Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.

Background: Sepsis triggers myocardial injury and dysfunction, leading to a high mortality rate in patients. Cardiomyocyte apoptosis plays a positive regulatory role in septic myocardial injury and dysfunction. However, the mechanism is unclear. Methods: Bioinformatics analysis was used to identify differentially expressed genes in septic mice heart and validate key genes and pathways. The correlation of protein-protein and protein-pathway was analyzed. Sequentially, the cecal ligament and puncture (CLP) was used to induce septic mice, followed by Serpine1 inhibitor treatment. Finally, the regulatory relationship of Yes-associated protein1 (YAP1), Serpine1, and caspase-3 was verified in LPS-exposed mouse cardiomyocytes. Results: Bioinformatic analysis found that Serpine1 expression is decreased in septic mice heart tissue and closely related to the HIPPO signaling pathway, while YAP1 is negatively correlated with apoptosis. In vivo, CLP induced a reduction of survival rate, cardiac dysfunction, and an increase in Serpine1 and Cleaved Caspase-3 expression, which could be reversed by a Serpine1 inhibitor. In vitro, LPS induced the mouse cardiomyocytes apoptosis, which could be reversed by Serpine1 inhibitor. Silencing YAP1 and Serpine1 reversed the LPS-induced increase in Serpine1 and Cleaved Caspase-3 expression, but silencing Serpine1 did not affect the LPS-induced YAP1 expression. Conclusion: Sepsis induced mouse cardiomyocytes apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway.

The Efficacy of Vitamins in the Prevention and Treatment of Cardiovascular Disease.

Vitamins are known to affect the regulation of several biochemical and metabolic pathways that influence cellular function. Adequate amounts of both hydrophilic and lipophilic vitamins are required for maintaining normal cardiac and vascular function, but their deficiencies can contribute to cardiovascular abnormalities. In this regard, a deficiency in the lipophilic vitamins, such as vitamins A, D, and E, as well as in the hydrophilic vitamins, such as vitamin C and B, has been associated with suboptimal cardiovascular function, whereas additional intakes have been suggested to reduce the risk of atherosclerosis, hypertension, ischemic heart disease, arrhythmias, and heart failure. Here, we have attempted to describe the association between low vitamin status and cardiovascular disease, and to offer a discussion on the efficacy of vitamins. While there are inconsistencies in the impact of a deficiency in vitamins on the development of cardiovascular disease and the benefits associated with supplementation, this review proposes that specific vitamins may contribute to the prevention of cardiovascular disease in individuals at risk rather than serve as an adjunct therapy.

How to utilize current guidelines to manage patients with cancer at high risk for heart failure.

Heart failure (HF) in patients with cancer is associated with high morbidity and mortality. The success of cancer therapy has resulted in an exponential rise in the population of cancer survivors, however cardiovascular disease (CVD) is now a major life limiting condition more than 5 years after cancer diagnosis [Sturgeon, Deng, Bluethmann, et al 40(48):3889-3897, 2019]. Prevention and early detection of CVD, including cardiomyopathy (CM) and HF is of paramount importance. The European Society of Cardiology (ESC) published guidelines on Cardio-Oncology (CO) [Lyon, López-Fernández, Couch, et al 43(41):4229-4361, 2022] detailing cardiovascular (CV) risk stratification, prevention, monitoring, diagnosis, and treatment throughout the course and following completion of cancer therapy. Here we utilize a case to summarize aspects of the ESC guideline relevant to HF clinicians, with a focus on risk stratification, early detection, prevention of CM and HF, and the role for guideline directed medical therapy in patients with cancer.

CBR-470-1 protects against cardiomyocyte death in ischaemia/reperfusion injury by activating the Nrf2-GPX4 cascade.

Cardiac ischaemia/reperfusion (I/R) impairs mitochondrial function, resulting in excessive oxidative stress and cardiomyocyte ferroptosis and death. Nuclear factor E2-related factor 2 (Nrf2) is a key regulator of redox homeostasis and has cardioprotective effects against various stresses. Here, we tested whether CBR-470-1, a noncovalent Nrf2 activator, can protect against cardiomyocyte death caused by I/R stress. Compared with vehicle treatment, the administration of CBR-470-1 (2 mg/kg) to mice significantly increased Nrf2 protein levels and ameliorated the infarct size, the I/R-induced decrease in cardiac contractile performance, and the I/R-induced increases in cell apoptosis, ROS levels, and inflammation. Consistently, the beneficial effects of CBR-470-1 on cardiomyocytes were verified in a hypoxia/reoxygenation (H/R) model in vitro, but this cardioprotection was dramatically attenuated by the GPX4 inhibitor RSL3. Mechanistically, CBR-470-1 upregulated Nrf2 expression, which increased the expression levels of antioxidant enzymes (NQO1, SOD1, Prdx1, and Gclc) and antiferroptotic proteins (SLC7A11 and GPX4) and downregulated the protein expression of p53 and Nlrp3, leading to the inhibition of ROS production and inflammation and subsequent cardiomyocyte death (apoptosis, ferroptosis and pyroptosis). In summary, CBR-470-1 prevented I/R-mediated cardiac injury possibly through inhibiting cardiomyocyte apoptosis, ferroptosis and pyroptosis via Nrf2-mediated inhibition of p53 and Nlrp3 and activation of the SLC7A11/GPX4 pathway. Our data also highlight that CBR-470-1 may serve as a valuable agent for treating ischaemic heart disease.

Resistant starch confers protection of dietary against diabetic cardiomyopathy.

Long-term dysfunction of glucose metabolism causes cardiac dysfunction called diabetic cardiomyopathy (DCM). To investigate the effect and underlying mechanism of RS on the process of DCM, mouse models induced by a high-fat diet (HFD) and streptozotocin (STZ) were fed RS (2 g/kg/day) and vehicle treatment (by oral gavage) for 14 weeks. Various analyses, including qRT-PCR, western blot, immunofluorescence staining, histology staining, cardiac function, and diversity detection of intestinal microbiota were performed. RS intervention could directly improve myocardial fibrosis, hypertrophy, apoptosis, and cardiac insufficiency in DCM. These beneficial effects may be achieved by elevating the expression of IGF-1, activating the ERK phosphorylation. Furthermore, by carrying out nano LC-MS/MS analyses and 16S rDNA sequencing, we found RS might primarily affect proteins in the cytoplasm involved in post-translational modification, protein conversion, and signal transduction mechanisms. RS altered intestinal microbiota and improved intestinal mucosal permeability towards a favorable direction in DCM. This multidimensional assessment of RS suggests that might be a promising approach towards the treatment of DCM.

The effect of intravenous milrinone in adult critically ill patients: A meta-analysis of randomized clinical trials.

BACKGROUND: Milrinone is widely used for enhancing myocardial contractility, however, there is inadequate data to suggest whether it is preferable to other inotropic agents in critically ill patients. To observe the effect of milrinone on prognosis in adult critically ill patients, we conducted this meta-analysis. METHODS: A search of the following databases was conducted: Medline, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases, and eligible randomized controlled trials including adult critically ill patients were screened. Two reviewers collected data separately, information was retrieved including study design, center number, sample size, gender, age, intervention and outcome. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA). RESULTS: Twenty studies including 2036 critically ill patients which compared milrinone with control group were enrolled. When compared to control group, there was no significant difference of all-cause mortality, while the incidence of ventricular arrhythmia decreased significantly in patients with cardiac surgery who using milrinone, but not in patients with cardiac dysfunction and shock. There was no significant reduction in the incidence of myocardial infarction and no improvement of hemodynamic parameters in the milrinone group. TSA indicated lack of firm evidence for a beneficial effect. CONCLUSION: The meta-analysis showed when compared with control group, although no significant reduction in mortality and the incidence of myocardial infarction was found in the milrinone group, the incidence of ventricular arrhythmia decreased significantly in patients with cardiac surgery. More randomized controlled trials are needed to determine the reliable and conclusive evidence for milrinone's effects.

Polysialic acid driving cardiovascular targeting co-delivery 1,8-cineole and miR-126 to synergistically alleviate lipopolysaccharide-induced acute cardiovascular injury.

Infection-induced cardiovascular damage is the primary pathological mechanism underlying septic cardiac dysfunction. This condition affects the majority of patients in intensive care unit and has an unfavorable prognosis due to the lack of effective therapies available. Vascular cell adhesion molecule-1 (VCAM-1) plays a vital role in coordinating the inflammatory response and recruitment of leukocytes in cardiac tissue, making it a potential target for developing novel therapies. MicroRNA-126 (miR-126) has been shown to downregulate VCAM-1 expression in endothelial cells, reducing leukocyte adhesion and exerting anti-inflammatory effects. Therefore, this work described a polysialic acid (PSA) modified ROS-responsive nanosystem to targeted co-delivery 1,8-Cineole and miR-126 for mitigating septic cardiac dysfunction. The nanosystem consists of 1,8-Cineole nanoemulsion (CNE) conjugated with PEI/miR126 complex by a ROS-sensitive linker, with PSA on its surface to facilitate targeted delivery via specific interactions with selectins on endothelial cells. CNE has demonstrated protective effects against inflammation in the cardiovascular system and synergistic anti-inflammatory effects when combined with miR-126. The targeted nanosystem successfully delivered miR-126 and 1,8-Cineole to the injured heart tissues and vessels, reducing inflammatory responses and improving cardiac function. In summary, this work provides a promising therapy for alleviating the inflammatory response in sepsis while boosting cardiovascular protection.

RRAGD variants cause cardiac dysfunction in a zebrafish model.

The Ras-related GTP-binding protein D (RRAGD) gene plays a crucial role in cellular processes. Recently, RRAGD variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences of RRAGD variants at organismal level is unknown. Therefore, this study investigated the impact of RRAGD variants on cardiac function using zebrafish embryo model. Furthermore, the potential usage of rapamycin, an mTOR inhibitor, as a therapy was assessed in this model. Zebrafish embryos were injected with RRAGD p.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression of RRAGD mutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. In RRAGD S76L-injected embryos, lower survival and heartbeat were observed, while survival was unaffected in RRAGD P119R embryos. These observations were reversible following therapy with the mTOR inhibitor rapamycin. Moreover, no effects on electrolyte homeostasis were observed. Together, these findings indicate a crucial role of RRAGD for cardiac function. In the future, the molecular mechanisms by which RRAGD variants result in cardiac dysfunction, and if the effects of rapamycin are specific for RRAGD-dependent cardiomyopathy should be studied in clinical studies.

Cardiac wasting in patients with cancer.

Patients with cancer face a significant risk of cardiovascular death, regardless of time since cancer diagnosis. Elderly patients are particularly more susceptible as cancer-associated cardiac complications present in advanced stage cancer. These patients may often present with symptoms observed in chronic heart failure (HF). Cardiac wasting, commonly observed in these patients, is a multifaceted syndrome characterized by systemic metabolic alterations and inflammatory processes that specifically affect cardiac function and structure. Experimental and clinical studies have demonstrated that cancer-associated cardiac wasting is linked with cardiac atrophy and altered cardiac morphology, which impairs cardiac function, particularly pertaining to the left ventricle. Therefore, this review aims to present a summary of epidemiologic data and pathophysiological mechanisms of cardiac wasting due to cancer, and future directions in this field.

Qiliqiangxin capsule alleviates cardiac hypertrophy and cardiac dysfunction by regulating miR-382-5p/ATF3 axis.

OBJECTIVE: Qiliqiangxin Capsule (QL) was investigated for its possible role in cardiac hypertrophy in this study. METHODS: QL (0.5 mg/mL) was pre-treated in Neonatal Mouse Ventricular Cardiomyocytes (NMVCs) before induction of cardiomyocyte hypertrophy by Angiotensin II (Ang-II). Immunofluorescence staining for α-actinin was conducted to determine cell surface area. Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) of hypertrophy markers were examined. Ang-II infusion was given to stimulate cardiac hypertrophy in mice. The cardiac function of mice was detected by echocardiography, and the pathological status of myocardial tissue was observed. RESULTS: The surface of cardiomyocytes was enlarged by Ang-II, and ANP and BNP levels were increased. QL processing could save these changes. miR-382-5p was upregulated in Ang-II-treated NMVCs, and reducing miR-382-5p could further enhance the therapeutic effect of QL while elevating miR-382-5p weakened the protective effect of QL. QL could inhibit miR-382-5p expression to negatively regulate Activated Transcription Factor 3 (ATF3) expression. Enhancing ATF3 expression rescued miR-382-5p upregulation-mediated role in NMVCs. In addition, QL alleviated Ang-II-stimulated cardiac hypertrophy and cardiac dysfunction in mice. CONCLUSION: QL may alleviate cardiac hypertrophy and cardiac dysfunction via the miR-382-5p/ATF3 axis.

Ccn2 Deletion Reduces Cardiac Dysfunction, Oxidative Markers, and Fibrosis Induced by Doxorubicin Administration in Mice.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.

Strain surveillance during chemotherapy to improve cardiovascular outcomes: the SUCCOUR-MRI trial.

BACKGROUND AND AIMS: The detection of cancer therapy-related cardiac dysfunction (CTRCD) by reduction of left ventricular ejection fraction (LVEF) during chemotherapy usually triggers the initiation of cardioprotective therapy. This study addressed whether the same approach should be applied to patients with worsening of global longitudinal strain (GLS) without attaining thresholds of LVEF. METHODS: Strain sUrveillance during Chemotherapy for improving Cardiovascular Outcomes (SUCCOUR-MRI) was a prospective multicentre randomized controlled trial involving 14 sites. Of 355 patients receiving anthracyclines with normal baseline LVEF, 333 patients (age 59±13 years, 79% women) with at least one other CTRCD risk factor, able to undergo magnetic resonance imaging (MRI), GLS and 3D echocardiography were tracked over 12 months. A total of 105 patients (age 59±13 years, 75% women, 69% breast cancer) developing GLS-CTRCD (>12% relative reduction of GLS without a change in LVEF) between cardioprotection with neurohormonal antagonists versus usual care were randomized. The primary endpoint was 12-month change in MRI-LVEF; the secondary endpoint was MRI LVEF-defined CTRCD. RESULTS: During follow-up, 2 patients died and 2 developed heart failure. Most patients were randomized at 3 months (62%). Median doses of angiotensin inhibition/blockade and beta-blockade were 75% and 50% of respective targets; 21 (43%) had side-effects attributed to cardioprotection. Due to a smaller LVEF change from baseline with cardioprotection than usual care (-2.5±5.4% vs -5.6±5.9%, p=0.009), follow-up LVEF was higher after cardioprotection (59±5% vs 55±6%, p<0.0001). After adjustment for baseline LVEF, the mean (95% confidence interval) difference in the change in LVEF between the two groups was -3.6% (-1.8% to -5.5%, p<0.001). After cardioprotection, 1/49 patients developed 12-month LVEF-CTRCD, compared to 6/56 in usual care (p=0.075). GLS improved at 3 months post-randomization in the cardioprotection group, with little change with usual care. CONCLUSIONS: In patients with isolated GLS reduction after anthracyclines, cardioprotection is associated with better preservation of 12-month MRI-LVEF compared with usual care.

Differentiating Ischemic Hepatitis from Acetaminophen Overdose in Acute Liver Failure: Role of Acetaminophen Adducts-Ischemic Hepatitis vs Acetaminophen Overdose.

BACKGROUND AND AIMS: Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis. METHODS: Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication. RESULTS: With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role. CONCLUSIONS: Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases.

PPARγ Agonist Pioglitazone Prevents Hypoxia-induced Cardiac Dysfunction by Reprogramming Glucose Metabolism.

The heart relies on various defense mechanisms, including metabolic plasticity, to maintain its normal structure and function under high-altitude hypoxia. Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ), sensitizes insulin, which in turn regulates blood glucose levels. However, its preventive effects against hypoxia-induced cardiac dysfunction at high altitudes have not been reported. In this study, pioglitazone effectively prevented cardiac dysfunction in hypoxic mice for 4 weeks, independent of its effects on insulin sensitivity. In vitro experiments demonstrated that pioglitazone enhanced the contractility of primary cardiomyocytes and reduced the risk of QT interval prolongation under hypoxic conditions. Additionally, pioglitazone promoted cardiac glucose metabolic reprogramming by increasing glycolytic capacity; enhancing glucose oxidation, electron transfer, and oxidative phosphorylation processes; and reducing mitochondrial reactive ROS production, which ultimately maintained mitochondrial membrane potential and ATP production in cardiomyocytes under hypoxic conditions. Notably, as a PPARγ agonist, pioglitazone promoted hypoxia-inducible factor 1α (HIF-1α) expression in hypoxic myocardium. Moreover, KC7F2, a HIF-1α inhibitor, disrupted the reprogramming of cardiac glucose metabolism and reduced cardiac function in pioglitazone-treated mice under hypoxic conditions. In conclusion, pioglitazone effectively prevented high-altitude hypoxia-induced cardiac dysfunction by reprogramming cardiac glucose metabolism.

Serum CIAPIN1 is lower in septic patients with cardiac dysfunction.

The study aimed to investigate the clinical significance of serum cytokine-induced apoptosis inhibitor 1 (CIAPIN1) and its potential impact on cardiac dysfunction and inflammatory response induced by sepsis. A cross-sectional study was conducted in an intensive care unit (ICU) involving 80 healthy individuals and 95 severe sepsis patients. The data were analyzed to establish the correlation between CIAPIN1 levels and the onset of cardiac dysfunction in patients with sepsis. The associations have been established by the Pearson correlation test, one-way ANOVA, Bonferroni post hoc test, and plotting the receiver operating characteristic (ROC). H9c2 cells were treated with LPS (1 µg/mL) for 24 h to establish an in vitro model of septic cardiomyopathy. Meanwhile, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were detected by enzyme-linked immunosorbent assay (ELISA). Serum CIAPIN1 levels were considerably lower in sepsis patients with cardiac dysfunction. CIAPIN1 expression levels were negatively correlated with TNF-α (r = -0.476, P<0.001), IL-1ß (r = -0.584, P<0.001), IL-6 (r = -0.618, P<0.001), creatine kinase- MB (CK-MB) (r = -0.454, P<0.001), and high-sensitive cardiac troponin T (hs-cTnT) (r = -0.586, P<0.001). The ROC curve showed that CIAPIN1 significantly identify sepsis patients from healthy individuals. CIAPIN1 knockdown decreases cardiomyocyte proliferation and increases apoptosis induced by LPS. In addition, CIAPIN1 knockdown reduced cardiac dysfunction and increased inflammatory response in H9c2 rat cardiomyocytes. CIAPIN1 could be a potential biomarker for detecting sepsis patients and suppressing CIAPIN1 expression in H9c2 rat cardiomyocytes, attenuating sepsis-induced cardiac dysfunction.

The association of glycaemic risk factors and diabetes duration with risk of heart failure in people with type 2 diabetes: A systematic review and meta-analysis.

AIMS: To conduct a systematic review in order to better understand the association of glycaemic risk factors and diabetes duration with risk of heart failure (HF) in individuals with type 2 diabetes (T2D). METHODS: We identified longitudinal studies investigating the association of glycaemic factors (glycated haemoglobin [HbA1c], HbA1c variability, and hypoglycaemia) and diabetes duration with HF in individuals with T2D. Hazard ratios and odds ratios were extracted and meta-analysed using a random-effects model where appropriate. Risk of bias assessment was carried out using a modified Newcastle-Ottawa Scale. Egger's test along with the trim-and-fill method were used to assess and account for publication bias. RESULTS: Forty studies representing 4 102 589 people met the inclusion criteria. The risk of developing HF significantly increased by 15% for each percentage point increase in HbA1c, by 2% for each additional year of diabetes duration, and by 43% for having a history of severe hypoglycaemia. Additionally, variability in HbA1c levels was associated with a 20%-26% increased risk of HF for each unit increase in the metrics of variability (HbA1c standard deviation, coefficient of variation, and average successive variability). All included studies scored high in the risk of bias assessment. Egger's test suggested publication bias, with trim-and-fill analyses revealing a significant 14% increased risk of HF per percentage point increase in HbA1c. CONCLUSIONS: Glycaemic risk factors and diabetes duration significantly contribute to the heightened risk of HF among individuals with T2D. A reduction in risk of HF is anticipated with better management of glycaemic risk factors.

Empagliflozin alleviates obesity-related cardiac dysfunction via the activation of SIRT3-mediated autophagosome formation.

BACKGROUND: Empagliflozin (EMPA) has demonstrated efficacy in providing cardiovascular benefits in metabolic diseases. However, the direct effect of EMPA on autophagy in obesity-related cardiac dysfunction remains unclear. Therefore, this study aimed to determine changes in cardiac autophagy during diet-induced obesity and clarify the exact mechanism by which EMPA regulates autophagic pathways. METHODS: Male C57BL/6J mice were fed a 12-week high-fat diet (HFD) followed by 8 weeks of EMPA treatment. Body composition analysis and echocardiography were performed to evaluate metabolic alterations and cardiac function. Histological and immunofluorescence staining was used to evaluate potential enhancements in myocardial structure and biological function. Additionally, H9c2 cells were transfected with small interfering RNA targeting sirtuin 3 (SIRT3) and further treated with palmitic acid (PA) with or without EMPA. Autophagy-related targets were analyzed by western blotting and RT‒qPCR. RESULTS: EMPA administration effectively ameliorated metabolic disorders and cardiac diastolic dysfunction in HFD-fed mice. EMPA prevented obesity-induced myocardial hypertrophy, fibrosis, and inflammation through the activation of SIRT3-mediated autophagosome formation. The upregulation of SIRT3 triggered by EMPA promoted the initiation of autophagy by activating AMP-activated protein kinase (AMPK) and Beclin1. Furthermore, activated SIRT3 contributed to the elongation of autophagosomes through autophagy-related 4B cysteine peptidase (ATG4B) and autophagy-related 5 (ATG5). CONCLUSIONS: EMPA promotes SIRT3-mediated autophagosome formation to alleviate damage to the cardiac structure and function of obese mice. Activated SIRT3 initiates autophagy through AMPK/Beclin1 and further stimulates elongation of the autophagosome membrane via ATG4B/ATG5. These results provide a new explanation for the cardioprotective benefits of EMPA in obesity.

Subclinical left ventricular dysfunction in rheumatoid arthritis: findings from the prospective Porto-RA cohort.

AIM: Patients with rheumatoid arthritis (RA) have an increased risk of cardiac dysfunction and heart failure (HF) due to a pro-inflammatory state. Detecting cardiac dysfunction in RA is challenging as these patients often present preserved ejection fraction (EF) but may have subclinical ventricular dysfunction. Echocardiographic strain analysis is a promising tool for early detection of subclinical left ventricular systolic dysfunction (LVSD). This study assesses the prognostic role of strain analysis in RA. METHODS AND RESULTS: Prospective study of 277 RA patients without known heart disease and preserved EF, categorized by left ventricular global longitudinal strain (GLS): normal GLS (≤ - 18%) vs. subclinical LVSD (> - 18%). Primary outcome was a composite of myocardial infarction, HF hospitalization, stroke, or cardiovascular death (MACE). Mean age was 57 years, 79% female. Although mean GLS was within normal (- 20 ± 3%), subclinical LVSD was observed in 24% of patients (n = 67) and was positively correlated with older age (OR 1.54 per 10 years; p < 0.001) and comorbid conditions, such as dyslipidemia (OR 2.27; p = 0.004), obesity (OR 2.29; p = 0.015), and chronic kidney disease (OR 8.39; p = 0.012). Subclinical LVSD was independently associated with a 3.9-fold higher risk of MACE (p = 0.003) and a 3.4-fold higher risk of HF hospitalization/cardiovascular death (p = 0.041). A GLS threshold of > - 18.5% provided optimal sensitivity (78%) and specificity (74%) in identifying patients at elevated MACE risk (AUC = 0.78; p < 0.001). CONCLUSION: Subclinical LVSD, identified by reduced GLS, was strongly associated with adverse cardiovascular events in RA. Whether these findings have therapeutic implications is worth exploring in clinical trials.

Cancer Therapy-Related Cardiac Dysfunction: Strategies for Enhancing Cardiac Recovery.

Chemotherapy has markedly improved cancer outcomes, yet cancer therapy-related cardiac dysfunction (CTRCD) poses a significant challenge, affecting around 10% of patients. CTRCD can be asymptomatic or present with heart failure symptoms. Multimodality imaging, particularly echocardiography, remains pivotal for monitoring cardiac function. Potential biomarkers for CTRCD assessment include troponin and B-type natriuretic peptide. Pharmacological interventions, such as dexrazoxane, angiotensin-converting enzyme inhibitors, and statins, play a crucial role in primary prevention and mitigating cardiotoxicity alongside cardiac rehabilitation programs. Thus, a comprehensive approach is essential for optimal cardiac recovery and improved patient outcomes.

The role of protein kinase D (PKD) in obesity: Lessons from the heart and other tissues.

Obesity causes a range of tissue dysfunctions that increases the risk for morbidity and mortality. Protein kinase D (PKD) represents a family of stress-activated intracellular signalling proteins that regulate essential processes such as cell proliferation and differentiation, cell survival, and exocytosis. Evidence suggests that PKD regulates the cellular adaptations to the obese environment in metabolically important tissues and drives the development of a variety of diseases. This review explores the role that PKD plays in tissue dysfunction in obesity, with special consideration of the development of obesity-mediated cardiomyopathy, a distinct cardiovascular disease that occurs in the absence of common comorbidities and leads to eventual heart failure and death. The downstream mechanisms mediated by PKD that could contribute to dysfunctions observed in the heart and other metabolically important tissues in obesity, and the predicted cell types involved are discussed to suggest potential targets for the development of therapeutics against obesity-related disease.