively. Surgery for mitral valve dysfunction, however, occurred in 20.4% versus 2.2% (p < 0.001) at 1 year and 24.8% versus 5.5% (p < 0.001) at 4 years. CONCLUSIONS: Patients treated with percutaneous repair of the mitral valve more commonly required surgery to treat residual MR; however, after the first year of follow-up, there were few surgeries required after either percutaneous or surgical treatment and no difference in the prevalence of moderate-severe and severe MR or mortality at 4 years. (Endovascular Valve Edge-to-Edge Repair Study [EVEREST II]; NCT00209274).

Family history of cardiovascular disease and offspring echocardiographic left ventricular structure and function: the Asklepios Study.

BACKGROUND: Moderate to small heritability has been observed for left ventricular (LV) structure and function in genetic epidemiology and genomewide association studies. The aim of this study was to explore whether this would be mirrored in an independent association between LV structure and function and a family history (FH) of cardiovascular disease (CVD) in a large population of middle-aged adults. METHODS: Subjects enrolled in the Asklepios Study, a population-based sample of 2,524 male and female volunteers, aged 35 to 55 years, free of overt CVD at baseline, were studied. LV structure and function were assessed using transthoracic echocardiography (by a single sonographer). FH data spanning 4 generations were acquired using a questionnaire. RESULTS: In unadjusted analyses, only small effects of FH of CVD on LV structure (relative wall thickness, P = .042; interventricular septal thickness, P = .002; LV mass, P = .038; allometrically adjusted LV mass, P = .014) and diastolic function (mitral annular e', P = .02) were observed. After adjusting for the more adverse risk factor profile associated with FH, no significant associations persisted. These results did not appreciably change using a more extended definition of FH of CVD or FH of hypertension. CONCLUSIONS: A positive FH for CVD was associated with differences in offspring cardiac structure and function, largely mediated by (but not independent from) a more adverse risk profile in those subjects with positive FH.

Enhanced characterization of ventricular performance after coarctation repair in neonates and young children.

BACKGROUND: Within the group of patients undergoing coarctectomy today, two subgroups can be identified: neonates with a critical coarctation and nonneonatal patients. We hypothesize that patients who have to undergo repair in the neonatal period will have more persistent impairment of ventricular performance postoperatively. Accordingly, we aimed to characterize biventricular performance after coarctectomy in neonatal and nonneonatal patients. METHODS: Children (aged 0 to 17 years) undergoing a coarctectomy were prospectively included and classified as neonatal (<1 month old) or nonneonatal patients. Age-matched controls were included for each measurement occasion. To evaluate left (LV) and right ventricular (RV) performance, fractional shortening, peak systolic (S') and early diastolic (E') tissue Doppler imaging velocities, and E/E' were assessed preoperatively, at discharge, and 1 year postoperatively (11.4 ± 8.3 months). RESULTS: In neonatal (n = 18) and nonneonatal (n = 19) patients LV performance significantly improved within the first postoperative year. Yet 1 year postoperatively, LV S' was still lower in neonatal patients vs controls (4.8 ± 1.1 vs 6.1 ± 1.6 cm/s; p = 0.036), whereas comparable results were observed in nonneonatal patients and controls. One year postoperatively, LV diastolic performance was impaired in neonatal (LV E' 8.7 ± 3.1 vs 13.2 ± 3.9 cm/s, p = 0.005) and nonneonatal patients (LV E' 12.1 ± 3.5 vs 15.1 ± 2.4 cm/s, p = 0.008) vs controls. In RV performance variables, no differences were observed 1 year postoperatively between neonatal and nonneonatal patients and controls. CONCLUSIONS: In both subgroups, LV diastolic performance does not recover to normal values within the first postoperative year. However, LV systolic performance remains more persistently impaired in patients who have to undergo repair in the neonatal period vs nonneonatal repair.

Thyroid hormone improves the mechanical performance of the post-infarcted diabetic myocardium: a response associated with up-regulation of Akt/mTOR and AMPK activation.

OBJECTIVE: Thyroid hormone (TH) is shown to be protective against cardiac and pancreatic injury. Thus, this study explored the potential effects of TH treatment on the functional status of the postinfarcted diabetic myocardium. Diabetic patients have worse prognosis after acute myocardial infarction (AMI). MATERIALS/METHODS: AMI was induced by left coronary ligation in rats previously treated with 35 mg/kg streptozotocin (STZ), (DM-AMI). TH treatment was initiated at 2 weeks after AMI and continued for 6 weeks (DM-AMI+TH), while sham-operated animals served as control (DM-SHAM). RESULTS: TH treatment increased cardiac mass, improved wall stress and favorably changed cardiac geometry. TH significantly increased echocardiographic left ventricular ejection fraction (LVEF%): [54.2 (6.5) for DM-AMI+TH vs 37 (2.0) for DM-AMI, p<0.05]. TH treatment resulted in significantly increased insulin and decreased glucose levels in serum. The ratios of phosphorylated (p)-Akt/total Akt and p-mTOR/total mTOR were increased 2.0 fold and 2.7 fold in DM-AMI+TH vs DM-AMI respectively, p<0.05. Furthermore, the ratio of p-AMPK/total AMPK was found to be increased 1.6 fold in DM-AMI+TH vs DM-AMI, p<0.05. CONCLUSION: TH treatment improved the mechanical performance of the post-infarcted myocardium in rats with STZ-induced diabetes, an effect which was associated with Akt/mTOR and AMPK activation.

Cross-Sectional and Longitudinal Observation of Cardiac Adaptation in Student Athletes / 体力科学

The purpose of this study was to ascertain whether exercise training cardiac adaptation exists in student rugby athletes, to define an adaptive pattern and to observe the student rugby athletics cardiac adaptive process. Subjects consisted of 42 male senior high school student rugby athletes, who participated in sports in junior high school, and a control group of sedentary students from the same senior high school who were matched for age. Student athletes were measured once a year over a three-year period. Left ventricular internal dimension at the end-diastole (LVIDd) and left ventricular posterior wall thickness at the end-diastole (PWT) were both measured by echocardiography. Because all subjects were growing adolescents, allometric scaling data (which is LVIDd/BSA<SUP>0.5</SUP> and PWT/BSA<SUP>0.5</SUP>) was used for comparison, to preclude the effect of differences in body size on LVIDd and PWT. Cross-sectional comparisons of athletic students with controls were conducted for each of the three senior high school grades, respectively. The data of student athletes during the three-year study was used for longitudinal comparisons. The results of cross-sectional comparisons showed that LVIDd/BSA<SUP>0, 5</SUP> in a student athlete group consisting of the three grades combined was greater than the corresponding control group (P<0.05, P<0.01, respectively) . PWT/BSA<SUP>0.5</SUP> in the athletic group was greater than the control group for the third grade level (P<0.05) . The results of the longitudinal comparison revealed that no significant differences were present in LVIDd/BSA<SUP>0.5</SUP> during the three-year investigation (P>0.05, respectively) . PWT/BSA<SUP>0.5</SUP> at the second and third grade level were obviously greater than at the first grade level (P<0.05, respectively) ; however, no dif. ference between the second and third grade levels existed. The results of this present study suggest that regular rugby exercise training during senior high school obviously induced left ventricular posterior wall thickening in the athletic students. An enlarged left ventricular cavity was observed at the first grade level of senior high school and did not significantly change during three years of senior high school.