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.

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.

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.

Uric acid-lowering effects of sodium-glucose cotransporter 2 inhibitors for preventing cardiovascular events and mortality: A systematic review and meta-analysis.

BACKGROUND: To evaluate the effect of a 1 mg/dl reduction in uric acid (UA) on cardiovascular events and mortality in patients treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors. RESEARCH DESIGN AND METHODS: We performed a systematic review of the MEDLINE and EMBASE databases searched up to 30 June 2023 (PROSPERO, CRD42022355479) to identify large-scale SGLT2 inhibitor trials. Random-effects meta-analyses were used to pool the estimates. RESULTS: In total, five SGLT2 inhibitor trials (31 535 patients, 54% with heart failure) were analysed. Over a median follow-up of 2.2 years, the mean reduction in UA was -0.79 mg/dl (95% confidence interval (CI), -1.03 to -0.54). Every 1 mg/dl reduction in UA was associated with a significantly lower risk of a composite of cardiovascular death and hospitalization for heart failure [hazard ratio, 0.64 (95% CI, 0.46-0.88)] and hospitalization for heart failure (0.68; 95% CI, 0.62-0.74), with a similar risk of mortality. CONCLUSIONS: SGLT2 inhibitors reduced UA levels and cardiovascular events independently of heart failure status.

Empagliflozin to elderly and obese patients with increased risk of developing heart failure: Study protocol for the Empire Prevent trial program.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF. METHODS: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m2) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up. DISCUSSION: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition. TRIAL REGISTRATION: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome.

The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes: an updated systematic review and meta-analysis.

BACKGROUND: The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) use. Since then, additional trials of relevance for SGLT2i have been published. This update re-evaluates the clinical recommendations for using SGLTi and their indirect comparison with existing evidence on GLP-1RA as compared to the standard of care to reduce cardiorenal morbidity and mortality. METHODS: We updated our existing search and screening of the literature from September 2021 to April 2023 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. We conducted risk of bias assessment, data extraction and updated our meta-analysis of studies with similar interventions and components. The certainty of the evidence was determined using GRADE. RESULTS: Evidence from three new trials and additional results from an updated existing trial on SGLT2i met our inclusion criteria after an updated search. Across all the included studies, the total sample size was 151,023 adults, with 90,943 in SGLT2i trials and 60,080 in GLP-1 RA trials. The mean age ranged from 59.9 to 68.4 years. Compared with standard care, the use of SGLT2i and GLP-1 RA showed significant reductions in the outcomes of cardiovascular (CV) mortality (14% & 13%), any-cause mortality (12% & 12%), major adverse CV events (MACE) (11% & 14%), heart failure (HF) hospitalization (30% & 9%), CV death or HF hospitalization (23% & 11%), and kidney composite outcome (32% & 22%). In participants with T2D, both classes demonstrated significant cardiorenal protection. But, only GLP-1RA showed a reduction in non-fatal stroke (16%) and only SGLT2i showed a reduction in HF hospitalization (30%) in this population of people living with T2D. CONCLUSIONS: This updated and comprehensive meta-analysis substantiates and strengthens the clinical recommendations of the CCS cardiorenal guidelines.

Prioritizing the primary prevention of heart failure: Measuring, modifying and monitoring risk.

With the rising incidence of heart failure (HF) and increasing burden of morbidity, mortality, and healthcare expenditures, primary prevention of HF targeting individuals in at-risk HF (Stage A) and pre-HF (Stage B) Stages has become increasingly important with the goal to decrease progression to symptomatic (Stage C) HF. Identification of risk based on traditional risk factors (e.g., cardiovascular health which can be assessed with the American Heart Association's Life's Essential 8 framework), adverse social determinants of health, inherited risk of cardiomyopathies, and identification of risk-enhancing factors, such as patients with viral disease, exposure to cardiotoxic chemotherapy, and history of adverse pregnancy outcomes should be the first step in evaluation for HF risk. Next, use of guideline-endorsed risk prediction tools such as Pooled Cohort Equations to Prevent Heart Failure provide quantification of absolute risk of HF based in traditional risk factors. Risk reduction through counseling on traditional risk factors is a core focus of implementation of prevention and may include the use of novel therapeutics that target specific pathways to reduce risk of HF, such as mineralocorticoid receptor agonists (e.g., fineronone), angiotensin-receptor/neprolysin inhibitors, and sodium glucose co-transporter-2 inhibitors. These interventions may be limited in at-risk populations who experience adverse social determinants and/or individuals who reside in rural areas. Thus, strategies like telemedicine may improve access to preventive care. Gaps in the current knowledge base for risk-based prevention of HF are highlighted to outline future research that may target approaches for risk assessment and risk-based prevention with the use of artificial intelligence, genomics-enhanced strategies, and pragmatic trials to develop a guideline-directed medical therapy approach to reduce risk among individuals with Stage A and Stage B HF.

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.

Coronary artery complications after left bundle branch area pacing: An increasingly reported issue in the era of physiologic pacing.

Coronary artery lesions related to pacemaker implantation are rare complications. With the increasing adoption of the technique of permanent transseptal pacing of the left bundle branch area pacing (LBBAP), an increase in the incidence of these complications may be expected. We report two cases of coronary lesions after permanent transeptal pacing of the LBBAP: the first with a small coronary artery fistula, and the second with an extrinsic coronary compression. Both complications occurred with stylet-driven pacing leads with extendable helix. In the first case, since the shunt volume was small and no major complications were reported, the patient was treated conservatively with good outcome. The second case required lead repositioning due to acute decompensated heart failure.

Optimal Screening for Predicting and Preventing the Risk of Heart Failure Among Adults With Diabetes Without Atherosclerotic Cardiovascular Disease: A Pooled Cohort Analysis.

BACKGROUND: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD). METHODS: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated. RESULTS: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358). CONCLUSIONS: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF.

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.

Clinical outcomes of left bundle branch area pacing: Prognosis and specific applications.

Cardiac pacing has become a widely accepted treatment strategy for bradyarrhythmia and heart failure. However, conventional right ventricular pacing (RVP) has been associated with electrical dyssynchrony, which may result in atrial fibrillation and heart failure. To achieve physiological pacing, Deshmukh et al. reported the first case of His bundle pacing (HBP) in 2000. This strategy was reported to have preserved ventricular synchronization by activating the conventional conduction system. Nonetheless, due to the anatomical location of the His bundle (HB), several issues such as high pacing thresholds, lead fixation, and early battery depletion may pose a challenge. Recently, left bundle branch area pacing (LBBAP) has emerged as a novel physiological pacing strategy to achieve conduction system pacing by capturing the left bundle branch through the deep septum. Additionally, several studies have investigated the clinical outcomes of LBBAP. In this paper, we describe the pacing parameters, QRS duration (QRSd), cardiac function, complications, and specific applications of LBBAP in recent years.

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.

Comparison of Coenzyme Q10 (Ubiquinone) and Reduced Coenzyme Q10 (Ubiquinol) as Supplement to Prevent Cardiovascular Disease and Reduce Cardiovascular Mortality.

PURPOSE OF REVIEW: According to the World Health Organization (WHO), cardiovascular disease is the leading cause of death worldwide. Heart failure has been defined as a global pandemic leading to millions of deaths. Recent research clearly approved the beneficial effect of Coenzyme Q10 supplementation in treatment and prevention of cardiovascular disease in patients with heart failure in clinical trials but did not distinguish between the oxidised form CoQ10 and reduced form CoQH2 of Coenzyme Q10. The aim of this study is to determine differences in medical application of CoQ10 and CoQH2 supplementation and evaluate the efficacy of CoQ10 and CoQH2 supplementation to prevent cardiovascular disease in patients with heart failure. RECENT FINDINGS: A PubMed search for the terms "ubiquinone" and "ubiquinol" was conducted, and 28 clinical trials were included. Our findings go along with the biochemical description of CoQ10 and CoQH2, recording cardiovascular benefits for CoQ10 and antioxidative and anti-inflammatory properties for CoQH2. Our main outcomes are the following: (I) CoQ10 supplementation reduced cardiovascular death in patients with heart failure. This is not reported for CoQH2. (II) Test concentrations leading to cardiovascular benefits are much lower in CoQ10 studies than in CoQH2 studies. (III) Positive long-term effects reducing cardiovascular mortality are only observed in CoQ10 studies. Based on the existing literature, the authors recommend CoQ10 instead of CoQH2 to treat and prevent cardiovascular disease in patients with heart failure.

20(S)-ginsenoside Rh2 inhibits angiotensin-2 mediated cardiac remodeling and inflammation associated with suppression of the JNK/AP-1 pathway.

BACKGROUND: Enhanced levels of angiotensin-2 (Ang-II) causes hypertensive heart failure (HHF) through non-hemodynamical and hemodynamical alterations. 20(S)-ginsenoside Rh2 (20(S)-Rh2) is a natural ginseng compound with numerous cardiovascular benefits. This investigation elucidates the influence of 20(S)-Rh2 on Ang-II-induced heart failure and cardiac alterations. METHODS: Ang-II was administered in C57BL/6 mice for 4 weeks to induce HHF. In the last 2 weeks of treatment, 20(S)-Rh2 was orally administered in mice to assess the potential 20(S)-Rh2 mechanism. Subsequently, RNA sequencing was carried out. RESULTS: It was indicated that 20(S)-Rh2 suppresses myocardial fibrosis, hypertrophy, and inflammation, thereby inhibiting cardiac disruption in Ang-II-challenged mice without affecting blood pressure. According to the RNA sequencing data, this cardio-protective effect was linked with the (JNK)/AP 1 pathway. 20(S)-Rh2 alleviated heart tissue and cardiomyocytes inflammation by inhibiting the Ang-II-mediated JNK/AP-1 pathway. Within cardiomyocytes, JNK or AP-1 absence abolished the anti-inflammatory effects of 20(S)-Rh2. CONCLUSION: This study investigation indicated that 20(S)-Rh2 prevents cardiovascular dysfunction induced by Ang-II induced by decreasing JNK-regulated inflammatory responses, providing evidence for its use as an efficient regimen for HHF.