The Combination of Valsartan and Spironolactone Mitigated Mitral Regurgitation-Induced Cardiac Dysfunction in a Novel Rat Model.

ABSTRACT: Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin-aldosterone system inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction, its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/d), spironolactone (80 mg/kg/d), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared with that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced heart failure.

Impact of chronic kidney disease on left atrial appendage occlusion: A meta-analysis of procedural outcomes and complications.

BACKGROUND: Patients with chronic kidney disease (CKD) experience atrial fibrillation more frequently. The balance of medical management for stroke prevention and bleeding events presents a challenging issue in CKD population. Left atrial appendage occlusion (LAAO) may be an effective solution for stroke prevention in patients who experience frequent bleeding with oral anticoagulants. However, the specific impact of CKD on the procedural success, complications, and outcomes of LAAO implantations remains underexplored. METHODS: We conducted a search of various databases for articles published before October 31, 2023. This search yielded 7 studies, comparing outcomes between CKD and non-CKD cohorts undergoing LAAO implantation. Our analysis focused on CHA2DS2-VASc scores, average eGFR, use of oral anticoagulants, procedural success rates, procedural complications, and associated outcomes. RESULTS: The meta-analysis included data from 2576 patients, with 1131 identified as having CKD. The CKD group also had higher CHA2DS2-VASc scores (4.7 ±â€…1.4 vs 4.0 ±â€…1.5; P < .001) and HAS-BLED scores (3.8 ±â€…1.1 vs 3.1 ±â€…1.0; P < .001) than the non-CKD group. CKD patients showed a nonreduction in procedural success rates and a nonsignificant increase in total complications. The risks of stroke and transient ischemic attack, major bleeding, and cardiovascular mortality were not significantly different between the 2 groups. However, a significantly lower rate of total mortality was observed in the non-CKD group (odds ratio: 0.43; 95% confidence interval, 0.32-0.60). CONCLUSION: While CKD is associated with a nonsignificant decrease in procedural success and a nonsignificant increase in complication risks, the outcomes of LAAO implantation are comparably favorable between CKD and non-CKD groups. Despite similar procedural outcomes, the CKD group exhibited a higher rate of all-cause mortality.

Assessing the diversity and determinants of health-related quality of life measures in patients with acute heart failure.

AIMS: Heart failure with reduced ejection fraction (HFrEF) significantly impacts health-related quality of life (HR-QoL). Existing HR-QoL questionnaires can show inconsistencies, potentially misrepresenting patient self-reports. This study examines the variation in HR-QoL measurement tools for HFrEF patients, identifying related determinants. METHODS AND RESULTS: We retrospectively analysed 134 hospitalized patients with acute decompensated HFrEF at a Taiwanese tertiary centre's Heart Failure Post-Acute-Care (HF-PAC) programme. Participants completed the EuroQol-5 dimension (EQ-5D) questionnaire, the EQ-5D visual analogue scale (VAS), and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Utility values were obtained from the EQ-5D questionnaire. Demographic features were depicted using descriptive statistics, while multivariate regression was used to ascertain relationships between HR-QoL measurements and determinants. Average scores for EQ-5D, MLHFQ, EQ-5D utility, and VAS were 6.1 ± 1.6, 21.8 ± 21.3, 81.7 ± 27.0, and 59.5 ± 14.6, respectively. Significant correlations were observed among the three tools. The New York Heart Association functional class showed a notable association with all tool scores. Other associations encompassed EQ-5D with coronary artery disease, mineralocorticoid receptor antagonists, and the 6 min walk test; EQ-5D VAS with chronic kidney disease; and MLHFQ with age. CONCLUSIONS: This study illuminates the variance in HR-QoL measurement tools for Taiwanese HFrEF patients. Using a range of these tools is beneficial in unveiling diverse determinants and approaching comprehensive patient-centred care. However, for a more precise HR-QoL assessment in Taiwanese HFrEF patients, recalibrating the EQ-5D-derived utility scores might be necessary, emphasizing the importance of patient-specific considerations within the HF-PAC programme.

Impact of the Integrated Activation System on Door-to-Balloon Times and Clinical Outcomes in STEMI Patients Receiving Primary PCI.

Background: The door-to-balloon (D2B) time is a critical quality measure in managing ST-segment elevation myocardial infarction (STEMI) patients receiving primary percutaneous coronary intervention (PCI). We developed an integrated STEMI activation system, named Acute Myocardial Infarction Software Aids (AMISTAD), to optimize care for STEMI patients. This study aimed to evaluate the impact of the AMISTAD system on D2B times and clinical outcomes. Methods: We retrospectively collected data of consecutive STEMI patients receiving primary PCI between July 2017 and December 2018 at a single center. The patients were categorized into AMISTAD and non-AMISTAD groups. Outcomes included D2B time, length of hospital stay, and 12-month cardiovascular outcomes. Data were analyzed using multiple regression models; subgroup and sensitivity analyses were applied to examine the robustness of the results. Results: A total of 114 STEMI patients were enrolled (38 AMISTAD, 76 non-AMISTAD). The AMISTAD group had a significantly shorter mean D2B time (66.7 ± 13.2 vs. 76.6 ± 24.9 minutes, p = 0.02) and non-significantly shorter length of hospital stay (4.7 vs. 7.2 days, p = 0.09). The 12-month cardiovascular outcomes between the two groups were not significantly different (adjusted hazard ratio 0.79, 95% confidence interval 0.30-2.09, p = 0.64). Subgroup and sensitivity analyses had consistent outcomes. Conclusions: Integrating the AMISTAD system into the STEMI workflow was associated with a reduced D2B time and shorter hospital stay. Further research involving larger cohorts and extended follow-up periods is needed to assess the generalizability and impact on cardiovascular outcomes. The AMISTAD system has the potential to improve the quality of care for STEMI patients.

Ivabradine could not decrease mitral regurgitation triggered atrial fibrosis and fibrillation compared with carvedilol.

BACKGROUND: Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta-blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta-blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model. METHODS AND RESULTS: Using a novel echo-guided mini-invasive surgery, MR was created in 12-weeks-old Sprague-Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two-week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR-induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR-induced chamber dilatation (end-systolic volume and end-diastolic volume; MR vs. MR + Carvedilol; P < 0.05) and decreased compliance (end-systolic pressure-volume relationship; MR vs. MR + Carvedilol; P < 0.05). Compared with ivabradine, a shorter duration (MR vs. MR + Carvedilol; P < 0.05) and reduced inducibility (MR vs. MR + Carvedilol and MR vs. MR + Ivabradine; P < 0.05) of AF were observed in MR rats treated with carvedilol. Similarly, reduced cardiac fibrosis and apoptosis were observed in the MR rat model in the treatment groups, especially in those treated with carvedilol (MR vs. MR + Carvedilol; P < 0.01). CONCLUSIONS: Although both ivabradine and carvedilol, at least in part, mitigated MR-induced chamber dilatation and decreased compliance, carvedilol had a better effect on reversing MR-induced cardiac fibrosis, apoptosis, and arrhythmogenesis than ivabradine. When compared with Ivabradine, MR rats treated with carvedilol exhibited a shorter duration and reduced inducibility of AF, thus providing more effective suppression of HCN4. Further investigations are required to validate our findings.

Transpulmonary Expression of Exosomal microRNAs in Idiopathic and Congenital Heart Disease-Related Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)-related PAH. METHODS AND RESULTS: During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD-related PAH. Next-generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR-21, miR-139-5p, miR-155-5p, let-7f-5p, miR-328-3p, miR-330-3p, and miR-103a-3p in patients with CHD-related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR-21 exhibited the highest expression in patients with CHD-related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD-related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR-21. Suppressing miR-21 rescued the shear stress-induced downregulation of the RAS/phosphatidylinositol 3-kinase/protein kinase B pathway, leading to a mitigation of apoptosis. CONCLUSIONS: Our study identified a pronounced expression of transpulmonary exosomal miR-21, particularly in patients with CHD-related PAH, through next-generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR-21 in the pathophysiology of PAH.

Dapagliflozin protects against doxorubicin-induced nephrotoxicity associated with nitric oxide pathway-A translational study.

Doxorubicin (Dox) is a potent anticancer agent, but its associated organ toxicity, including nephrotoxicity, restricts clinical applications. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, has been shown to slow the progression of kidney disease in patients with and without diabetes. However, the effect of DAPA to counteract Dox-induced nephrotoxicity remains uncertain. Therefore, in this study, we aimed to elucidate the effects of DAPA in mitigating Dox-induced nephrotoxicity. We analyzed the Taiwan National Health Insurance Database to evaluate the incidence of renal failure among breast cancer patients receiving Dox treatment compared to those without. After adjusting for age and comorbidities, we found that the risk of renal failure was significantly higher in Dox-treated patients (incidence rate ratio, 2.45; confidence interval, 1.41-4.26; p = 0.0014). In a parallel study, we orally administered DAPA to Sprague-Dawley rats for 6 weeks, followed by Dox for 4 weeks. DAPA ameliorated Dox-induced glomerular atrophy, renal fibrosis, and dysfunction. Furthermore, DAPA effectively suppressed Dox-induced apoptosis and reactive oxygen species production. On a cellular level, DAPA in HK-2 cells mitigated Dox-mediated suppression of the endothelial NOS pathway and reduced Dox-induced activities of reactive oxygen species and apoptosis-associated proteins. DAPA improved Dox-induced apoptosis and renal dysfunction, suggesting its potential utility in preventing nephrotoxicity in patients with cancer undergoing Dox treatment.

Sodium-Glucose Cotransporter 2 Inhibitors First Strategy Improve Decongestion in Patients with Symptomatic Heart Failure and Reduced Ejection Fraction When Compared to Angiotensin Receptor Neprilysin Inhibitor First Strategy.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. METHODS: From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician's choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. RESULTS: In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49-100] days vs. 112 [86-138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319-2507] pg/mL vs. 570 [206-1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. CONCLUSIONS: In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.

Comparing Vitamin K Antagonists and Direct Oral Anticoagulants in Patients With Atrial Fibrillation Undergoing Transcatheter Aortic Valve Replacement: A Meta-Analysis.

Aortic stenosis (AS) is the most prevalent valvular disease in the elderly population and the prevalence of atrial fibrillation (AF) increases in the elderly population. Transcatheter aortic valve replacement (TAVR) becomes an important treatment for patients with AS at high surgical risk. This metanalysis aimed to compare the efficacy and safety of vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) in patients with AF undergoing TAVR. We searched the different databases for articles published before January 31, 2022. In total, 7 studies including 25,255 patients were analyzed. Data on demographics, comorbidities, CHA2DS2-VASc score, Society of Thoracic Surgeons (STS) score, and incidences of all-cause mortality, major bleeding, intracranial hemorrhage (ICH), stroke, and thromboembolic events were obtained and analyzed. The VKA group had a lower CHA2DS2-VASc score (3.2 ± 1.2 vs 3.3 ± 1.2; P < .001) and a higher STS score (6.6 ± 3.2 vs 6.1 ± 2.9; P < .001) than the DOAC group. The risks of all-cause mortality (odds ratio [OR]: 0.88; 95% confidence interval [CI], 0.67-1.16), ischemic stroke (OR: 1.06; 95% CI, 0.90-1.24), and thromboembolism (OR: 1.24; 95% CI, 0.63-2.47) in the DOAC group were comparable to the VKA group. The risks of major bleeding (OR: 0.77; 95% CI, 0.71-0.84) and ICH (OR: 0.62; 95% CI, 0.42-0.90) were lower in the DOAC group compared to the VKA group. DOACs were associated with lower risks of major bleeding and ICH, and comparable risks of all-cause mortality, ischemic stroke, and thromboembolism in patients with AF undergoing TAVR compared to VKAs.

Mineralocorticoid Receptor Antagonists Mitigate Mitral Regurgitation-Induced Myocardial Dysfunction.

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can ameliorate degenerative MR remains unknown. Herein, we investigate the efficacy of spironolactone in improving cardiac remodeling in MR-induced HF compared with that of a loop diuretic, furosemide. Using a novel and mini-invasive technique, we established a rat model of MR. We treated the rats with spironolactone or furosemide for twelve weeks. The levels of cardiac fibrosis, apoptosis, and stress-associated proteins were then measured. In parallel, we compared the cardiac remodeling of 165 patients with degenerative MR receiving either spironolactone or furosemide. Echocardiography was performed at baseline and at six months. In MR rats treated with spironolactone, left ventricular function-especially when strained-and the pressure volume relationship significantly improved compared to those of rats treated with furosemide. Spironolactone treatment demonstrated significant attenuation of cardiac fibrosis and apoptosis in left ventricular tissue compared to furosemide. Further, spironolactone suppressed the expression of apoptosis-, NADPH oxidase 4 (NOX4)- and inducible nitric oxide synthase (iNOS)-associated proteins. Similarly, compared with MR patients receiving furosemide those prescribed spironolactone demonstrated a trend toward reduction in MR severity and showed improvement in left ventricular function. Collectively, MR-induced cardiovascular dysfunction, including fibrosis and apoptosis, was effectively attenuated by spironolactone treatment. Our findings suggest a potential therapeutic option for degenerative MR-induced HF.

Regular use of aspirin is associated with a lower cardiovascular risk in prostate cancer patients receiving gonadotropin-releasing hormone therapy.

Gonadotropin-releasing hormone (GnRH) therapy has been known to increase risks of major adverse cardiovascular and cerebrovascular events (MACCEs). Herein, we aim to estimate whether regular use of aspirin attenuates risks of MACCEs in prostate cancer patients receiving GnRHs. Using Taiwanese National Health Insurance Research Database (NHIRD), we identified 7719 patients diagnosed with prostate cancer who were either aspirin-naïve, received irregular or regular aspirin from 2008 to 2015. Through a multivariable logistic regression model, we investigated the impact of aspirin on MACCEs. Compared with nonusers and irregular users, most patients receiving regular aspirin were older and had more comorbidities. The crude incidence of one-year MACCEs was lowest in aspirin nonusers but highest in irregular users of aspirin compared with regular users of aspirin (2.65% vs. 4.41% vs. 2.85%, p=0.0099). After adjusting for age, cancer stage and comorbidities, irregular aspirin users had a higher risk of one-year MACCEs (adjusted OR: 1.33; 95% CI: 0.93-1.90, p=0.1139) than aspirin nonusers, but conversely, there was a trend of reducing the risk of MACCEs among those who received regular aspirin (adjusted OR: 0.79; 95% CI: 0.44-1.42, p=0.4256). In the subgroup analysis, there were age- and cancer stage-independent higher risks of MACCEs in patients who took aspirin irregularly compared to those in patients who did not take aspirin. The risks were attenuated in patients receiving regular aspirin. Collectively, regular use of aspirin presented a trend of reducing risks of MACCEs in prostate cancer patients receiving GnRHs. However, irregular use of aspirin diminished the benefits.

miR-21 upregulation exacerbates pressure overload-induced cardiac hypertrophy in aged hearts.

Young and aging hearts undergo different remodeling post pressure overload, but the regulator that determines responses to pressure overload at different ages remains unknown. With an angiotensin II (Ang II)-induced hypertensive model, miR-21 knockout mice (miR-21-/-) were observed regarding the effects of miR-21 on hypertension-induced cardiac remodeling in young (12 week-old) and old (50 week-old) mice. Although the aged heart represented a more significant hypertrophy and was associated with a higher expression of miR-21, Ang II-induced cardiac hypertrophy was attenuated in miR-21-/- mice. Upon results of cardiac-specific arrays in miR-21-overexpressing cardiomyocytes, we found a significant downregulation of S100a8. In both in vitro and in vivo models, miR-21/S100a8/NF-κB/NFAT pathway was observed to be associated with pressure overload-induced hypertrophic remodeling in aged hearts. To further investigate whether circulating miR-21 could be a biomarker reflecting the aged associated cardiac remodeling, we prospectively collected clinical and echocardiographic information of patients at young (<65 y/o) and old ages (≥65 y/o) with and without hypertension. Among 108 patients, aged subjects presented with a significantly higher expression of circulating miR-21, which was positively correlated with left ventricular wall thickness. Collectively, miR-21 was associated with a prominently hypertrophic response in aged hearts under pressure overload. Further studies should focus on therapeutic potentials of miR-21.

An artificial intelligence approach for predicting cardiotoxicity in breast cancer patients receiving anthracycline.

Although anti-cancer therapy-induced cardiotoxicity is known, until now it lacks a reliable risk predictive model of the subsequent cardiotoxicity in breast cancer patients receiving anthracycline therapy. An artificial intelligence (AI) with a machine learning approach has yet to be applied in cardio-oncology. Herein, we aimed to establish a predictive model for differentiating patients at a high risk of developing cardiotoxicity, including cancer therapy-related cardiac dysfunction (CTRCD) and symptomatic heart failure with reduced ejection fraction. This prospective single-center study enrolled patients with newly diagnosed breast cancer who were preparing for anthracycline therapy from 2014 to 2018. We randomized the patients into a 70%/30% split group for ML model training and testing. We used 15 variables, including clinical, chemotherapy, and echocardiographic parameters, to construct a random forest model to predict CTRCD and heart failure with a reduced ejection fraction (HFrEF) during the 3-year follow-up period (median, 30 months). Comparisons of the predictive accuracies among the random forest, logistic regression, support-vector clustering (SVC), LightGBM, K-nearest neighbor (KNN), and multilayer perceptron (MLP) models were also performed. Notably, predicting CTRCD using the MLP model showed the best accuracy compared with the logistic regression, random forest, SVC, LightGBM, and KNN models. The areas under the curves (AUC) of MLP achieved 0.66 with the sensitivity and specificity as 0.86 and 0.53, respectively. Notably, among the features, the use of trastuzumab, hypertension, and anthracycline dose were the major determinants for the development of CTRCD in the logistic regression. Similarly, MLP, logistic regression, and SVM also showed higher AUCs for predicting the development of HFrEF. We also validated the AI prediction model with an additional set of patients developing HFrEF, and MLP presented an AUC of 0.81. Collectively, an AI prediction model is promising for facilitating physicians to predict CTRCD and HFrEF in breast cancer patients receiving anthracycline therapy. Further studies are warranted to evaluate its impact in clinical practice.

Deletion of MicroRNA-21 Impairs Neovascularization Following Limb Ischemia: From Bedside to Bench.

With an increasing prevalence, peripheral arterial disease (PAD), cause by atherosclerosis is a new threat to public health beyond coronary artery disease and involves aberrant vascular endothelial cell proliferation and angiogenesis. The degree of vascular remodeling is influenced by the processes described. MicroRNA-21 (miR-21) has been found to play a critical role in cellular functions, including angiogenesis. Nevertheless, the effect of miR-21 on endothelial cells in response to hypoxia is largely unknown. Using wild-type C57BL/6J and miR-21-/- mice, we compared the capability of angiogenesis in response to hindlimb hypoxic/ischemia. In an in vitro study, we further studied whether overexpression of miR-21 mitigates hypoxia-induced apoptosis and impaired angiogenesis. Also, we prospectively collected the sera of patients with limb ischemia and followed the clinical information, including major adverse limb events (MALEs). Using laser Doppler perfusion imaging and CD31 staining, compared with miR-21-/- mice, wild-type mice expressed a significantly higher capability of angiogenesis and less apoptosis following 28 days of hindlimb hypoxic/ischemic surgery. In our in vitro study, after 24 h of hypoxia, proliferation, migration, and tube formation were significantly impaired in cells treated with the miR-21 inhibitor but rescued by the miR-21 mimic. Mechanistically, by suppressing PTEN/PI3K/AKT, miR-21 promoted angiogenesis and suppressed apoptosis in endothelial cells post hypoxia. In patients with limb ischemia, the high expression of circulating miR-21 was associated with less subsequent MALE. Collectively, miR-21 could be a biomarker associated with the endogenous ability of angiogenesis and reflect subsequent MALE in patients. Additionally, abolishing miR-21 impairs angiogenesis and promotes apoptosis post limb ischemia. Further studies are required to elucidate the clinical applications of miR-21.

Association of Gonadotropin-Releasing Hormone Therapies With Venous Thromboembolic Events in Patients With Prostate Cancer: A National Cohort Study.

Although androgen deprivation therapy (ADT) has been proposed to be associated with a higher risk of venous thromboembolisms (VTEs), whether gonadotropin-releasing hormones (GnRHs), such as both agonists and antagonists, are also associated with VTEs remain unclear. Using the Taiwan Cancer Registry (TCR) linked with the National Health Insurance Research Database, we identified patients diagnosed with prostate cancer from 2008 to 2015. Patients who received GnRH were 1:1 propensity score matched with non-GnRH users by age and cancer stage at diagnosis and clinical stage. Cox regression analysis was applied to estimate the incidences of VTEs with death as a competing event at the 5-year follow-up. The VTE incidence among GnRH users was 1.13% compared with 0.98% among non-users. After adjusting with potential confounding factors, the risk of VTEs showed borderline statistical significance among GnRH users and non-users. Notably, in the subgroup analysis among patients receiving GnRH therapy, those younger than 70 years old or at an earlier stage (stage I/II) were at a higher risk of VTEs. Different from previous studies, our findings highlighted critical concerns regarding the cardiac safety of GnRH therapies in prostate cancer patients at a relatively younger age or at an earlier stage.

Dapagliflozin protects against doxorubicin-induced cardiotoxicity by restoring STAT3.

Doxorubicin (Dox), an effective therapy in different types of cancer, is known to exhibit cardiotoxic effects. Despite previous studies indicating the benefits of dapagliflozin (DAPA) in patients experiencing heart failure, it remains uncertain whether DAPA exerts a protective effect on Dox-induced cardiac dysfunction. Signal transducer and activator of transcription 3 (STAT3) participates in various mechanisms of cardioprotection. Herein, we aimed to investigate the effects of DAPA on Dox-induced cardiotoxicity and the role of STAT3. Sprague-Dawley rats were pretreated with oral DAPA for 6 weeks followed by Dox for 4 weeks. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes were treated with 10 µM DAPA and subsequently exposed to 1 µM Dox. The expression of reactive oxygen species- and apoptosis-related proteins was measured. Using STAT3 siRNA, we further examined the effects of STAT3 effect on DAPA-associated protection against Dox-induced apoptosis. In rats treated with Dox, DAPA significantly reduced cardiac fibrosis and improved cardiac function and hemodynamics. Additionally, DAPA effectively inhibited Dox-induced apoptosis and reactive oxygen species (ROS) in cardiomyocytes. Mechanistically, we showed that DAPA decreased cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2 expression. DAPA also significantly rescued Dox-suppressed STAT3 expression. Conversely, knocking down STAT3 in cardiomyocytes reversed the DAPA-related protective effects on Dox-induced cell apoptosis and ROS. Collectively, our findings indicate that DAPA could be useful for preventing Dox-induced cardiotoxicity by restoring STAT3.

Dynamic Changes in miR-21 Regulate Right Ventricular Dysfunction in Congenital Heart Disease-Related Pulmonary Arterial Hypertension.

Right ventricular (RV) failure is a major cause of mortality in pulmonary arterial hypertension (PAH), but its mechanism remains largely unknown. MicroRNA-21 (miR-21) is involved in flow-mediated stress in the vasculature, but its effects on RV remodeling require investigations. Herein, we aim to study the mechanism of miR-21 in the early (compensated) and late (decompensated) phases of PAH-induced RV dysfunction. Using aorto-venous fistula (AVS) surgery, we established a rat model of PAH. To mimic the microenvironment of PAH, we treated cardiomyocytes with flow-mediated shear stress in 6 dyne for 3 and 8 h. To evaluate whether miR-21 could be a biomarker, we prospectively collected the sera of patients with congenital heart disease- (CHD) related PAH. Additionally, clinical, echocardiographic and right heart catheterization information was collected. The primary endpoint was hospitalization for decompensated heart failure (HF). It is of note that, despite an initial increase in miR-21 expression in hypertrophic RV post AVS, miR-21 expression decreased with RV dysfunction thereafter. Likewise, the activation of miR-21 in cardiomyocytes under shear stress at 3 h was downregulated at 6 h. The downregulated miR-21 at the late phase was associated with increased apoptosis in cardiomyocytes while miR-21 mimic rescued it. Among 76 CHD-induced PAH patients, 19 who were hospitalized for heart failure represented with a significantly lower expression of circulating miR-21. Collectively, our study revealed that the upregulation of miR-21 in the early phase (RV hypertrophy) and downregulation in the late phase (RV dysfunction) under PAH triggered a biphasic regulation of cardiac remodeling and cardiomyocyte apoptosis.

Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated Cardiovascular Toxicities.

BACKGROUND: Despite the increasing prevalence of therapies utilizing immune checkpoint inhibitors (ICIs), the associated cardiovascular complications have been poorly reported. Given the fatality of ICI-related complications, especially myocarditis, optimal risk stratification to predict major adverse cardio- and cerebrovascular events (MACCEs) in patients receiving ICIs is mandatory. METHODS: We collected clinical data from patients receiving ICIs, and the primary outcomes were MACCEs, including myocarditis, heart failure, and ischemic stroke. Other systemic immune responses relating to ICIs were also recorded. The median follow-up duration was 3 years. RESULTS: Among 580 patients, the incidence of MACCEs was 3.9%. Older patients, male patients, and patients with lung cancer, liver cirrhosis, or diabetes had higher risks of MACCEs. There was no significant difference between the use of PD-1/PD-L1 inhibitors or CTLA inhibitors in terms of developing cardiovascular toxicities. The development of ICI-related MACCEs was associated with worse survival. Notably, after re-review by specialists, three patients eventually diagnosed with ICI-related myocarditis had not previously been identified. Only one was treated with pulse steroids, and none survived. The most common concomitant extracardiac immune-related adverse events were myositis/dermatitis, endocrine toxicity and hepatitis. CONCLUSIONS: Collectively, ICIs may lead to severe cardiovascular toxicities and require more attention. Early identification, proper diagnosis, and prompt treatment are pivotal for improving survival.

Comparison of Surgical or Medical Castration-Related Cardiotoxicity in Patients with Prostate Cancer.

PURPOSE: Androgen deprivation therapy (ADT) includes bilateral orchiectomy or long-acting gonadotropin-releasing hormone (GnRH) agonists/antagonists. It remains controversial with respect to ADT associated cardiovascular outcomes. Hereby, we compared the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with prostate cancer receiving either surgical castration or GnRH therapies. MATERIALS AND METHODS: Using the Taiwan Cancer Registry and Taiwan's National Health Insurance Research Database, we identified 8,413 patients receiving GnRH therapies compared with 694 receiving surgical castration from 2008 to 2017. The median followup duration was 3 years. RESULTS: The crude incidences of 3-year mortality and MACCEs were 19.90% vs 26.51% and 8.23% vs 8.65% in patients receiving GnRH therapies or surgical castration, respectively. After adjusting for age, cancer stage and comorbidities, despite no significant differences in MACCEs between groups there was a slight increase in the incidence of acute myocardial infarction (AMI) in patients receiving surgical castration compared with those receiving GnRH therapies. The mortality adjusted hazard ratios of MACCEs and AMI among patients receiving surgical castration were 1.11- and 1.8-fold higher than those receiving GnRH therapies. Notably, in subgroup analysis regarding cancer stage, patients with cancer stage IV showed the most significantly increasing risk of AMI in those receiving surgical castration compared with GnRH therapies. CONCLUSIONS: Collectively, we indicated an increased risk of AMI in patients with prostate cancer, especially in patients receiving surgical castration rather than those receiving GnRH therapies. Our findings highlight concerns regarding the cardiac safety of surgical castration compared with GnRH therapies.