Cardioprotective Effects In Patients Research Articles

Cardioprotective role of statins in breast cancer patients treated with anthracyclines and/or trastuzumab: a systematic review and meta-analysis

Abstract Background Statins may have cardioprotective effects in patients undergoing cardiotoxic chemotherapy regimens. Yet, their role in mitigating anthracycline and/or trastuzumab-induced cardiotoxicity in patients with breast cancer remains unclear. Purpose To perform a systematic review and meta-analysis to evaluate the efficacy of statins in mitigating anthracycline and/or trastuzumab-induced cardiotoxicity among patients with breast cancer. Methods We systematically searched PubMed, Embase, and Cochrane databases until January 2024 for studies comparing the efficacy of statin therapy versus no statin therapy in breast cancer patients receiving either anthracyclines, trastuzumab, or both. Cardiotoxicity was defined as per the definition of each individual study. A random-effects model was used to assess pooled risk ratios (RR) and mean differences (MD) with corresponding 95% confidence intervals. Statistical analyses were performed using Review Manager version 5.4.1. Results We included five studies, of which two were randomised trials. The pooled population comprised 1,839 anthracyclines and/or trastuzumab-treated patients with breast cancer, of whom 864 (47%) received statin therapy. In the pooled analyses, cardiotoxicity was significantly lower in the statin therapy group as compared with the no statin therapy group (RR 0.45; 95% CI 0.27 to 0.72; p=0.001; Figure 1A), additionally statin therapy was associated with a significantly lower reduction in left ventricular ejection fraction as compared with no statin therapy (MD 4.11%; 95% CI 2.68 to 5.53; p<0.00001; Figure 1B). Conclusion In this meta-analysis, statin therapy in anthracyclines and/or trastuzumab-treated patients with breast cancer was associated with lower cardiotoxicity and decline in left ventricular ejection fraction.

Febuxostat leads to better cardiovascular outcomes compared to allopurinol in patients with advanced chronic kidney disease: A Population-based Cohort Study

ObjectiveHyperuricemia is a risk factor for cardiovascular disease complications in patients with chronic kidney disease. The impact of febuxostat on cardiovascular disease in advanced chronic kidney disease remains unclear. This study aimed to explore the cardiovascular benefits of xanthine oxidase inhibitors, particularly febuxostat and allopurinol, in patients with advanced chronic kidney disease. MethodsA retrospective population-based cohort study was conducted using data from Taiwan's National Health Insurance Research Database (NHIRD) (2006–2017). The TriNetX dataset served as an external validation dataset. The study involved 13,187 patients with advanced chronic kidney disease treated with febuxostat or allopurinol. After propensity score matching, a balanced cohort of 976 patients (488 in each arm) was created. Hazard ratios (HRs) were calculated for all-cause mortality and hospitalizations, utilizing the competing risk regression model. ResultsFebuxostat was associated with lower all-cause mortality (HR, 0.79; 95% confidence interval [CI], 0.64–0.98) and fewer hospitalizations (HR, 0.53; 95% CI, 0.44–0.63) than allopurinol. After adjustments, febuxostat also reduced hospitalizations for heart failure (HR, 0.59; 95% CI, 0.43–0.80) and infection (HR, 0.65; 95% CI, 0.52–0.82). This cardiovascular benefit of febuxostat was consistently observed in the TriNetX dataset. Moreover, subgroup analysis revealed that febuxostat was better in reducing death and heart failure events than allopurinol across most of the subgroups. ConclusionsFebuxostat may confer cardioprotective effects in patients with advanced chronic kidney disease compared with allopurinol, thereby potentially useful in reducing cardiovascular risks in this high-risk population.

High-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent anthracycline cardiotoxicity: the Cardiac CARE RCT

Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met. Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy. Limitations Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded. Future work Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Effect of sex on sodium-glucose co-transporter-2 antagonists and glucagon-like peptide-1 agonists in heart failure.

Recent evidence suggests that medications not primarily targeting the cardiovascular (CV) system may have cardioprotective effects in patients with heart failure (HF), in particular the anti-diabetic therapies sodium-glucose co-transporter-2 (SGLT-2) antagonists and glucagon-like peptide-1 (GLP-1) agonists. We conducted a systematic review to assess the pooled evidence for the use of SGLT-2 antagonists and GLP-1 agonists in patients with HF and the effect of biological sex on the results. MEDLINE, Embase, Cochrane Library and clinical trial databases were searched until February 2023. Randomized controlled trials (RCTs) published in English that included adult participants with HF who were randomized to an SGLT-2 antagonist or GLP-1 agonist with a primary or secondary outcome of HF hospitalization (HFH) or CV death were eligible for inclusion. Data pooling was undertaken using a random effects model and odds ratios (ORs) to determine the association between drug and outcome. Sub-group analyses to investigate sex differences were conducted. Six RCTs were included (24781 patients). Four studies investigated SGLT-2 antagonists, and two studies examined GLP-1 agonists. SGLT-2 antagonists improved HFH {OR [95% confidence interval (CI)]: 0.69 [0.63, 0.77], P<0.001} and CV death [0.87 (0.78, 0.97), P=0.01] independent of diabetes status, with excellent homogeneity across all four studies. No beneficial effects were found for GLP-1 agonists. The effects of SGLT-2 antagonists on HFH and CV death were similar in men and women [OR (95% CI): HFH, 0.70 (0.64, 0.76), P<0.001 and 0.58 (0.46, 0.74), P<0.001, respectively; CV death, 0.86 (0.78, 0.95), P=0.003 and 0.84 (0.73, 0.96), P=0.01, respectively], and the neutral effect of GLP-1 agonists on HFH and CV death was similar in men and women (all P>0.05). SGLT-2 antagonists but not GLP-1 agonists beneficially affect HFH and CV death in patients with HF with or without diabetes. We show for the first time that GLP-1 agonists have a neutral effect on HFH and CV death in both male and female HF patients and a reduction in HFH and CV death in male and female HF patients taking SGLT-2 antagonists.

Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure

BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure.Methods26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed.ResultsSGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects.ConclusionsOur results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

Shexiang Baoxin Pill enriches Lactobacillus to regulate purine metabolism in patients with stable coronary artery disease

BackgroundIt has been clinically confirmed that the Shexiang Baoxin Pill (SBP) dramatically reduces the frequency of angina in patients with stable coronary artery disease (SCAD). However, potential therapeutic mechanism of SBP has not been fully explored. PurposeThe study explored the therapeutic mechanism of SBP in the treatment of SCAD patients. MethodsWe examined the serum metabolic profiles of patients with SCAD following SBP treatment. A rat model of acute myocardial infarction (AMI) was established, and the potential therapeutic mechanism of SBP was explored using metabolomics, transcriptomics, and 16S rRNA sequencing. ResultsSBP decreased inosine production and improved purine metabolic disorders in patients with SCAD and in animal models of AMI. Inosine was implicated as a potential biomarker for SBP efficacy. Furthermore, SBP inhibited the expression of genes involved in purine metabolism, which are closely associated with thrombosis, inflammation, and platelet function. The regulation of purine metabolism by SBP was associated with the enrichment of Lactobacillus. Finally, the effects of SBP on inosine production and vascular function could be transmitted through the transplantation of fecal microbiota. ConclusionOur study reveals a novel mechanism by which SBP regulates purine metabolism by enriching Lactobacillus to exert cardioprotective effects in patients with SCAD. The data also provide previously undocumented evidence indicating that inosine is a potential biomarker for evaluating the efficacy of SBP in the treatment of SCAD.

Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial

BackgroundSodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium.MethodsThis post hoc analysis of the EMMY trial investigated the changes in serum β-hydroxybutyrate (3-βOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-βOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio).ResultsThe mean 3-βOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-βOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-βOHB value was negatively associated with LVEF (coefficient: − 0.464, 95%CI − 0.863;− 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-βOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, − 1.170;− 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: − 2.099, − 3.443;− 0.755, 0.002; LVEDV: − 2.406, − 4.341;− 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-βOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant.ConclusionThis post hoc analysis showed that SGLT2i increased 3-βOHB levels after AMI compared to placebo. Higher baseline 3-βOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-βOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-βOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study

BackgroundNo randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups.MethodsWe identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE – MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3–4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF).ResultsWe identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex.ConclusionsThe cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

The Role of SGLT2 Inhibitors in Cardiovascular Management.

Cardiovascular disease is a major cause of morbidity and mortality worldwide in patients with type 2 diabetes. Type 2 diabetes confers an elevated risk of developing heart failure and atherosclerotic cardiovascular disease. Until recently, there have been limited options to prevent and reduce the cardiovascular complications of type 2 diabetes. However, recent therapeutic advances have led to the adoption of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in cardiovascular management. Though SGLT2i were originally used for antihyperglycemic treatment, a series of landmark trials found that SGLT2i may confer cardio-protective effects in patients with heart failure and atherosclerotic cardiovascular disease, particularly a reduction in cardiovascular mortality and hospitalizations for heart failure. The cardiovascular benefits of SGLT2i were similarly demonstrated in patients with and without type 2 diabetes. Though previous trials found SGLT2i to be cardio-protective in heart failure with reduced ejection fraction, recent trials demonstrated that SGLT2i may also provide cardiovascular benefits in heart failure with mildly reduced and preserved ejection fraction. These advances have led SGLT2i to become an instrumental component of cardiovascular therapy.

Persistence on Novel Cardioprotective Antihyperglycemic Therapies in the United States

Selected glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have cardioprotective effects in patients with type 2 diabetes mellitus (T2D) and elevated cardiovascular risk. Prescription and consistent use of these medications are essential to realizing their benefits. In a nationwide deidentified United States administrative claims database of adults with T2D, the prescription practices of GLP-1RAs and SGLT-2i were evaluated across guideline-directed co-morbidity indications from 2018 to 2020. The monthly fill rates were assessed for 12months after the initiation of therapy by calculating the proportion of days with consistent medication use. Of 587,657 subjects with T2D, 80,196 (13.6%) were prescribed GLP-1RAs and 68,149 (11.5%) SGLT-2i from 2018 to 2020, representing 12.9% and 11.6% of patients with indications for each medication, respectively. In new initiators, 1-year fill rate was 52.5% for GLP-1RAs and 52.9% for SGLT-2i, which was higher for patients with commercial insurance than those with Medicare Advantage plans for both GLP-1RAs (59.3% vs 51.0%, p<0.001) and SGLT-2i (63.4% vs 50.3%, p <0.001). After adjusting for co-morbidities, there were higher rates of prescription fills for patients with commercial insurance (odds ratio1.17, 95% confidence interval 1.06 to 1.29 for GLP-1RAs, and 1.59 [1.42 to 1.77] for SGLT-2i); and higher income (odds ratio1.09 [1.06 to 1.12] for GLP-1RAs, and 1.06 [1.03 to 1.1] for SGLT-2i). From 2018 to 2020, the use of GLP-1RAs and SGLT-2i remained limited to fewer than 1 in 8 patients with T2D and indications, with 1-year fill rates around 50%. The low and inconsistent use of these medications compromises their longitudinal health outcome benefits in a period of expanding indications for their use.

Empagliflozin ameliorates cardiac dysfunction in heart failure mice via regulating mitochondrial dynamics

Empagliflozin has cardioprotective effects in patients with heart failure (HF). However, the mechanism by which empagliflozin protects against HF remains controversial. Study aimed to evaluate the effect of empagliflozin on myocardial fibrosis and cardiac function in HF mice and its possible mechanism. C57BL/6 mice were induced with HF by ligation of the left anterior descending coronary artery. At 4 weeks postoperation, mice were randomly given normal saline or empagliflozin for 8 weeks. Echocardiography was used to assess cardiac function. Masson's staining, immunohistochemistry and Western blot analysis were used to detect the degree of myocardial fibrosis. Changes in mitochondria were detected by observing mitochondrial morphology, measuring mitochondrial dynamics-related proteins and analysing the levels of adenosine triphosphate (ATP), adenosine monophosphate (AMP) and adenosine diphosphate (ADP). The mitochondrial fission inhibitor, mdivi1, was used to detect the relationship between mitochondrial dysfunction and cardiac dysfunction in HF mice. HF led to myocardial fibrosis and cardiac dysfunction. However, treatment with empagliflozin reduced these effects. Empagliflozin inhibited mitochondrial fission and improved energy metabolic efficiency in HF mice by regulating the expression of mitochondrial dynamics-related proteins. Similarly, mdivi1 attenuated mitochondrial dysfunction and cardiac dysfunction by inhibiting mitochondrial fission in HF mice. Regulation of mitochondrial dynamics, especially inhibition of mitochondrial fission, may be a potential target for reducing cardiac damage in patients with HF. Empagliflozin improved myocardial fibrosis and cardiac dysfunction by modulating mitochondrial dynamics in HF mice. Thus, the cardiac protective effect of empagliflozin may be related to the normalization of mitochondria and the increase in ATP production.

Dapagliflozin exhibits class I antiarrhythmic effects which suppress action potential formation in human atrial cardiomyocytes

Abstract Background Recently, inhibitors of sodium-glucose transporter 2 (SGLT2i) were shown to have tremendous cardioprotective effects in patients with type 2 diabetes mellitus (T2DM) as well as heart failure (HF) patients, regardless of their glycemic status. Among other beneficial effects on cardiovascular outcome an antiarrhythmic effect of SGLT2i was indicated. In patients with T2DM therapy with SGLT2i was associated with a significantly reduced risk of atrial arrhythmias and sudden cardiac death. As sodium-glucose transporter 2 (SGLT2) is not expressed within the heart underlying molecular modes of action remain unclear. Therefore, investigating possible antiarrhythmic mechanisms is crucial to determine whether SGLT2i might be beneficial for all patients suffering from arrhythmias, regardless of other comorbidities. Purpose To assess antiarrhythmic effects of SGLT2i on a molecular and cellular level. Therefore, direct electrophysiological effects of dapagliflozin – the most advanced SGLT2i in clinical trials – on action potential (AP) formation in atrial cardiomyocytes (CM) was investigated. Methods Effects of dapagliflozin on human NaV1.5, heterologously expressed in Chinese hamster ovary (CHO) cells, was investigated using the patch-clamp method. Further, effects on voltage-gated sodium channels (NaV) were also measured in human atrial CM. Consequences of dapagliflozin treatment on AP formation were studied on isolated human and porcine atrial CM using the patch-clamp technique. APs were elicited in current-clamp mode by injection of brief current pulses. Results Dapagliflozin (100 μM) significantly decreased peak sodium currents in human atrial CM as well as CHO cells, expressing human NaV1.5 channel subunits. Additionally, half-activation potential of voltage-gated sodium channels was significantly increased after administration of dapagliflozin. Furthermore, dapagliflozin (100 μM) suppressed AP formation in CM isolated from human and porcine left and right atrial tissue. In human CM action potential amplitude (APA) was significantly reduced by 34.3%, while APA inhibition by dapagliflozin averaged out at 30.7% for porcine CM. In porcine CM action potential duration at 50% (APD50) and 90% repolarization (APD90) were also significantly reduced. Conclusion Dapagliflozin suppresses AP formation in human and porcine atrial CM by inhibiting voltage-gated sodium currents. Therefore, we suppose that dapagliflozin exhibits class I antiarrhythmic effects. Funding Acknowledgement Type of funding sources: None.

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

BackgroundMalignant 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.MethodsRats 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.ResultsHigh-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.ConclusionDAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Impact of Prior Statin Therapy on In-Hospital Outcome of STEMI Patients Treated with Primary Percutaneous Coronary Intervention.

Background: Prior statin therapy has a cardioprotective effect in patients undergoing elective or urgent percutaneous coronary intervention (PCI). However, data on patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI are still controversial. We retrospectively evaluated the effect of prior statin therapy on in-hospital clinical outcomes in consecutive STEMI patients undergoing primary PCI. Methods: A total of 1790 patients (mean age 67 ± 11 years, 1354 men) were included. At admission, all patients were interrogated about prior (>6 months) statin therapy. The primary endpoint of the study was the composite of in-hospital mortality, acute pulmonary edema, and cardiogenic shock in patients with or without prior statin therapy. Results: A total of 427 patients (24%) were on prior statin therapy. The incidence of the primary endpoint was similar in patients with or without prior statin therapy (15% vs. 16%; p = 0.38). However, at multivariate analysis, prior statin therapy was associated with a lower risk of the primary endpoint, after adjustment for major prognostic predictors (odds ratio 0.61 [95% CI 0.39–0.96]; p = 0.03). Conclusions: This study demonstrated that prior statin therapy is associated with a better in-hospital clinical outcome in patients with STEMI undergoing primary PCI compared to those without prior statin therapy.

Cardioprotection of Repeated Remote Ischemic Conditioning in Patients With ST-Segment Elevation Myocardial Infarction.

BackgroundRepeated remote ischemic conditioning (RIC) after myocardial infarction (MI) has been shown to improve left ventricular (LV) remodeling in the experimental studies, but its cardioprotective effect in patients with ST-segment elevation myocardial infarction (STEMI) is still unknown.ObjectiveTo investigate whether repeated RIC started early after primary percutaneous coronary intervention (PCI) can improve LV function in patients with STEMI.MethodsPatients with STEMI treated by primary PCI were included and randomized to the repeated RIC group (n = 30) or the control group (n = 30). RIC was started within 24 h after PCI and repeated daily for 1 week, using an Auto RIC device. 3D speckle-tracking echocardiography (STE) was used to assessed LV function. The primary study endpoint was the change in LV global longitudinal strain (GLS) from baseline to 1 month after PCI.ResultsThe repeated RIC group and the control group were well-matched at baseline including mean GLS (−9.8 ± 2.6% vs. −10.1 ± 2.5%, P = 0.62). Despite there was no significant difference in mean GLS at 1 month between the two groups (−11.9 ± 2.1% vs. −10.9 ± 2.7%, P = 0.13), the mean change in GLS from baseline to 1 month was significantly higher in the treatment group than in the control group (−2.1 ± 2.5% vs. −0.8 ± 2.3%, P = 0.04). There were no significant differences in the changes in global circumferential strain (GCS), global area strain (GAS), global radial strain (GRS), LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) between the two groups. Peak creatine kinase isoenzyme-MB, peak high-sensitivity troponin T, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at 24 h after PCI did not differ significantly between the two groups, but NT-proBNP levels at 1 week were significantly lower in the treatment group than in the control group [357.5 (184.8–762.8) vs. 465.0 (305.8–1525.8) pg/ml, P = 0.04].ConclusionDaily repeated RIC started within 24 h after PCI can improve GLS and reduce plasma NT proBNP levels in patients with STEMI.

Effects of transcutaneous electrical nerve stimulation on myocardial protection in patients undergoing aortic valve replacement: a randomized clinical trial

BackgroundCardiopulmonary bypass-related myocardial ischemia-reperfusion injury is a major contributor to postoperative morbidity. Although transcutaneous electrical nerve stimulation (TENS) has been found to have cardioprotective effects in animal studies and healthy volunteers, its effects on cardiac surgery under cardiopulmonary bypass patients have not been evaluated. We investigated the effects of TENS on myocardial protection in patients undergoing aortic valve replacement surgery using cardiopulmonary bypass.MethodsThirty patients were randomized to receive TENS or sham in three different anesthetic states – pre-anesthesia, sevoflurane, or propofol (each n = 5). TENS was applied with a pulse width of 385 μs and a frequency of 10 Hz using two surface electrodes at the upper arm for 30 min. Sham treatment was provided without stimulation. The primary outcome was the difference in myocardial infarct size following ischemia-reperfusion injury in rat hearts perfused with pre- and post-TENS plasma dialysate obtained from the patients using Langendorff perfusion system. The cardioprotective effects of TENS were determined by assessing reduction in infarct size following treatment.ResultsThere were no differences in myocardial infarct size between pre- and post-treatment in any group (41.4 ± 4.3% vs. 36.7 ± 5.3%, 39.8 ± 7.3% vs. 27.8 ± 12.0%, and 41.6 ± 2.2% vs. 37.8 ± 7.6%; p = 0.080, 0.152, and 0.353 in the pre-anesthesia, sevoflurane, and propofol groups, respectively).ConclusionsIn our study, TENS did not show a cardioprotective effect in patients undergoing aortic valve replacement surgery.Trial registrationThis study was registered at clinicaltrials.gov (NCT03859115, on March 1, 2019).

Effects of ischaemic postconditioning in aortic valve replacement: a multicenter randomized controlled trial.

The effect of ischaemic postconditioning (IPost) on postcardioplegic cardiac function is not known. We hypothesized that IPost was cardioprotective in adult patients undergoing elective aortic valve replacement. In a multicentre, prospective, randomized trial, patients (n = 209) were randomized to either a standard operation (controls) or postconditioning. Immediately before the cross-clamp was released, patients in the postconditioning group underwent 3 cycles of flow/non-flow (2 min each) of normothermic blood via the antegrade cardioplegia line. The primary end point was cardiac index. Secondary end points included additional haemodynamic measurements, biomarkers of cardiomyocyte injury, renal function parameters, intra- and postoperative arrhythmias and use of inotropic agents. There was no significant difference between the groups regarding cardiac index [mean between-group difference, 95% confidence interval (CI), 0.11 (-0.1 to 0.3), P = 0.27]. Postconditioning had no effect on other haemodynamic parametres. There was no between-group difference regarding troponin T or creatine kinase MB. Postconditioning reduced the relative risk for arrhythmias by 45% (P = 0.03) when postoperative atrial fibrillation and intraoperative ventricular fibrillation were combined. There were no differences in patients with/without diabetes, patients above/below 70 years of age or between the centres. However, after postconditioning, the cardiac index [95% CI, 0.46 (0.2-0.7), P = 0.001], cardiac output (P < 0.001), mean arterial pressure (P < 0.001) and left ventricular stroke work index (P < 0.001) were higher in males compared to females. IPost had no overall cardioprotective effects in patients undergoing aortic valve replacement but improved postoperative cardiac performance in men compared to women.

987-P: Comparative Cardiovascular (CV) Effectiveness of SGLT2 Inhibitors (SGLT2i) and GLP-1 Receptor Agonists (GLP-1 RA) in Patients with Type 2 Diabetes Mellitus (T2DM): A Large National Database Study

Introduction: SGLT2i (S) and GLP-1 RA (G) are both known to have well established cardio protective effects in patients with T2DM. However, the comparative CV efficacy of these drugs is not well known.Methods: We used a national hospital-based database (Explorys Inc, IBM) to compare the CV outcomes (CVO) among patients receiving S or G. T2DM patients were divided in 3 groups- combination therapy (G+S), only G and only S. First, CVO were compared among G+S and the other two. Subsequently G and S were compared amongst themselves. OR and 95% CI were calculated for these CVO [(combination of acute MI (AMI), acute stroke (CVA), and acute HF (AHF)].Results: G+S therapy (N= 59410) resulted in lower CVO when compared to isolated therapy with G (N = 143690) [3.4 % vs. 6.2%, OR 0.54 (0.51-0.56)] or S (N= 212560) [3.4 % vs. 6.7%, OR 0.50 (0.47-0.52)] (Table 1). Additionally, G had a slightly better outcome profile than S ([6.2 % vs. 6.7%, OR 0.92 (0.90-0.95)].Conclusion: Combination therapy of SGLT2i and GLP-1 RA confers the highest CV risk mitigation when compared to isolated therapy (50% reduction in relative risk). Furthermore, isolated therapy with GLP-1 fared better than SGLT-2i. The latter was driven by a reduction in AMI and CVA. Heart failure outcomes were similar among the two. Prospective studies are needed to confirm these findings.View largeDownload slideView largeDownload slide DisclosureO. A. Alaber: None. A. K. Chandar: None. A. Singh: None. A. Smer: None. N. Manivannan: None. S. A. Pitts: None. A. Rajpal: None.

Effect of nicorandil treatment adjunctive to percutaneous coronary intervention in patients with acute myocardial infarction: a systematic review and meta-analysis.

ObjectiveThere is controversy whether nicorandil treatment has cardioprotective effects in patients with acute myocardial infarction (AMI) following percutaneous coronary intervention (PCI). This meta-analysis was conducted to assess the efficacy of nicorandil on functional and clinical outcomes after PCI.MethodsSystematic databases were searched to retrieve studies that compared the effect of nicorandil with a control group in patients with AMI who underwent PCI. Outcomes related to coronary blood flow, and functional and clinical outcomes were extracted and a meta-analysis was performed. Trial sequential analysis was conducted to estimate the required sample size for statistical power.ResultsTwenty-four trials involving 2965 patients with AMI were enrolled. Pooled results showed that nicorandil treatment significantly suppressed the incidence of no-reflow phenomenon and reperfusion arrhythmia after reperfusion, improved the left ventricular ejection fraction and left ventricular end-systolic volume index, and reduced major adverse cardiovascular events and cardiovascular death. Trial sequential analysis confirmed the effect of nicorandil in reducing the incidence of no-reflow phenomenon and follow-up major adverse cardiovascular events in patients with AMI after PCI.ConclusionOur findings suggest that nicorandil treatment adjunctive to reperfusion therapy improves myocardial reperfusion, cardiac function, and clinical outcomes in patients with AMI.

Sodium-glucose cotransporter2 inhibitors: A drug with antidiabetic and cardioprotective properties.

Recently, two large double-blind randomized controlled trials testing the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure with and without diabetes have led to a paradigm shift for the indication of this class of drugs. Key clinical features and main results in these two studies are summarized in Table 1 and 2. The dapagliflozin and prevention of adverse outcomes in heart failure (DAPA-HF) trial included 4744 patients with heart failure and a reduced ejection fraction (HFrEF).