Aspirin and Celecoxib Regulate Notch1/Hes1 Pathway to Prevent Pressure Overload-Induced Myocardial Hypertrophy.

This study aimed to investigate the molecular mechanisms underlying the protective effects of cyclooxygenase (cox) inhibitors against myocardial hypertrophy.Rat H9c2 cardiomyocytes were induced by mechanical stretching. SD rats underwent transverse aortic constriction to induce pressure overload myocardial hypertrophy. Rats were subjected to echocardiography and tail arterial pressure in 12W. qPCR and western blot were used to detect the expression of Notch-related signaling. The inflammatory factors were tested by ELISA in serum, heart tissue, and cell culture supernatant.Compared with control, levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-1ß were increased and anti-inflammatory cytokine IL-10 was reduced in myocardial tissues and serum of rat models. Levels of Notch1 and Hes1 were reduced in myocardial tissues. However, cox inhibitor treatment (aspirin and celecoxib), the improvement of exacerbated myocardial hypertrophy, fibrosis, dysfunction, and inflammation was parallel to the activation of Notch1/Hes1 pathway. Moreover, in vitro experiments showed that, in cardiomyocyte H9c2 cells, application of ~20% mechanical stretching activated inflammatory mediators (IL-6, TNF-α, and IL-1ß) and hypertrophic markers (ANP and BNP). Moreover, expression levels of Notch1 and Hes1 were decreased. These changes were effectively alleviated by aspirin and celecoxib.Cox inhibitors may protect heart from hypertrophy and inflammation possibly via the Notch1/Hes1 signaling pathway.

Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart.

Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.

Semaglutide ameliorates pressure overload-induced cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome.

Pathological cardiac hypertrophy is an important cause of heart failure(HF). Recent studies reveal that glucagon-like peptide-1 receptor (GLP1R) agonists can improve mortality and left ventricular ejection fraction in the patients with type 2 diabetes and HF. The present study aims to investigate whether semaglutide, a long-acting GLP1R agonist, can ameliorate cardiac hypertrophy induced by pressure overload, and explore the potential mechanism. The rats were performed transverse aortic constriction (TAC) to mimic pressure overload model. The rats were divided into four groups including Sham, TAC, TAC + semaglutide, and TAC + semaglutide + HCQ (hydroxychloroquine, an inhibitor of mitophagy). The rats in each experimental group received their respective interventions for 4 weeks. The parameters of left ventricular hypertrophy(LVH) were measured by echocardiography, Hematoxylin-eosin (HE) staining, western-blot and immunohistochemistry (IHC), respectively. The changes of mitophagy were reflected by detecting cytochrome c oxidase subunit II (COXII), LC3II/LC3I, mitochondria, and autophagosomes. Meanwhile, NLRP3, Caspase-1, and interleukin-18 were detected to evaluate the activation of NLRP3 inflammasome in each group. The results suggest that LVH, impaired mitophagy, and activation of NLRP3 inflammasome were present in TAC rats. Semaglutide significantly reduced LVH, improve mitophagy, and down-regulated NLRP3 inflammatory signal pathway in TAC rats. However, the reversed effect of semaglutide on cardiac hypertrophy was abolished by HCQ, which restored the activation of NLRP3 inflammasome suppressed by improved mitophagy. In conclusion, semaglutide ameliorates the cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Semaglutide may be a novel potential option for intervention of cardiac hypertrophy induced by pressure overload.

PM2.5-induced iron homeostasis imbalance triggers cardiac hypertrophy through ferroptosis in a selective autophagy crosstalk manner.

Exposure to PM2.5 is correlated with cardiac remodeling, of which cardiac hypertrophy is one of the main clinical manifestations. Ferroptosis plays an important role in cardiac hypertrophy. However, the potential mechanism of PM2.5-induced cardiac hypertrophy through ferroptosis remains unclear. This study aimed to explore the molecular mechanism of cardiac hypertrophy caused by PM2.5 and the intervention role of MitoQ involved in this process. The results showed that PM2.5 could induce cardiac hypertrophy and dysfunction in mice. Meanwhile, the characteristics of ferroptosis were observed, such as iron homeostasis imbalance, lipid peroxidation, mitochondrial damage and abnormal expression of key molecules. MitoQ treatment could effectively mitigate these alternations. After treating human cardiomyocyte AC16 with PM2.5, ferroptosis activator (Erastin) and inhibitor (Fer-1), it was found that PM2.5 could promote ferritinophagy and lead to lipid peroxidation, mitochondrial dysfunction as well as the accumulation of intracellular and mitochondrial labile iron. Subsequently, mitophagy was activated and provided an additional source of labile iron, enhancing the sensitivity of AC16 cells to ferroptosis. Furthermore, Fer-1 alleviated PM2.5-induced cytotoxicity and iron overload in the cytoplasm and mitochondria of AC16 cells. It was worth noting that during the process of PM2.5 caused ferroptosis, abnormal iron metabolism mediated the activation of ferritinophagy and mitophagy in a temporal order. In addition, NCOA4 knockdown reversed the iron homeostasis imbalance and lipid peroxidation caused by PM2.5, thereby alleviating ferroptosis. In summary, our study found that iron homeostasis imbalance-mediated the crosstalk of ferritinophagy and mitophagy played an important role in PM2.5-induced ferroptosis and cardiac hypertrophy.

Association of cardiovascular risk factors and myocardial hypertrophy in women with preeclampsia history.

AIMS: A historic of preeclampsia (PE) has been associated with cardiovascular disease (CVD) in women. There are substantial evidences that cardiovascular changes resulting from PE can persist even after pregnancy end. Therefore, the aims was to evaluate the prevalence of myocardial hypertrophy in young women 12 months after PE event as well as try to identify risk factors for these changes. MATERIALS AND METHODS: Single-center observational prospective cross-sectional study that included 118 consecutive patients after 12 months of PE. Clinical and laboratory evaluations, echocardiogram were performed. Myocardial hypertrophy (LVH) was defined as an index myocardial mass ≥ 45 g/m2.7, for women. Classical risk factors for CVD were considered. Analysis included linear or logistic regression and Spearman's correlation coefficient. Significance level of 5 %. KEY FINDINGS: Systemic arterial hypertension (SAH) was identified in 52 patients (44 %), overweight/obesity (OOB) in 82 (69 %), dyslipidemia in 68 (57 %) and metabolic syndrome in 47 patients (40 %). LVH was present in 35 cases (29 %) and associated with OOB (OR = 4.51; CI95%:1.18-17.17, p < 0.001), in a model corrected for age and SAH diagnosis. When only the metabolic syndrome components were analyzed, in the multiple logistic regression model, the abdominal circumference was the only clinical variable associated with LVH (OR = 17.65; CI95%:3.70-84.17; p < 0.001). SIGNIFICANCE: It was observed a high prevalence of ventricular hypertrophy in young women with a history of pre-eclampsia. This condition was associated with the presence of obesity.

The Role and Mechanism of STIM1/Orai1-Regulated Ca2+ Influx in Myocardial Hypertrophy in Type 2 Diabetes Mellitus.

OBJECTIVE: Diabetic cardiomyopathy (DCM) is the most common cardiovascular complication of type 2 diabetes mellitus (T2DM). Patients affected with DCM face a notably higher risk of progressing to congestive heart failure compared to other populations. Myocardial hypertrophy, a clearly confirmed pathological change in DCM, plays an important role in the development of DCM, with abnormal Ca2+ homeostasis serving as the key signal to induce myocardial hypertrophy. Therefore, investigating the mechanism of Ca2+ transport is of great significance for the prevention and treatment of myocardial hypertrophy in T2DM. METHODS: The rats included in the experiment were divided into wild type (WT) group and T2DM group. The T2DM rat model was established by feeding the rats with high-fat and high-sugar diets for three months combined with low dose of streptozotocin (100mg/kg). Afterwards, primary rat cardiomyocytes were isolated and cultured, and cardiomyocyte hypertrophy was induced through high-glucose treatment. Subsequently, mechanistic investigations were carried out through transfection with si-STIM1 and oe-STIM1. Western blot (WB) was used to detect the expression of the STIM1, Orai1 and p-CaMKII. qRT-PCR was used to detect mRNA levels of myocardial hypertrophy marker proteins. Cell surface area was detected using TRITC-Phalloidin staining, and intracellular Ca2+ concentration in cardiomyocytes was measured using Fluo-4 fluorescence staining. RESULTS: Through animal experiments, an upregulation of Orai1 and STIM1 was revealed in the rat model of myocardial hypertrophy induced by T2DM. Meanwhile, through cell experiments, it was found that in high glucose (HG)-induced hypertrophic cardiomyocytes, the expression of STIM1, Orai1, and p-CaMKII was upregulated, along with increased levels of store-operated Ca2+ entry (SOCE) and abnormal Ca2+ homeostasis. However, when STIM1 was downregulated in HG-induced cardiomyocytes, SOCE levels decreased and p-CaMKII was downregulated, resulting in an improvement in myocardial hypertrophy. To further elucidate the mechanism of action involving SOCE and CaMKII in T2DM-induced myocardial hypertrophy, high-glucose cardiomyocytes were respectively treated with BTP2 (SOCE blocker) and KN-93 (CaMKII inhibitor), and the results showed that STIM1 can mediate SOCE, thereby affecting the phosphorylation level of CaMKII and improving cardiomyocyte hypertrophy. CONCLUSION: STIM1/Orai1-mediated SOCE regulates p-CaMKII levels, thereby inducing myocardial hypertrophy in T2DM.

Cardiac recovery from pressure overload is not altered by thyroid hormone status in old mice.

Introduction: Thyroid hormones (THs) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases is still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Methods: Mice at the age of 12 months underwent TAC and received T4 or anti-thyroid medication in drinking water over the course of 4 weeks after induction of left ventricular pressure overload. Results: T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis, and interstitial fibrosis), and mortality. This is surprising because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. Comparing the gene expression of deiodinases (Dio) 2 and 3 and TH receptor alpha (TRα) 1 and the dominant-negative acting isoform TRα2 between young and aged mice revealed that aged mice exhibited a higher expression of TRα2 and Dio3, while expression of Dio2 was reduced compared with young mice. These changes in Dio2 and 3 expressions might lead to reduced TH availability in the hearts of 12-month-old mice accompanied by reduced TRα action due to higher TRα2. Discussion: In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure-induced cardiac damage. This observation seems to be the result of an altered expression of deiodinases and TRα isoforms, thus suggesting that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.

Stretch-induced compliance mechanism in pregnancy-induced cardiac hypertrophy and the impact of cardiovascular risk factors.

Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.

Fructose aggravates copper-deficiency-induced cardiac remodeling by inhibiting SERCA2a.

OBJECTIVES: Accumulating evidence demonstrates that copper deficiency (CuD) is a risk factor for cardiovascular diseases, besides, fructose has been strongly linked to the development of cardiovascular diseases. However, how CuD or fructose causes cardiovascular diseases is not clearly delineated. The present study aims to investigate the mechanism of CuD or fructose on cardiac remodeling. METHODS: We established a model of CuD- or fructose-induced cardiac hypertrophy in 3-week-old male Sprague-Dawley (SD) rats by CuD diet supplemented with or without 30% fructose for 4 weeks. In vitro study was performed by treating cardiomyocytes with tetrathiomolydbate (TM) and fructose. Echocardiography, histology analysis, immunofluorescence, western blotting, and qPCR were performed. KEY FINDINGS: Our findings revealed that CuD caused noticeable cardiac hypertrophy either in the presence or absence of fructose supplement. Fructose exacerbated CuD-induced cardiac remodeling and intramyocardial lipid accumulation. Furthermore, we presented that the inhibition of autophagic flux caused by Ca2+ disturbance is the key mechanism by which CuD- or fructose-induced cardiac remodeling. The reduced expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in cardiomyocytes accounts for the elevated cytoplasmic Ca2+ concentration. CONCLUSIONS: Collectively, our study suggested that fructose aggravated CuD-induced cardiac remodeling through the blockade of autophagic flux via SERCA2a decreasing-induced Ca2+ imbalance.

Idiopathic enlargement of the right atrium masking left atrial aneurysm in a neonate.

An idiopathic enlargement of the right atrium is an extremely rare cardiac malformation. There are no established guidelines for the management of this disease, especially concerning medical versus surgical therapeutic approach and the timing for an operation. We report in this case about a neonate that first was treated conservatively until the age of 5 month and finally got an operative resection of the aneurysm. After surgery, unexpected complications occurred. A second aneurysm in the left atrium was demasked. Furthermore, a progressive dilatation of both atrial chambers after resection required regular follow-up and ongoing evaluation of treatment.

Extubation failure after cardiac surgery in children with Down syndrome.

Extubation failure (EF) after cardiac surgery is associated with poorer outcomes. Approximately 50% of children with Down syndrome (DS) have congenital heart disease. Our primary aim was to describe the frequency of EF and identify risk factors for its occurrence in a population of patients with DS after cardiac surgery. Secondary aims were to describe complications, length of hospital stay, and mortality rates. This report was a retrospective case-control study and was carried out in a national reference congenital heart disease repair center of Chile. This study includes all infants 0-12 months old with DS who were admitted to pediatric intensive care unit after cardiac surgery between January 2010 and November 2020. Patients with EF (cases) were matched 1:1 with children who did not fail their extubation (controls) using the following criteria: age at surgery, sex, and type of congenital heart disease. Overall, 27/226 (11.3%) failed their first extubation. In the first analysis, before matching of cases and controls was made, we found association between EF and younger age (3.8 months vs 5 months; p = 0.003) and presence of coarctation of the aorta (p = 0.005). In the case-control univariate analysis, we found association between an increased cardiothoracic ratio (CTR) (p = 0.03; OR 5 (95% CI 1.6-16.7) for a CTR > 0.59) and marked hypotonia (27% vs 0%; p = 0.01) with the risk of EF. No differences were found in ventilatory management. CONCLUSIONS: In pediatric patients with DS, EF after cardiac surgery is associated with younger age, presence of aortic coarctation, higher CTR reflecting the degree of cardiomegaly and hypotonia. Recognition of these factors may be helpful when planning extubation for these patients. WHAT IS KNOWN: • Extubation failure after cardiac surgery is associated with higher morbidity and mortality rates. Some studies report higher rates of extubation failure in patients with Down syndrome. WHAT IS NEW: • In children with Down syndrome, extubation failure after cardiac surgery is associated with younger age, presence of aortic coarctation, higher CTR reflecting cardiomegaly and severe hypotonia.

O-GlcNAcylation-induced GSK-3ß activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice.

O-GlcNAc transferase (OGT) modulates many functions of proteins via O-GlcNAcylation that adds O-linked ß-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins. However, the role of O-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of O-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and Ogt transgenic (Ogt-Tg) mice. Four weeks after TAC (TAC4W), the heart function of Ogt-Tg mice was significantly lower than that of WT mice (reduced fractional shortening and increased ANP levels). The myocardium of left ventricle (LV) in Ogt-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, O-GlcNAcylation of GSK-3ß at Ser9 was increased and phosphorylation of GSK-3ß at Ser9 was reduced in the heart tissues of Ogt-Tg mice, resulting in its activation and subsequent inactivation of nuclear factor of activated T cell (NFAT) activity. Finally, the thinned LV wall and reduced cardiac function induced by TAC4W in Ogt-Tg mice was reversed by the treatment of a GSK-3ß inhibitor, TDZD-8. These results imply that augmented O-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy via O-GlcNAcylation of GSK-3ß, which deprives the phosphorylation site of GSK-3ß to constantly inactivate NFAT activity to prevent cardiac hypertrophy. Our findings may provide a new therapeutic strategy for cardiac hypertrophy and subsequent heart failure.

Protective effects of calorie restriction and 17-ß estradiol on cardiac hypertrophy in ovariectomized obese rats.

Obesity and menopause lead to cardiovascular diseases. Calorie restriction (CR) can modulate estrogen deficiency and obesity-related cardiovascular diseases. The protective effects of CR and estradiol on cardiac hypertrophy in ovariectomized obese rats were explored in this study. The adult female Wistar rats were divided into sham and ovariectomized (OVX) groups that received a high-fat diet (60% HFD) or standard diet (SD) or 30% CR for 16 weeks, and then, 1mg/kg E2 (17-ß estradiol) was injected intraperitoneally every 4 days for four weeks in OVX-rats. Hemodynamic parameters were evaluated before and after each diet. Heart tissues were collected for biochemical, histological, and molecular analysis. HFD consumption led to weight gain in sham and OVX rats. In contrast, CR and E2 led to body weight loss in these animals. Also, heart weight (HW), heart weight/body weight (HW/BW) ratio, and left ventricular weight (LVW) were enhanced in OVX rats that received SD and HFD. E2 reduced these indexes in both diet conditions but reduction effects of CR were seen only in HFD groups. HFD and SD feeding increased hemodynamic parameters, ANP (atrial natriuretic peptide) mRNA expression, and TGF-ß1(transforming growth factor-beta 1) protein level in the OVX animals, while CR and E2 reduced these factors. Cardiomyocyte diameter and hydroxyproline content were increased in the OVX-HFD groups. Nevertheless, CR and E2 decreased these indicators. The results showed that CR and E2 treatment reduced obesity-induced-cardiac hypertrophy in ovariectomized groups (20% and 24% respectively). CR appears to have almost as reducing effects as estrogen therapy on cardiac hypertrophy. The findings suggest that CR can be considered a therapeutic candidate for postmenopausal cardiovascular disease.

Tropisetron restores normal expression of BAD, SIRT1, SIRT3, and SIRT7 in the rat pressure overload-induced cardiac hypertrophy model.

Tropisetron exerts a protective effect against cardiac complications, particularly cardiac hypertrophy. Oxidative stress and apoptosis are the main contributors to the pathogenesis of cardiac hypertrophy. Sirtuins, a family of histone deacetylases, are connected to cellular oxidative stress signaling and antioxidant defense. Sirtuins are also linked to apoptosis which is an important mechanism in the progression of cardiac hypertrophy to heart failure. Literature also suggests that tropisetron impedes apoptosis, partly mediated through an antioxidant mechanism. Therefore, we examined if tropisetron fights cardiac hypertrophy by adjusting sirtuin family proteins (Sirts) and components of mitochondrial death pathway, Bcl-associated X (BAX), Bcl-2-associated death promoter (BAD). Male Sprague-Dawley rats got divided into four groups, including control (Ctl), tropisetron (Trop), cardiac hypertrophy (Hyp), and hypertrophic rats under tropisetron treatment (Hyp + Trop). Pathological cardiac hypertrophy was induced by surgical abdominal aortic constriction (AAC). The increased expression of brain natriuretic peptide (BNP) in the Hyp group confirms the cardiac hypertrophy establishment. The mRNA levels of SIRT1, SIRT3, SIRT7, and BAD also upregulated in the hypertrophic group (p < 0.001). Postoperational administration of tropisetron for 3 weeks lowered the increased expression of BNP (p < 0.05) and BAD (p < 0.001), though the reduction of BAX expression was statistically insignificant (p > 0.05). Tropisetron treatment also restored the normal level of SIRT1/3/7 genes expression in the Hyp + Trop group (p < 0.05). Present findings suggest that tropisetron can suppress cardiomyocyte hypertrophy progression to heart failure by counteracting BNP, SIRT1, SIRT3, Sirt7, and BAD overexpression-mediated apoptosis in a rat model of cardiac hypertrophy.

GPR30 Alleviates Pressure Overload-Induced Myocardial Hypertrophy in Ovariectomized Mice by Regulating Autophagy.

The incidence of heart failure mainly resulting from cardiac hypertrophy and fibrosis increases sharply in post-menopausal women compared with men at the same age, which indicates a cardioprotective role of estrogen. Previous studies in our group have shown that the novel estrogen receptor G Protein Coupled Receptor 30 (GPR30) could attenuate myocardial fibrosis caused by ischemic heart disease. However, the role of GPR30 in myocardial hypertrophy in ovariectomized mice has not been investigated yet. In this study, female mice with bilateral ovariectomy or sham surgery underwent transverse aortic constriction (TAC) surgery. After 8 weeks, mice in the OVX + TAC group exhibited more severe myocardial hypertrophy and fibrosis than mice in the TAC group. G1, the specific agonist of GPR30, could attenuate myocardial hypertrophy and fibrosis of mice in the OVX + TAC group. Furthermore, the expression of LC3II was significantly higher in the OVX + TAC group than in the OVX + TAC + G1 group, which indicates that autophagy might play an important role in this process. An in vitro study showed that G1 alleviated AngiotensionII (AngII)-induced hypertrophy and reduced the autophagy level of H9c2 cells, as revealed by LC3II expression and tandem mRFP-GFP-LC3 fluorescence analysis. Additionally, Western blot results showed that the AKT/mTOR pathway was inhibited in the AngII group, whereas it was restored in the AngII + G1 group. To further verify the mechanism, PI3K inhibitor LY294002 or autophagy activator rapamycin was added in the AngII + G1 group, and the antihypertrophy effect of G1 on H9c2 cells was blocked by LY294002 or rapamycin. In summary, our results demonstrate that G1 can attenuate cardiac hypertrophy and fibrosis and improve the cardiac function of mice in the OVX + TAC group through AKT/mTOR mediated inhibition of autophagy. Thus, this study demonstrates a potential option for the drug treatment of pressure overload-induced cardiac hypertrophy in postmenopausal women.

Aging Increases Susceptibility to Develop Cardiac Hypertrophy following High Sugar Consumption.

Aging and poor diet are independent risk factors for heart disease, but the impact of high-sucrose (HS) consumption in the aging heart is understudied. Aging leads to impairments in mitochondrial function that result in muscle dysfunction (e.g., cardiac remodeling and sarcopenia). We tested whether HS diet (60%kcal sucrose) would accelerate muscle dysfunction in 24-month-old male CB6F1 mice. By week 1 on HS diet, mice developed significant cardiac hypertrophy compared to age-matched chow-fed controls. The increased weight of the heart persisted throughout the 4-week treatment, while body weight and strength declined more rapidly than controls. We then tested whether HS diet could worsen cardiac dysfunction in old mice and if the mitochondrial-targeted drug, elamipretide (ELAM), could prevent the diet-induced effect. Old and young mice were treated with either ELAM or saline as a control for 2 weeks, and provided with HS diet or chow on the last week. As demonstrated in the previous experiment, old mice had age-related cardiac hypertrophy that worsened after one week on HS and was prevented by ELAM treatment, while the HS diet had no detectable effect on hypertrophy in the young mice. As expected, mitochondrial respiration and reactive oxygen species (ROS) production were altered by age, but were not significantly affected by HS diet or ELAM. Our findings highlight the vulnerability of the aged heart to HS diet that can be prevented by systemic targeting of the mitochondria with ELAM.

O-Ring Aortic Banding Versus Traditional Transverse Aortic Constriction for Modeling Pressure Overload-Induced Cardiac Hypertrophy.

Aortic banding in mice is one of the most commonly used experimental models for cardiac pressure overload-induced cardiac hypertrophy and the induction of heart failure. The previously used technique is based on a threaded suture around the aortic arch tied over a blunted 27 G needle to create stenosis. This method depends on the surgeon manually tightening the thread and, thus, leads to high variance in the diameter size. A newly refined method described by Melleby et al. promises less variance and more reproducibility after surgery. The new technique, o-ring- aortic banding (ORAB), uses a non-slip rubber ring instead of a suture with a thread, resulting in reduced variation in pressure overload and reproducible phenotypes of cardiac hypertrophy. During surgery, the o-ring is placed between the brachiocephalic and left carotid arteries. Successful constriction is confirmed by echocardiography. After 1 day, correct placement of the ring results in an increased flow velocity in the transverse aorta over the o-ring-induced stenosis. After 2 weeks, impaired cardiac function is proven by decreased ejection fraction and increased wall thickness. Importantly, besides less variance in the diameter size, ORAB is associated with lower intra- and post-operative mortality rates compared with transverse aortic constriction (TAC). Thus, ORAB represents a superior method to the commonly used TAC surgery, resulting in more reproducible results and a possible reduction in the number of animals needed.

Cardiomegaly secondary to patent ductus arteriosus causing extrinsic compression of left pulmonary vein.

Primary pulmonary vein (PV) stenosis is a challenging condition to manage. Recently, extrinsic compression of the PV is being detected has cause of narrowing and subsequent turbulence. This can be managed without direct intervention on the PV, reducing the risk of recurrence. We report a case of extrinsic compression of the PV due to cardiomegaly, relieved after patent ductus arteriosus ligation.