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.

Real-time artificial intelligence predicts adverse outcomes in acute pancreatitis in the emergency department: Comparison with clinical decision rule.

OBJECTIVE: Artificial intelligence (AI) prediction is increasingly used for decision making in health care, but its application for adverse outcomes in emergency department (ED) patients with acute pancreatitis (AP) is not well understood. This study aimed to clarify this aspect. METHODS: Data from 8274 ED patients with AP in three hospitals from 2009 to 2018 were analyzed. Demographic data, comorbidities, laboratory results, and adverse outcomes were included. Six algorithms were evaluated, and the one with the highest area under the curve (AUC) was implemented into the hospital information system (HIS) for real-time prediction. Predictive accuracy was compared between the AI model and Bedside Index for Severity in Acute Pancreatitis (BISAP). RESULTS: The mean ± SD age was 56.1 ± 16.7 years, with 67.7% being male. The AI model was successfully implemented in the HIS, with Light Gradient Boosting Machine (LightGBM) showing the highest AUC for sepsis (AUC 0.961) and intensive care unit (ICU) admission (AUC 0.973), and eXtreme Gradient Boosting (XGBoost) showing the highest AUC for mortality (AUC 0.975). Compared to BISAP, the AI model had superior AUC for sepsis (BISAP 0.785), ICU admission (BISAP 0.778), and mortality (BISAP 0.817). CONCLUSIONS: The first real-time AI prediction model implemented in the HIS for predicting adverse outcomes in ED patients with AP shows favorable initial results. However, further external validation is needed to ensure its reliability and accuracy.

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.

Utility of the ACD-GENE-CLI Score in Asian Patients with Critical Limb Ischemia Undergoing Endovascular Interventions.

AIMS: Critical limb ischemia (CLI) is an emerging public health threat and lacks a reliable score for predicting the outcomes. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD-GENE) risk score helps identify patients with coronary artery disease who have cytochrome P450 2C19 (CYP2C19) polymorphism-related drug resistance and are at risk for cardiovascular adverse events. However, its application to CLI remains unknown. In this study, we aim to validate a modified ACD-GENE-CLI score to improve the prediction of major adverse limb events (MALEs) in patients with CLI receiving clopidogrel. METHODS: Patients with CLI receiving clopidogrel post-endovascular intervention were enrolled prospectively in two medical centers. Amputation and revascularization as MALEs were regarded as the outcomes. RESULTS: A total of 473 patients were recruited, with a mean follow-up duration of 25 months. Except for obesity, old age, diabetes, chronic kidney disease (CKD), and CYP2C19 polymorphisms were significantly associated with MALEs. Using bootstrap regression analysis, we established a modified risk score (ACD-GENE-CLI) that included old age (≥ 65 years), diabetes, CKD, and CYP2C19 polymorphisms. At a cutoff value of 8, the ACD-GENE-CLI score was superior to the CYP2C19 deficiency only, and the conventional ABCD-GENE score in predicting MALEs (area under the curve: 0.69 vs. 0.59 vs. 0.67, p=0.01). The diagnostic ability of the ACD-GENE-CLI score was consistent in the external validation. Also, Kaplan-Meier curves showed that in CYP2C19 deficiency, the ABCD-GENE and ACD-GENE-CLI scores could all differentiate patients with CLI who are free from MALEs. CONCLUSIONS: The modified ACD-GENE-CLI score could differentiate patients with CLI receiving clopidogrel who are at risk of MALEs. Further studies are required to generalize the utility of the score.

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.

Assessment of subclinical cardiac dysfunction by speckle-tracking echocardiography among people living with human immunodeficiency virus.

Background: People living with HIV (PLWH) have an increased risk of developing cardiovascular diseases (CVD). As speckle-tracking echocardiography (STE) has been used to detect subclinical myocardial abnormalities, this study aims to detect early cardiac impairment among Asian PLWH using STE and to investigate the associated risk factors. Methods: We consecutively recruited asymptomatic PLWH without previous CVD from a medical center of Taiwan, and their cardiac function was evaluated by conventional echocardiogram and STE. Enrolled PLWH were classified as antiretroviral therapy (ART)-experienced and ART-naive, and multivariable regressions were used to assess the association between myocardial strain and risk factors including traditional CVD and HIV-associated factors. Results: A total of 181 PLWH (mean age: 36.4 ± 11.4 years, 173 males) were recruited and conventional echocardiogram parameters were within normal ranges. Decreased myocardial strain across the myocardium was found, with a mean left ventricular (LV) global longitudinal strain of -18.7 ± 2.9%. The LV strain in the ART-experienced group (-19.0 ± 2.9%) was significantly better than the ART-naive group (-17.9 ± 2.8%), despite a younger age and lesser CVD risk factors in the ART-naive group. Hypertension [B = 1.92, 95% confidence interval (95% CI) 0.19-3.62, p = 0.029] and ART-naive with both low and high viral loads (VL) (B = 1.09, 95% CI 0.03-2.16, p = 0.047; and B = 2.00, 95% CI, 0.22-3.79, p = 0.029) were significantly associated with reduced myocardial strain. Conclusion: This is the first and largest cohort using STE to investigate myocardial strain in Asian PLWH. Our results suggest that hypertension and detectable VL are associated with impaired myocardial strain. Thus, timely ART administration with VL suppression and hypertension control are crucial in preventing CVD when making the management parallel with the improved life expectancy of PLWH on ART.

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.

2023 Guidelines of the Taiwan Society of Cardiology on the Diagnosis and Management of Chronic Coronary Syndrome.

Coronary artery disease (CAD) covers a wide spectrum from persons who are asymptomatic to those presenting with acute coronary syndromes (ACS) and sudden cardiac death. Coronary atherosclerotic disease is a chronic, progressive process that leads to atherosclerotic plaque development and progression within the epicardial coronary arteries. Being a dynamic process, CAD generally presents with a prolonged stable phase, which may then suddenly become unstable and lead to an acute coronary event. Thus, the concept of "stable CAD" may be misleading, as the risk for acute events continues to exist, despite the use of pharmacological therapies and revascularization. Many advances in coronary care have been made, and guidelines from other international societies have been updated. The 2023 guidelines of the Taiwan Society of Cardiology for CAD introduce a new concept that categorizes the disease entity according to its clinical presentation into acute or chronic coronary syndromes (ACS and CCS, respectively). Previously defined as stable CAD, CCS include a heterogeneous population with or without chest pain, with or without prior ACS, and with or without previous coronary revascularization procedures. As cardiologists, we now face the complexity of CAD, which involves not only the epicardial but also the microcirculatory domains of the coronary circulation and the myocardium. New findings about the development and progression of coronary atherosclerosis have changed the clinical landscape. After a nearly 50-year ischemia-centric paradigm of coronary stenosis, growing evidence indicates that coronary atherosclerosis and its features are both diagnostic and therapeutic targets beyond obstructive CAD. Taken together, these factors have shifted the clinicians' focus from the functional evaluation of coronary ischemia to the anatomic burden of disease. Research over the past decades has strengthened the case for prevention and optimal medical therapy as central interventions in patients with CCS. Even though functional capacity has clear prognostic implications, it does not include the evaluation of non-obstructive lesions, plaque burden or additional risk-modifying factors beyond epicardial coronary stenosis-driven ischemia. The recommended first-line diagnostic tests for CCS now include coronary computed tomographic angiography, an increasingly used anatomic imaging modality capable of detecting not only obstructive but also non-obstructive coronary plaques that may be missed with stress testing. This non-invasive anatomical modality improves risk assessment and potentially allows for the appropriate allocation of preventive therapies. Initial invasive strategies cannot improve mortality or the risk of myocardial infarction. Emphasis should be placed on optimizing the control of risk factors through preventive measures, and invasive strategies should be reserved for highly selected patients with refractory symptoms, high ischemic burden, high-risk anatomies, and hemodynamically significant lesions. These guidelines provide current evidence-based diagnosis and treatment recommendations. However, the guidelines are not mandatory, and members of the Task Force fully realize that the treatment of CCS should be individualized to address each patient's circumstances. Ultimately, the decision of healthcare professionals is most important in clinical practice.

Economic evaluation of new blood pressure target for hypertensive patients in Taiwan according to the 2022 hypertension clinical practice guidelines of the Taiwan society of cardiology: a simulation modeling study.

With the promising cardiovascular benefits in the STEP and SPRINT trials, the 2022 Taiwan's hypertension guidelines redefined the hypertension threshold as 130/80 mmHg and a universal blood-pressure target of <130/80 mmHg. This study's objective was to examine the cost-effectiveness of the intensive blood-pressure target for hypertensive patients using estimated lifetime medical costs and quality-adjusted life years (QALY) from the Taiwan national payer's perspective. We developed a lifetime Markov model comparing the intensive and conservative blood-pressure targets. Incremental cost-effectiveness ratio (ICER) against the willing-to-pay thresholds at the one-time [US$34,000(NT$1,020,000)] and three-time [US$100,000(NT$3,000,000)] gross domestic product per capita were defined as very cost-effect and only cost-effective. The cost-effectiveness in different age stratifications and cardiovascular risks treated with a more intensive target (120 mmHg) were examined in the subgroup analyses. The new blood-pressure treatment target produced more lifetime medical costs [US$31,589(NT$947,670) versus US$26,788(NT$803,640)] and QALYs (12.54 versus 12.25), and the ICER was US$16,589(NT$497,670), which was 99.1% and 100% probability of a very cost-effective and cost-effective strategy. The ICERs in all age stratifications had more than a 90% probability of being very cost-effective, and ICERs decreased with age. More intensive control in patients with high cardiovascular risks produced a lower ICER [US$14,547(NT$436,410)]. In conclusion, Taiwan's new blood-pressure treatment target can prevent more cardiovascular events with acceptable costs per QALY below the willing-to-pay thresholds. The cost-effectiveness of intensive control is consistent across different ages and more pronounced with the increase in age and cardiovascular risk.

The Efficacy and Safety of Short-Term Tolvaptan Usage in Patients with Acute Decompensated Heart Failure.

Background: Patients admitted with acute decompensated heart failure (ADHF) have a poor prognosis and poor quality of life due to dyspnea and edema. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective water diuretic. This study aimed to evaluate the efficacy and safety of a short course of tolvaptan to treat volume overload in patients with ADHF. Methods: We conducted a phase III, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a short course of tolvaptan (15 mg/day for 4 days) in hospitalized ADHF patients with volume overload despite the use of conventional diuretics. The primary end-point was the change in body weight after 4 days of treatment. The secondary end-points were the change in intake/output balance, change in serum sodium/potassium concentrations, physician/patient assessed signs and symptoms of heart failure after 4 days of treatment, and all-cause mortality in 1 month. Results: A total of 110 patients were screened, and 91 were randomized to receive 15 mg/day of tolvaptan for 4 days (n = 46) or matching placebo (n = 45). Compared to the placebo-treated patients, tolvaptan significantly reduced body weight (-1.36 ± 2.13 kg in the tolvaptan group vs. -0.59 ± 1.27 kg in the placebo group, p = 0.0394). The tolvaptan group also had a negative intake/urine volume balance compared to the placebo group (-509.3 ± 2788.2 ml vs. 975.5 ± 1903.1 ml, p = 0.0059). The safety profile of tolvaptan was acceptable. Conclusions: Tolvaptan significantly reduced volume overload in hospitalized ADHF patients with volume overload despite the use of conventional diuretics.

Does AI explainability affect physicians' intention to use AI?

BACKGROUND: Artificial Intelligence (AI) is increasingly being developed to support clinical decisions for better health service quality, but the adoption of AI in hospitals is not as popular as expected. A possible reason is that the unclear AI explainability (XAI) affects the physicians' consideration of adopting the model. PURPOSE: To propose and validate an innovative conceptual model aimed at exploring physicians' intention to use AI with XAI as an antecedent variable of technology trust (TT) and perceived value (PV). METHODS: A questionnaire survey was conducted to collect data from physicians of three hospitals in Taiwan. Structural equation modeling (SEM) was used to validate the proposed model and test the hypotheses. RESULTS: A total of 295 valid questionnaires were collected. The research results showed that physicians expressed a high intention to use AI. The XAI was found to be of great importance and had a significant impact both on AI TT and PV. We also observed that TT in AI had a significant impact on PV. Moreover, physicians' PV and TT in AI had a significant impact on their behavioral intention to use AI (BI). However, XAI's impact on BI cannot be proved. CONCLUSIONS: The conceptual model developed in this study provides empirical evidence that could be used as guidelines to effectively explore physicians' intention to use medical AI from the antecedent of XAI. Our findings contribute crucial AI-human interaction insights in health care studies.

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.

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.

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.

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.

Effects of STAT3 on aging-dependent neovascularization impairment following limb ischemia: from bedside to bench.

Aging is a major risk factor for ischemic hypoxia-related diseases, including peripheral artery diseases (PADs). Signal transducer and activator of transcription 3 (STAT3) is a critical transcription activator in angiogenesis. Nevertheless, the effect of aging on endothelial cells and their responses to hypoxia are not well studied. Using a hindlimb hypoxic/ischemic model of aged mice, we found that aged mice (80-100-week-old) expressed significantly lower levels of angiogenesis than young mice (10-week-old). In our in vitro study, aged endothelial cells (≥30 passage) showed a significant accumulation of ß-galactosidase and a high expression of aging-associated genes, including p16, p21, and hTERT compared with young cells (<10 passage). After 24 hours of hypoxia exposure, proliferation, migration and tube formation were significantly impaired in aged cells compared with young cells. Notably, STAT3 and angiogenesis-associated proteins such as PI3K/AKT were significantly downregulated in aged mouse limb tissues and aged cells. Further, using STAT3 siRNA, we found that suppressing STAT3 expression in endothelial cells impaired proliferation, migration and tube formation under hypoxia. Correspondingly, in patients with limb ischemia we also observed a higher expression of circulating STAT3, associated with a lower rate of major adverse limb events (MALEs). Collectively, STAT3 could be a biomarker reflecting the development of MALE in patients and also a regulator of age-dependent angiogenesis post limb ischemia. Additional studies are required to elucidate the clinical applications of STAT3.

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.

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.

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.