Ivabradine-Stimulated Microvesicle Release Induces Cardiac Protection against Acute Myocardial Infarction.

Ivabradine can reduce heart rate through inhibition of the current I(f) by still unexplored mechanisms. In a porcine model of ischemia reperfusion (IR), we found that treatment with 0.3 mg/kg Ivabradine increased plasma release of microvesicles (MVs) over Placebo, as detected by flow cytometry of plasma isolated from pigs 7 days after IR, in which a tenfold increase of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) containing (both high and low-glycosylated) MVs, was detected in response to Ivabradine. The source of MVs was investigated, finding a 37% decrease of CD31+ endothelial cell derived MVs, while CD41+ platelet MVs remained unchanged. By contrast, Ivabradine induced the release of HCN4+ (mostly cardiac) MVs. While no differences respect to EMMPRIN as a cargo component were found in endothelial and platelet derived MVs, Ivabradine induced a significant release of EMMPRIN+/HCN4+ MVs by day 7 after IR. To test the role of EMMPRIN+ cardiac MVs (EMCMV), H9c2 cell monolayers were incubated for 24 h with 107 EMCMVs, reducing apoptosis, and increasing 2 times cell proliferation and 1.5 times cell migration. The in vivo contribution of Ivabradine-induced plasma MVs was also tested, in which 108 MVs isolated from the plasma of pigs treated with Ivabradine or Placebo 7 days after IR, were injected in pigs under IR, finding a significant cardiac protection by increasing left ventricle ejection fraction and a significant reduction of the necrotic area. In conclusion ivabradine induces cardiac protection by increasing at least the release of EMMPRIN containing cardiac microvesicles.

The Role of Frailty in Acute Coronary Syndromes in the Elderly.

BACKGROUND: Myocardial infarction (MI) patients are increasingly older, and common risk scores include chronological age, but do not consider chronic comorbidity or biological age. Frailty status reflects these variables and may be independently correlated with prognosis in this setting. OBJECTIVE: This study investigated the impact of frailty on the prognosis of elderly patients admitted due to MI. METHODS: This prospective and observational study included patients ≥75 years admitted to three tertiary hospitals in Spain due to MI. Frailty assessment was performed at admission using the Survey of Health, Ageing and Retirement in Europe Frailty Index (SHARE-FI) tool. The primary endpoint was the composite of death or non-fatal reinfarction during a follow-up of 1 year. Overall mortality, reinfarction, the composite of death, reinfarction and stroke, major bleeding, and readmission rates were also explored. RESULTS: A total of 285 patients were enrolled. Frail patients (109, 38.2%) were older, with a higher score in the Charlson Comorbidity Index and with a higher risk score addressed in the GRACE and CRUSADE indexes. On multivariate analysis including GRACE, CRUSADE, maximum creatinine level, culprit lesion revascularization, complete revascularization, and dual antiplatelet therapy at discharge, frailty was an independent predictor of the composite of death and reinfarction (2.81, 95% CI 1.16-6.78) and overall mortality (3.07, 95% CI 1.35-6.98). CONCLUSION: Frailty is an independent prognostic marker of the composite of mortality and reinfarction and of overall mortality in patients aged ≥75 years admitted due to MI.

Incidence, angiographic features and outcomes of patients presenting with subtle ST-elevation myocardial infarction.

BACKGROUND: Borderline electrocardiograms represent a challenge in ST-segment elevation myocardial infarction (STEMI) management and are associated with inappropriate discharges and delays to intervention. OBJECTIVES: To assess angiographic characteristics and outcomes of patients presenting with subtle ST-elevation (STE) myocardial infarction. METHODS: A total of 504 consecutive patients with suspected STEMI treated by systematic primary percutaneous coronary intervention were prospectively included. Subtle STE was defined as a maximal preinterventional STE of 0.1 to 1 mm. Angiograms were interpreted by investigators unaware of the electrocardiographic data. RESULTS: The proportion of patients with subtle STE was 18.3%, 86% of them presented with Thrombolysis In Myocardial Infarction flow grade 0/1 and 91% underwent percutaneous coronary intervention. Despite having smaller infarcts, subtle STE patients associated more frequent multivessel disease (57% vs 44%, P = .02) and larger delays to reperfusion. During a follow-up of 19.0 ± 4.9 months, the rates of death or reinfarction were similar among groups (10.0% vs 12.6%, P = .467). Subtle STE was not associated with better outcomes neither in univariate nor after adjustment in a multivariate analysis (adjusted hazard ratio 0.79, 95% CI 0.37-1.69, P = .546). CONCLUSIONS: Subtle STEMI is frequent in clinical practice and is usually associated with acute total coronary occlusion. Therefore, it should be diagnosed and treated in the same expeditiously manner as marked STEMI.

Safety of an Early Discharge Strategy (≤48 h) after ST-Elevation Myocardial Infarction.

Background: Early discharge following ST-segment-elevation myocardial infarction (STEMI) confers notable advantages for both patients and healthcare systems. However, the adoption of a very early discharge strategy for selected patients remains limited due to safety considerations. We aimed to provide some insight into the safety of a discharge program with a hospital stay lasting <48 h after a primary percutaneous coronary intervention (PCI). Methods: Using a registry of 1105 patients undergoing primary PCI for STEMI in our hospital between January 2015 and October 2023, we enrolled all the patients who had a hospital stay ≤48 h, according to a prespecified institutional protocol. The primary objective was a combined rate of non-fatal stroke, non-fatal acute myocardial infarction, or cardiovascular death within 30 days of discharge. Emergency department visits or hospitalizations due to cardiovascular causes, along with the all-cause mortality, were measured during the same period. Results: A total of 453 (41%) patients were discharged ≤48 h after admission for a STEMI. The mean age was 62.4 (±12.5 years), 24.3% were women, and 17.9% were people with diabetes. Up to 96% of the procedures had been performed through radial artery access, and there were no major vascular complications. Regarding the primary endpoint, there was one event (0.2%; one patient suffered a non-fatal myocardial infarction). There were no cardiovascular deaths or deaths from other causes. Only five patients (1.1%) were re-hospitalized or visited the emergency department due to cardiovascular causes. Conclusions: An early discharge strategy for patients within 48 h of experiencing STEMI and undergoing primary PCI appears feasible and safe.

Invasive Treatment Strategy in Adults With Frailty and Non-ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The MOSCA-FRAIL randomized clinical trial compared invasive and conservative treatment strategies in patients with frailty with non-ST-segment elevation myocardial infarction (NSTEMI). It showed no differences in the number of days alive and out of the hospital at 1 year. Objective: To assess the outcomes of the MOSCA-FRAIL trial during extended follow-up. Design, Setting, and Participants: The MOSCA-FRAIL randomized clinical trial was conducted at 13 hospitals in Spain between July 7, 2017, and January 9, 2021, and included 167 adults (aged ≥70 years) with frailty (Clinical Frailty Scale score ≥4) and NSTEMI. In this preplanned secondary analysis, follow-up was extended to January 31, 2023. Data analysis was performed from April 5 to 29, 2023, using the intention-to-treat principle. Interventions: Patients were randomized to a routine invasive (coronary angiography and revascularization if feasible [n = 84]) or a conservative (medical treatment with coronary angiography only if recurrent ischemia [n = 83]) strategy. Main outcomes and measures: The primary end point was the difference in restricted mean survival time (RMST). Secondary end points included readmissions for any cause, considering recurrent readmissions. Results: Among the 167 patients included in the analysis, the mean (SD) age was 86 (5) years; 79 (47.3%) were men and 88 (52.7%) were women. A total of 93 deaths and 367 readmissions accrued. The RMST for all-cause death over the entire follow-up was 3.13 (95% CI, 2.72-3.60) years in the invasive and 3.06 (95% CI, 2.84-3.32) years in the conservative treatment groups. The RMST analysis showed inconclusive differences in survival time (invasive minus conservative difference, 28 [95% CI, -188 to 230] days). Patients under invasive treatment tended to have shorter survival in the first year (-28 [95% CI, -63 to 7] days), which improved after the first year (192 [95% CI, 90-230] days). Kaplan-Meier mortality curves intersected, displaying higher mortality to 1 year in the invasive group that shifted to a late benefit (landmark analysis hazard ratio, 0.58 [95% CI, 0.33-0.99]; P = .045). Early harm was more evident in the subgroup with a Clinical Frailty Scale score greater than 4. No differences were found for the secondary end points. Conclusions and Relevance: In this extended follow-up of a randomized clinical trial of patients with frailty and NSTEMI, an invasive treatment strategy did not improve outcomes at a median follow-up of 1113 (IQR, 443-1441) days. However, a differential distribution of deaths was observed, with early harm followed by later benefit. The phenomenon of depletion of susceptible patients may be responsible for this behavior. Trial registration: ClinicalTrials.gov Identifier: NCT03208153.

Geriatric conditions and invasive management in frail patients with NSTEMI. A subgroup analysis of a randomized clinical trial.

INTRODUCTION AND OBJECTIVES: Invasive management in frail patients with non-ST-segment elevation myocardial infarction (NSTEMI) remains controversial. We investigated the impact of various geriatric conditions. METHODS: The MOSCA-FRAIL trial included 167 adults aged ≥ 70 years with frailty (Clinical Frailty Scale [CFS] ≥ 4 points) and NSTEMI, who were randomized to either an invasive (n=84) or conservative (n=83) strategy. In addition to frailty, we measured activities of daily living (Barthel index), cognitive impairment (Pfeiffer test), and comorbidities (Charlson index). The primary endpoint was the difference (invasive minus conservative) in restricted mean survival time (RMST) for all-cause mortality at a median follow-up of 3.9 years. RESULTS: A total of 93 patients died. The RMST difference favored invasive management at the CFS 25th percentile (CFS=4; 157 days, 95%CI, 18-295; P=.027), which changed to a nonsignificant effect at the 50th and 75th percentiles. The RMST difference remained nonsignificant, irrespective of the severity of other geriatric assessments. In time-to-event analysis, invasive management was associated with an initially lower life expectancy, peaking at around 1 year, among all subgroups. However, patients with CFS=4 experienced a benefit at the end of follow-up (181 days, 95%CI, 19-343), whereas those with CFS >4 did not (-16 days, 95%CI, -217 to 186; interaction P=.16). Subgroups defined by other geriatric markers showed a similar time-dependent trend, albeit with weaker statistical interaction. CONCLUSIONS: Among adults with frailty and NSTEMI, the CFS might be useful for evaluating the relative risks and benefits of invasive management. A CFS >4 could serve as a valuable threshold for decision-making.

Effect of Routine Invasive vs Conservative Strategy in Older Adults With Frailty and Non-ST-Segment Elevation Acute Myocardial Infarction: A Randomized Clinical Trial.

Importance: To our knowledge, no randomized clinical trial has compared the invasive and conservative strategies in frail, older patients with non-ST-segment elevation acute myocardial infarction (NSTEMI). Objective: To compare outcomes of invasive and conservative strategies in frail, older patients with NSTEMI at 1 year. Design, Setting, and Participants: This multicenter randomized clinical trial was conducted at 13 Spanish hospitals between July 7, 2017, and January 9, 2021, and included 167 older adult (≥70 years) patients with frailty (Clinical Frailty Scale score ≥4) and NSTEMI. Data analysis was performed from April 2022 to June 2022. Interventions: Patients were randomized to routine invasive (coronary angiography and revascularization if feasible; n = 84) or conservative (medical treatment with coronary angiography for recurrent ischemia; n = 83) strategy. Main Outcomes and Measures: The primary end point was the number of days alive and out of the hospital (DAOH) from discharge to 1 year. The coprimary end point was the composite of cardiac death, reinfarction, or postdischarge revascularization. Results: The study was prematurely stopped due to the COVID-19 pandemic when 95% of the calculated sample size had been enrolled. Among the 167 patients included, the mean (SD) age was 86 (5) years, and mean (SD) Clinical Frailty Scale score was 5 (1). While not statistically different, DAOH were about 1 month (28 days; 95% CI, -7 to 62) greater for patients managed conservatively (312 days; 95% CI, 289 to 335) vs patients managed invasively (284 days; 95% CI, 255 to 311; P = .12). A sensitivity analysis stratified by sex did not show differences. In addition, we found no differences in all-cause mortality (hazard ratio, 1.45; 95% CI, 0.74-2.85; P = .28). There was a 28-day shorter survival in the invasive vs conservatively managed group (95% CI, -63 to 7 days; restricted mean survival time analysis). Noncardiac reasons accounted for 56% of the readmissions. There were no differences in the number of readmissions or days spent in the hospital after discharge between groups. Neither were there differences in the coprimary end point of ischemic cardiac events (subdistribution hazard ratio, 0.92; 95% CI, 0.54-1.57; P = .78). Conclusions and Relevance: In this randomized clinical trial of NSTEMI in frail older patients, there was no benefit to a routine invasive strategy in DAOH during the first year. Based on these findings, a policy of medical management and watchful observation is recommended for older patients with frailty and NSTEMI. Trial Registration: ClinicalTrials.gov Identifier: NCT03208153.

Serum microRNAs are key predictors of long-term heart failure and cardiovascular death after myocardial infarction.

BACKGROUND: Patients with acute myocardial infarction (MI) are at high risk of upcoming events, in particular heart failure (HF), but reliable stratification methods are lacking. Our goal was to evaluate the potential role of circulating miRNAs as prognostic biomarkers in patients presenting with MI. METHODS AND RESULTS: We conducted a prospective study among 311 consecutive patients hospitalized with MI (65% ST-segment elevation MI & median age of 55 years) with long-term follow-up. An initial screening was conducted to select candidate miRNAs, with subsequent study of 14 candidate miRNAs. The primary outcome was the composite of hospital admission for HF or cardiovascular death. During a mean follow-up of 2.1 years miR-21-5p, miR-23a-3p, miR27b-3p, miR-122-5p, miR210-3p, and miR-221-3p reliably predicted the primary outcome. Multivariate Cox regression analyses highlighted that miR-210-3p [hazard ratio (HR) 2.65 per 1 SD increase, P < 0.001], miR-23a-3p (HR 2.11 per 1 SD increase, P < 0.001), and miR-221-3p (HR 2.03 per 1 SD increase, P < 0.001) were able to accurately predict the primary outcome, as well as cardiovascular death, HF hospitalizations, and long-term New York Heart Association (NYHA) functional class. These three miRNAs clearly improved the performance of multivariate clinical models: ΔC-statistic = 0.10 [95% confidence interval (CI), 0.03-0.17], continuous net reclassification index = 34.8% (95%CI, 5.8-57.4%), and integrated discrimination improvement (P < 0.001). CONCLUSIONS: This is the largest study evaluating the prognostic value of circulating miRNAs for HF-related events among patients with MI. We show that several miRNAs predict HF hospitalizations, cardiovascular mortality, and poor long-term NYHA status and improve current risk prediction methods.

Theranostic Contribution of Extracellular Matrix Metalloprotease Inducer-Paramagnetic Nanoparticles Against Acute Myocardial Infarction in a Pig Model of Coronary Ischemia-Reperfusion.

BACKGROUND: Rapid screening and accurate diagnosis of acute myocardial infarction are critical to reduce the progression of myocardial necrosis, in which proteolytic degradation of myocardial extracellular matrix plays a major role. In previous studies, we found that targeting the extracellular matrix metalloprotease inducer (EMMPRIN) by injecting nanoparticles conjugated with the specific EMMPRIN-binding peptide AP9 significantly improved cardiac function in mice subjected to ischemia/reperfusion. METHODS: In a porcine model of coronary ischemia/reperfusion, we tested the theragnostic effects of administering 0.1 mg/kg gadolinium-containing nanoparticles conjugated with AP9 (NAP9), a synthetic peptide that targets EMMPRIN or a control nanoparticle (NAPSC). Cardiac magnetic resonance assessment of the infarct progression, ventricular function, and nanoparticle distribution was performed the next 7 days. We also measured the infarcted area of the heart and cardiac remodeling at 7 or 21 days after ischemia/reperfusion. RESULTS: After 21 days of ischemia/reperfusion, NAP9 reduced the extension of cardiac necrosis (14.1±9.7 versus 35.5±1.8) and the levels of collagenolytic activity of MMPs (matrix metalloproteases), along with a significant reduction in collagen deposition (7.5±4.5 versus 41.3±20); including the ratio of type I versus III collagen fibers in the necrotic myocardium. In terms of cardiac function, the response to NAP9 administration resulted in a significant improvement of cardiac performance overtime, as evidenced by the left ventricle ejection fraction (64.0±7.8), when compared with those present in the NAPSC group (47.3±4.7). As shown by magnetic resonance imaging, noninvasive molecular imaging of NAP9 enabled us to find a significant reduction in cardiac necrosis, myocardial edema, hemorrhage, and microvascular obstruction, suggesting that NAP9 may reduce myocardial injury and preserve left ventricular function, at least, by preventing the effect of EMMPRIN on extracellular matrix degradation. CONCLUSIONS: Our data point towards NAP9 as a promising theragnostic tool in managing acute myocardial infarction, by inhibiting EMMPRIN-induced extracellular matrix degradation and allowing noninvasive visualization of cardiac necrosis progression over time.