Evidence that tirzepatide protects against diabetes-related cardiac damages.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. METHODS: A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. RESULTS: Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40-0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. CONCLUSION: Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.

Targeted Gene Deletion or Antagonism of the Prostaglandin E2 EP3 Receptor Protects Against Cardiac Injury Postmyocardial Infarction.

BACKGROUND: Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1-EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its expression increases after a myocardial infarction (MI), mediating the reduction in cardiac function. In contrast, cardiac overexpression of the EP4 receptor in MI substantially improves cardiac function. Moreover, we recently reported that mice overexpressing EP3 have heart failure under basal conditions and worsened cardiac function after MI. Thus, the deleterious effects of the prostaglandin E2 EP receptors in the heart are mediated via its EP3 receptor. We, therefore, hypothesized that cardiomyocyte-specific knockout (CM-EP3 KO) or antagonism of the EP3 receptor protects the heart after MI. METHODS: To test our hypothesis, we made the novel CM-EP3 KO mouse and subjected CM-EP3 KO or controls to sham or MI surgery for 2 weeks. In separate experiments, C57BL/6 mice were subjected to 2 weeks of MI and treated with either the EP3 antagonist L798 106 or vehicle starting 3 days post-MI. RESULTS: CM-EP3 KO significantly prevented a decline in cardiac function after MI compared with WT animals and prevented an increase in hypertrophy and fibrosis. Excitingly, mice treated with L798 106 3 days after MI had significantly better cardiac function compared with vehicle-treated mice. CONCLUSIONS: Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function, and pharmaceutical targeting of the EP3 receptor may be a therapeutic option in the treatment of heart failure.

Dietary antioxidant intake is associated with heart failure: Results from the NHANES 2003-2019.

BACKGROUND: Growing evidence has shown that antioxidant diets protect against heart failure (HF). However, the association between the composite dietary antioxidant index (CDAI), an important measure of overall antioxidants in the diet, and HF has received little attention. OBJECTIVE: The purpose of this study was to examine the relationship between the CDAI and HF. METHODS: A secondary cross-sectional analysis of the 2003 to 2019 National Health and Nutrition Examination Survey (NHANES) was performed. Weighted multivariable logistic regression was used to test the association between the CDAI and HF in four different models, with subgroup analysis and an interaction test subsequently performed. RESULTS: A total of 37,390 participants were included. The HF groups had lower CDAI levels than those in the non-HF group (0.29 ± 0.04 vs. -0.74 ± 0.16, p < 0.0001). After adjusting for demographic characteristics, lifestyle factors, and disease history, a negative association was found between the CDAI and HF (OR: 0.97, 95 % CI: 0.94, 1.00). There was an inverse trend whereby increasing the CDAI was associated with decreasing the odds of HF (p for trend < 0.001). The subgroup analysis and interaction test showed no significant dependence on demographic characteristics, lifestyle factors, and disease history with regard to this association (all p for interaction > 0.05). CONCLUSION: The CDAI was inversely associated with HF in US adults, with higher CDAI levels possibly being associated with a lower incidence of HF, suggesting that dietary antioxidants may help prevent HF.

Targeting S100A9 Prevents ß-Adrenergic Activation-Induced Cardiac Injury.

Altered cardiac innate immunity is highly associated with the progression of cardiac disease states and heart failure. S100A8/A9 is an important component of damage-associated molecular patterns (DAMPs) that is critically involved in the pathogenesis of heart failure, thus considered a promising target for pharmacological intervention. In the current study, initially, we validated the role of S100A8/A9 in contributing to cardiac injury and heart failure via the overactivation of the ß-adrenergic pathway and tested the potential use of paquinimod as a pharmacological intervention of S100A8/A9 activation in preventing cardiac dysfunction, collagen deposition, inflammation, and immune cell infiltration in ß-adrenergic overactivation-mediated heart failure. This finding was further confirmed by the cardiomyocyte-specific silencing of S100A9 via the use of the adeno-associated virus (AAV) 9-mediated short hairpin RNA (shRNA) gene silencing system. Most importantly, in the assessment of the underlying cellular mechanism by which activated S100A8/A9 cause aggravated progression of cardiac fibrosis and heart failure, we discovered that the activated S100A8/A9 can promote fibroblast-macrophage interaction, independent of inflammation, which is likely a key mechanism leading to the enhanced collagen production. Our results revealed that targeting S100A9 provides dual beneficial effects, which is not only a strategy to counteract cardiac inflammation but also preclude cardiac fibroblast-macrophage interactions. The findings of this study also indicate that targeting S100A9 could be a promising strategy for addressing cardiac fibrosis, potentially leading to future drug development.

Mycn ameliorates cardiac hypertrophy-induced heart failure in mice by mediating the USP2/JUP/Akt/ß-catenin cascade.

BACKGROUND: Pathological cardiac hypertrophy is associated with cardiac dysfunction and is a key risk factor for heart failure and even sudden death. This study investigates the function of Mycn in cardiac hypertrophy and explores the interacting molecules. METHODS: A mouse model of cardiac hypertrophy was induced by isoproterenol (ISO). The cardiac dysfunction was assessed by the heart weight-to-body weight ratio (HW/BW), echocardiography assessment, pathological staining, biomarker detection, and cell apoptosis. Transcriptome alteration in cardiac hypertrophy was analyzed by bioinformatics analysis. Gain- or loss-of-function studies of MYCN proto-oncogene (Mycn), ubiquitin specific peptidase 2 (USP2), and junction plakoglobin (JUP) were performed. The biological functions of Mycn were further examined in ISO-treated cardiomyocytes. The molecular interactions were verified by luciferase assay or immunoprecipitation assays. RESULTS: Mycn was poorly expressed in ISO-treated mice, and its upregulation reduced HW/BW, cell surface area, oxidative stress, and inflammation while improving cardiac function of mice. It also reduced apoptosis of cardiomyocytes in mice and those in vitro induced by ISO. Mycn bound to the USP2 promoter to activate its transcription. USP2 overexpression exerted similar myocardial protective functions. It stabilized JUP protein by deubiquitination modification, which blocked the Akt/ß-catenin pathway. Knockdown of JUP restored phosphorylation of Akt and ß-catenin protein level, which negated the protective effects of USP2. CONCLUSION: This study demonstrates that Mycn activates USP2 transcription, which mediates ubiquitination and protein stabilization of JUP, thus inactivating the Akt/ß-catenin axis and alleviating cardiac hypertrophy-induced heart failure.

Intraoperative prophylactic right ventricular assist device in prevention of postcardiotomy failure.

OBJECTIVES: In patients at risk of developing right ventricular failure after cardiac surgery, right ventricular support with a ventricular assist device may be a promising strategy to reduce mortality. We present our experience with intraoperative right ventricular assist device implantation as a prevention strategy of right ventricular failure after cardiac surgery. METHODS: Between 2016 and 2022, we implanted four right ventricular assist devices prophylactically in a series of patients with surgical indication for valvular heart disease and high risk of postoperative right ventricular failure. Indications for the right ventricular assist device were suprasystemic pulmonary hypertension or severe right ventricular dysfunction. RESULTS: Externalization of the device cannulas through intercostal spaces was performed in three patients, allowing early mobilization and withdrawal without resternotomy. Removal of the device ocurred on the eighth postoperative day. ICU and hospital length of stay was 12 (±1.6) and 23 days (±4.2) respectively. Hospital mortality was null. No patient died during follow-up, mean follow-up was 32.5 months [1-72]. Patients improved their NYHA functional class up to grade II during follow-up. CONCLUSIONS: Acute right ventricular failure after cardiac surgery remains a significant cause of morbidity and mortality. Prophylactic strategies to prevent postoperative right ventricular dysfunction may decrease the incidence of refractory postoperative right ventricular failure. We propose a novel approach to prevent right failure after cardiac surgery with prophylactic intraoperative ventricular assist device implantation.

Hypothetical 22-Year Intervention With the Dietary Approaches to Stop Hypertension and Risk of Heart Failure in a General Population.

We used design principles of target trial methodology to emulate the effect of sustained adherence to the Dietary Approaches to Stop Hypertension (DASH) diet on the 22-year risk of heart failure. Women and men aged 45-83 years without previous heart failure, who answered questionnaires in 1997 from the Swedish Mammography Cohort and the Cohort of Swedish Men, were eligible. Follow-up questionnaires were sent in 2008-2009. Incidence of heart failure was ascertained using the Swedish Patient Register, updated until December 31, 2019. The parametric g-formula was used to estimate the 22-year risk of heart failure under sustained adherence to a population-adapted DASH diet compared with no intervention. Intakes before 1997 for before-baseline adjustment was available only for women. In total, 31,238 women and 34,939 men were eligible. The 22-year risk of heart failure was 14.5% with long-term adherence to the DASH diet compared with 15.2% with no intervention (risk difference = -0.7%, 95% confidence interval: 1.6, 0.0%) in women and correspondingly in men 15.3% vs. 16.2% (risk difference = -0.9%, 95% confidence interval: -1.6, -0.2%). Our hypothetical intervention suggests that sustained adherence to the population-adapted DASH diet may reduce risk of heart failure in middle-aged and elderly Swedish women and men.

Dapagliflozin protects against chronic heart failure in mice by inhibiting macrophage-mediated inflammation, independent of SGLT2.

The specific mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) needs to be elucidated. In this study, we use SGLT2-global-knockout (KO) mice to assess the mechanism of SGLT2 inhibitor on HF. Dapagliflozin ameliorates both myocardial infarction (MI)- and transverse aortic constriction (TAC)-induced HF. Global SGLT2 deficiency does not exert protection against adverse remodeling in both MI- and TAC-induced HF models. Dapagliflozin blurs MI- and TAC-induced HF phenotypes in SGLT2-KO mice. Dapagliflozin causes major changes in cardiac fibrosis and inflammation. Based on single-cell RNA sequencing, dapagliflozin causes significant differences in the gene expression profile of macrophages and fibroblasts. Moreover, dapagliflozin directly inhibits macrophage inflammation, thereby suppressing cardiac fibroblasts activation. The cardio-protection of dapagliflozin is blurred in mice treated with a C-C chemokine receptor type 2 antagonist. Taken together, the protective effects of dapagliflozin against HF are independent of SGLT2, and macrophage inhibition is the main target of dapagliflozin against HF.

Inhibition of lncRNA DANCR Prevents Heart Failure by Ameliorating Cardiac Hypertrophy and Fibrosis Via Regulation of the miR-758-3p/PRG4/Smad Axis.

The current work was developed to explore the functions and possible mechanism of PRG4 in cardiac hypertrophy and heart failure. Ang II-stimulated H9c2 cells and AC16 cells were used as in vitro cell models. The binding relation between genes in cells was explored using luciferase reporter assays and RNA immunoprecipitation assay. The cardiac functions of rats received transverse-ascending aortic constriction (TAC) surgery and adeno-associated virus (AAV) injection were examined with echocardiography. The myocardial histological changes were observed using H&E, wheat germ agglutinin, and sirius red staining. It was discovered that PRG4 silencing attenuated cell hypertrophy and fibrosis and inactivated the Smad pathway under Ang II treatment. PRG4 was targeted by miR-758-3p, and miR-758-3p interacted with long noncoding RNA DANCR. DANCR silencing inhibited cardiac dysfunction, fibrosis, and TGFß1/Smad pathway. In addition, DANCR was highly expressed in myocardial extracellular vesicles. Overall, DANCR depletion prevents heart failure by inhibiting cardiac hypertrophy and fibrosis via the miR-758-3p/PRG4/Smad pathway.

Statins as preventive therapy for anthracycline cardiotoxicity: a meta-analysis of randomized controlled trials.

BACKGROUND: Cardiotoxicity occurs in 5-20% of cancer patients who receive anthracyclines. The aim of this study was to pool all the randomized controlled trials (RCTs) investigating the cardio-protective role of statins in patients treated with anthracyclines. METHODS: PubMed and Scopus electronic databases were scanned for eligible studies up to May 3rd, 2023. A total of 5 RCTs with 808 patients were included. Efficacy endpoints were the rate of anthracycline-mediated cardiotoxicity, the incidence of hospitalization for heart failure (HF), left ventricular ejection fraction (LVEF) value after anthracycline treatment, and ∆LVEF calculated as the difference in LVEF before and after anthracycline therapy. Safety endpoints [i.e., the incidence of muscle pain and serious adverse events (SAE)] were also assessed. RESULTS: On pooled analysis, the statin-treated group had a lower incidence of cardiotoxicity compared to the placebo group [risk ratio (RR) 0.52, 95% confidence Interval (CI) 0.33-0.83, P = 0.01; I2 = 0%], as well as higher mean LVEF [Mean difference (MD) 1.88, 95% CI 0.66-3.1, P < 0.01; I2 = 57.3%)] and a more favorable ∆LVEF during follow-up (MD 2.38, 95% CI -0.03 - +4.79, P = 0.05; I2 = 99%), despite no significant difference in terms of hospitalization for HF and rate of adverse events. Of note, severe heterogeneity affected the analyses for both LVEF and ΔLVEF. CONCLUSIONS: The current meta-analysis of all RCTs conducted so far shows an overall beneficial effect of statins on the risk of anthracyclines-induced cardiotoxicity and LVEF preservation. No difference was observed in the rate of HF hospitalization. More powered RCTs are needed to fully investigate the impact of statins on prognosis in patients receiving anthracyclines therapy.

Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.

Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.

Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating ß-Hydroxybutyrate-activated Citrate Synthase.

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended in the AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (60% calories from lard) + N [w] -nitro- l -arginine methyl ester ( l -NAME-0.5 g/L) (2 Hit) in male Sprague Dawley rats to effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing ß-hydroxybutyric acid (ß-OHB) levels, directing the activation of citrate synthase, reducing acetyl coenzyme A (acetyl-CoA) pools, modulating adenosine 5'-triphosphate production, and increasing the expression of mitochondrial oxidative phosphorylation system complexes I-V. In addition, following clinical DAPA therapy, the blood levels of ß-OHB and citrate synthase increased and the levels of acetyl-CoA in the blood of HFpEF patients decreased. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.

An Evidence Base for Heart Disease Prevention using a Mediterranean Diet Comprised Primarily of Vegetarian Food.

Dietary patterns, nutrition, physical activity, air pollution, tobacco smoke, ethnicity and genetics affect heart disease. Vegetarian food diets are one of the important factors in its prevention and control. People living in the five blue zones, mostly consuming the Mediterranean diet (MedDiet), have the highest longevity in the world and the least incidence of heart disease. There are several forms of heart pathology, e.g., the most common coronary heart disease, myocardial infarction, congestive heart failure, heart valve disease and abnormal heart rhythms. Heart disease is the leading cause of death in the world and varies by race, where indigenous and people of color have a higher risk for its complications than the white population. The morbidity of cardiovascular pathology in the Afro-American community persists high and is a primary source of disparities in life expectancy between Afro-Americans and whites in the United States. Adherence to healthy diets higher in vegetable foods and lower in animal foods is correlated with a lower risk of cardiovascular disease, morbidity and mortality in the general population. A detailed literature review was performed of the Medline, EMBASE, and Ebsco databases to synthesize and compare evidence on this topic to produce a review of the importance of a Mediterranean diet in the prevention of heart disease. Consumption of a MedDiet consisting of fruits and vegetables (including berries due to their high fibre and antioxidant content), nuts, whole grains, leafy greens, beans like chickpeas, eggplants, Greek yogurt and extra virgin olive oil are associated with longer life and lower incidence of heart disease. The latter diet is superior to consuming large quantities of meat and refined carbohydrates, such as sucrose, high fructose corn syrup and grains that have had the fibrous and nutritious parts removed.

Updates for Cardio-Kidney Protective Effects by Angiotensin Receptor-Neprilysin Inhibitor: Requirement for Additional Evidence of Kidney Protection.

The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor-neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin-angiotensin system inhibitors (RAS-Is) in large clinical trials such as the PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS-Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM-HF trial, ARNI was associated with more albuminuria compared with RAS-I; thus, it is unclear whether long-term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS-I in patients with chronic kidney disease in the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS-I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

Smoking Cessation Reduces the Risk of Heart Failure: A Nationwide Cohort Study.

BACKGROUND: There is a lack of data for the incidence of heart failure (HF) according to changes in smoking behaviors. OBJECTIVES: The authors aimed to investigate the effects of smoking behavior change on development of HF. METHODS: In this population-based, retrospective cohort study using the Korean National Health Insurance System database, the authors identified 778,608 current smokers who participated in a health screening program in 2009 and in a follow-up screening in 2011. Participants were categorized into quitters, reducers I (≥50% reduction) and II (<50% reduction), sustainers, and increasers. RESULTS: During a median follow-up of 6.3 years, there were 23,329 HF events (4.8 per 1,000 person-years). Compared with sustainers, the risk of HF was increased among increasers (adjusted hazard ratio [aHR]: 1.06 [95% CI: 1.02-1.10]). By contrast, quitters had a reduced risk for HF (aHR: 0.86 [95% CI: 0.83-0.90]). Even heavy smokers who quit smoking had a lower risk for HF than those who sustained heavy smoking (aHR: 0.90 [95% CI: 0.85-0.95]). In reducers, the risk of HF was not reduced but rather increased slightly (≥50% reduction, aHR: 1.06 [95% CI: 1.01-1.11]; <50% reduction, aHR: 1.04 [95% CI: 1.00-1.08]). CONCLUSIONS: Current smokers who increased their smoking amount were associated with a higher risk for HF development compared to sustainers, whereas self-reported smoking cessation was associated with a lower risk of HF. There was no benefit from reduction in smoking amount. Self-reported smoking cessation should be reinforced whenever possible to prevent HF.

Association between first-line monotherapy with metformin and the risk of atrial fibrillation (AMRAF) in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) has a strong association with atrial fibrillation (AF) which increases risk of thromboembolic events, heart failure, and frequent hospitalizations. Metformin is the first-line medication for T2D with proposed anti-inflammatory, pro-metabolic, and cardio-protective benefits. Our objective was to investigate if initial therapy with metformin is associated with reduced incidence of AF in comparison to other non-insulin anti-hyperglycemic agents in patients with newly diagnosed T2D. METHODS: This retrospective cohort analysis included adults with a new diagnosis of T2D who were started on monotherapy (except insulin) between 2007 and 2017, without prior anti-hyperglycemic agent use, history of arrhythmias, or estimated GFR (eGFR) ≤ 30 ml/min. A multivariate analysis was performed using a fine-gray regression competing risk analysis to control for confounding variables after which pooled hazard ratios and 95 % confidence intervals were reported. Patients were followed until the end of study date, development of AF, addition of more anti-hyperglycemic agents, or death, whichever occurred first. RESULTS: Among 4584 metformin initiators compared to 1080 non-metformin monotherapy initiators, 10-year cumulative incidence of AF in metformin group was 5.2 % as compared to 8.1 % with other agents which was not statistically significant. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92, 95 % CI 0.69 to 1.21; P = 0.55). Increased age and the presence of congestive heart failure were associated with significantly higher risk of AF in both groups (HR: 1.29, 95 % CI: 1.21 to 1.37; P ≤ 0.001; HR: 2.73, 95 % CI: 1.62 to 4.61; P ≤ 0.001, respectively). CONCLUSION: Initiation of metformin as a first line monotherapy for T2D, when compared to other non-insulin monotherapies, was not associated with decreased risk of developing AF in this retrospective observational study.

Prevention of vasoplegia with CytoSorb in heart failure patients undergoing cardiac surgery (CytoSorb-HF trial): protocol for a randomised controlled trial.

INTRODUCTION: Vasoplegia is a common complication after cardiac surgery and is associated with poor prognosis. It is characterised by refractory hypotension despite normal or even increased cardiac output. The pathophysiology is complex and includes the systemic inflammatory response caused by cardiopulmonary bypass (CPB) and surgical trauma. Patients with end-stage heart failure (HF) are at increased risk for developing vasoplegia. The CytoSorb adsorber is a relatively new haemoadsorption device which can remove circulating inflammatory mediators in a concentration based manner. The CytoSorb-HF trial aims to evaluate the efficacy of CytoSorb haemoadsorption in limiting the systemic inflammatory response and preventing postoperative vasoplegia in HF patients undergoing cardiac surgery with CPB. METHODS AND ANALYSIS: This is an investigator-initiated, single-centre, randomised, controlled clinical trial. In total 36 HF patients undergoing elective cardiac surgery with an expected CPB duration of more than 120 min will be randomised to receive CytoSorb haemoadsorption along with standard surgical treatment or standard surgical treatment alone. The primary endpoint is the change in systemic vascular resistance index with phenylephrine challenge after CPB. Secondary endpoints include inflammatory markers, sublingual microcirculation parameters and 30-day clinical indices. In addition, we will assess the cost-effectiveness of using the CytoSorb adsorber. Vascular reactivity in response to phenylephrine challenge will be assessed after induction, after CPB and on postoperative day 1. At the same time points, and before induction and on postoperative day 4 (5 time points in total), blood samples will be collected and the sublingual microcirculation will be recorded. Study participants will be followed up until day 30. ETHICS AND DISSEMINATION: The trial protocol was approved by the Medical Ethical Committee of Leiden The Hague Delft (METC LDD, registration number P20.039). The results of the trial will be published in peer-reviewed medical journals and through scientific conferences. TRIAL REGISTRATION NUMBER: NCT04812717.

Initiation of the SGLT2 inhibitor canagliflozin to prevent kidney and heart failure outcomes guided by HbA1c, albuminuria, and predicted risk of kidney failure.

BACKGROUND: Sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of kidney and heart failure events independent of glycemic effects. We assessed whether initiation of the SGLT2 inhibitor canagliflozin guided by multivariable predicted risk based on clinical characteristics and novel biomarkers is more efficient to prevent clinical outcomes compared to a strategy guided by HbA1c or urinary-albumin-creatinine ratio (UACR) alone. METHODS: We performed a post-hoc analysis of the CANVAS trial including 3713 patients with available biomarker measurements. We compared the number of composite kidney (defined as a sustained 40% decline in eGFR, chronic dialysis, kidney transplantation, or kidney death) and composite heart failure outcomes (defined as heart failure hospitalization or cardiovascular (CV) death) prevented per 1000 patients treated for 5 years when canagliflozin was initiated in patients according to HbA1c ≥ 7.5%, UACR, or multivariable risk models consisting of: (1) clinical characteristics, or (2) clinical characteristics and novel biomarkers. Differences in the rates of events prevented between strategies were tested by Chi2-statistic. RESULTS: After a median follow-up of 6.1 years, 144 kidney events were recorded. The final clinical model included age, previous history of CV disease, systolic blood pressure, UACR, hemoglobin, body weight, albumin, estimated glomerular filtration rate, and randomized treatment assignment. The combined biomarkers model included all clinical characteristics, tumor necrosis factor receptor-1, kidney injury molecule-1, matrix metallopeptidase-7 and interleukin-6. Treating all patients with HbA1c ≥ 7.5% (n = 2809) would prevent 33.0 (95% CI 18.8 to 43.3 ) kidney events at a rate of 9.6 (95% CI 5.5 to 12.6) events prevented per 1000 patients treated for 5 years. The corresponding rates were 5.8 (95% CI 3.4 to 7.9), 16.6 (95% CI 9.5 to 22.0) (P < 0.001 versus HbA1c or UACR approach), and 17.5 (95% CI 10.0 to 23.0) (P < 0.001 versus HbA1c or UACR approach; P = 0.54 versus clinical model). Findings were similar for the heart failure outcome. CONCLUSION: Initiation of canagliflozin based on an estimated risk-based approach prevented more kidney and heart failure outcomes compared to a strategy based on HbA1c or UACR alone. There was no apparent gain from adding novel biomarkers to the clinical risk model. These findings support the use of risk-based assessment using clinical markers to guide initiation of SGLT2 inhibitors in patients with type 2 diabetes.

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling.

BACKGROUND: Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. METHODS: Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. RESULTS: High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. CONCLUSION: DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Long-Term Activation of Glucagon-like peptide-1 receptor by Dulaglutide Prevents Diabetic Heart Failure and Metabolic Remodeling in Type 2 Diabetes.

Background Mechanistic insights of glucagon-like peptide-1 receptor agonists remain incompletely identified, despite the efficacy in heart failure observed in clinical trials. Here, we evaluated the effects of dulaglutide on heart complications and illuminated its underlying mechanism. Methods and Results We used mice with high-fat diet (HFD)/streptozotocin-induced type 2 diabetes to investigate the effects of dulaglutide upon diabetic cardiac dysfunction. After the onset of diabetes, control and diabetic mice were injected subcutaneously with either dulaglutide (type 2 diabetes-dulaglutide and control-dulaglutide groups) or vehicle (type 2 diabetes-vehicle and control-vehicle groups) for 8 weeks. Subsequently, heart characteristics, cardiometabolic profile and mitochondrial morphology and function were evaluated. Also, we analyzed the effects of dulaglutide on neonatal rat ventricular myocytes treated with high glucose plus palmitic acid. In addition, wild type and AMP-activated protein kinase α2 mutant mice were used to evaluate the underlying mechanism. In type 2 diabetes mouse model, dulaglutide ameliorated insulin resistance, improved glucose tolerance, reduced hyperlipidemia, and promoted fatty acid use in the myocardium. Dulaglutide treatment functionally attenuated cardiac remodeling and dysfunction and promoted metabolic reprogramming in diabetic mice. Furthermore, dulaglutide improved mitochondria fragmentation in myocytes, and simultaneously reinstated mitochondrial morphology and function in diabetic hearts. We also found that dulaglutide preserved AMP-activated protein kinase α2-dependent mitochondrial homeostasis, and the protective effects of dulaglutide on diabetic heart was almost abated by AMP-activated protein kinase α2 knockout. Conclusions Dulaglutide prevents diabetic heart failure and favorably affects myocardial metabolic remodeling by impeding mitochondria fragmentation, and we suggest a potential strategy to develop a long-term activation of glucagon-like peptide-1 receptor-based therapy to treat diabetes associated cardiovascular complications.