Large Acute Myocardial Infarction Research Articles

Acute-on-chronic inflammation in acute myocardial infarction.

Acute myocardial infarction (AMI) is heralded by chronic inflammation and entails an excessive burst of acute-on-chronic inflammation (AoCI). This review describes the evolution from understanding atherosclerosis as a chronic inflammatory disease, to recent efforts in optimizing anti-inflammatory therapy to patients with AMI. It highlights the challenges and opportunities in selecting the optimal patient with AMI to derive maximal benefit from early anti-inflammatory therapy. The causal role of inflammation in atherosclerosis has been proven in large outcome trials. Since then, several smaller trials have sought to translate the concept of anti-inflammatory therapy targeting residual inflammatory risk to the dynamic early phase of AoCI after AMI. Current evidence highlights the importance of selecting patients with a high inflammatory burden. Surrogate criteria for large AMI (e.g., angiographic or electrocardiographic), as well as novel point-of-care biomarker testing may aid in selecting patients with particularly elevated AoCI. Additionally, patients presenting with AMI complicated by pro-inflammatory sequelae (e.g., atrial fibrillation, acute heart failure, left ventricular thrombosis) may dually profit from anti-inflammatory therapy. Improved understanding of the mechanisms and dynamics of acute and chronic inflammatory processes after AMI may aid the strive to optimize early anti-inflammatory therapy to patients with AMI.

Inflammation in acute myocardial infarction: the good, the bad and the ugly.

Convergent experimental and clinical evidence have established the pathophysiological importance of pro-inflammatory pathways in coronary artery disease. Notably, the interest in treating inflammation in patients suffering acute myocardial infarction (AMI) is now expanding from its chronic aspects to the acute setting. Few large outcome trials have proven the benefits of anti-inflammatory therapies on cardiovascular outcomes by targeting the residual inflammatory risk (RIR), i.e. the smouldering ember of low-grade inflammation persisting in the late phase after AMI. However, these studies have also taught us about potential risks of anti-inflammatory therapy after AMI, particularly related to impaired host defence. Recently, numerous smaller-scale trials have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after AMI. Targeting different pathways and implementing various treatment regimens, those trials have met with varied degrees of success. Promising results have come from those studies intervening early on the interleukin-1 and -6 pathways. Taking lessons from such past research may inform an optimized approach to target post-AMI inflammation, tailored to spare 'The Good' (repair and defence) while treating 'The Bad' (smouldering RIR) and capturing 'The Ugly' (flaming early burst of excess inflammation in the acute phase). Key constituents of such a strategy may read as follows: select patients with large pro-inflammatory burden (i.e. large AMI); initiate treatment early (e.g. ≤12 h post-AMI); implement a precisely targeted anti-inflammatory agent; follow through with a tapering treatment regimen. This approach warrants testing in rigorous clinical trials.

Cardiovascular magnetic resonance-derived left atrioventricular coupling index and major adverse cardiac events in patients following acute myocardial infarction

BackgroundRecently, a novel left atrioventricular coupling index (LACI) has been introduced providing prognostic value to predict cardiovascular events beyond common risk factors in patients without cardiovascular disease. Since data on cardiovascular magnetic resonance (CMR)-derived LACI in patients following acute myocardial infarction (AMI) are scarce, we aimed to assess the diagnostic and prognostic implications of LACI in a large AMI patient cohort. MethodsIn total, 1046 patients following AMI were included. After primary percutaneous coronary intervention CMR imaging and subsequent functional analyses were performed. LACI was defined by the ratio of the left atrial end-diastolic volume divided by the left ventricular (LV) end-diastolic volume. Major adverse cardiac events (MACE) including death, reinfarction or heart failure within 12 months after the index event were defined as primary clinical endpoint. ResultsLACI was significantly higher in patients with MACE compared to those without MACE (p < 0.001). Youden Index identified an optimal LACI cut-off at 34.7% to classify patients at high-risk (p < 0.001 on log-rank testing). Greater LACI was associated with MACE on univariate regression modeling (HR 8.1, 95% CI 3.4–14.9, p < 0.001) and after adjusting for baseline confounders and LV ejection fraction (LVEF) on multivariate regression analyses (HR 3.1 95% CI 1.0–9, p = 0.049). Furthermore, LACI assessment enabled further risk stratification in high-risk patients with impaired LV systolic function (LVEF ≤ 35%; p < 0.001 on log-rank testing). ConclusionAtrial-ventricular interaction using CMR-derived LACI is a superior measure of outcome beyond LVEF especially in high-risk patients following AMI.Trial registration ClinicalTrials.gov, NCT00712101 and NCT01612312

Abstract 10389: Interleukin-1 Blockade With Anakinra Restores Cardiac Contractility Reserve and Exercise Capacity in a Mouse Model of Ischemic Heart Failure

Background: Acute myocardial infarction (AMI) is associated with an intense inflammatory response promoting adverse cardiac remodeling, impaired cardiac reserve, and reduced exercise capacity, hallmarks of heart failure. Interleukin-1β (IL-1β) is the prototypical inflammatory cytokine that is increased in AMI and is sufficient to impair cardiac reserve when administered exogenously in mice. Whether blocking IL-1β signaling with recombinant IL-1 receptor antagonist, anakinra, can restore cardiac contractile reserve and improve exercise capacity in AMI is unknown. Methods: We induced ischemic heart failure due to large non-reperfused anterior AMI in mice via surgical permanent ligation of the left anterior descending artery via lateral thoracotomy in 10-week-old male CD1 mice (N=30, 32-37 g in weight) followed for 10 weeks. Anakinra was given as intraperitoneal injection of 10 mg/kg, 0.2 ml, for three consecutive days. Cardiac contractile reserve was measured assessing changes in left ventricular fractional shortening with isoproterenol challenges (N=5). A subgroup of mice that had been previously trained to run on treadmill were used to measure interval changes in exercise capacity 10 weeks after AMI and with three consecutive days of anakinra treatment (N=6). Data are presented as mean and standard error of mean. T-test for paired group analysis was used to compare values. Results: Cardiac contractile reserve was impaired at -10±5% and restored with anakinra given for three days to +49±11% (p=0.008). Exercise capacity was also significantly reduced with AMI at 191±39 m and restored to 247±46 m after anakinra treatment (p=0.03). Conclusion: Ischemic heart failure due to large non-reperfused AMI leads to a severe reduction in cardiac contractility reserve and exercise capacity that are reversed by IL-1 blockade with anakinra.

Abstract 15189: The ‘July Effect’ in the Management and Outcomes of Acute Myocardial Infarction: An 18-Year United States National Study

Introduction: Limited clinical experience of new trainees has been associated with poor outcomes in the first month of training (July) in teaching hospitals. It remains unclear if this ‘July effect’ continues to be present in contemporary era in patients with acute myocardial infarction (AMI). Methods: Adult hospitalizations for AMI in May and July in urban teaching and non-teaching hospitals in the United States were identified from the HCUP-NIS database (2000-2017). Admissions to rural hospitals, and those without in-hospital mortality data were excluded. In-hospital mortality was compared between those admitted in May and July. A difference-in-difference analysis comparing a change in outcome from May to July in teaching hospitals to a change in outcome from May to July in non-teaching hospitals was also performed to evaluate the July effect. Results: During the study period, there were a total of 1,312,006 hospitalizations for AMI admitted in urban teaching (54.2%) or non-teaching (45.8%) hospitals in the months of May and July. Demographic characteristics were comparable between those admitted in May and July, however, May admissions had greater comorbidity and higher rates of acute multiorgan failure when compared to July admissions in teaching and non-teaching hospitals. Additionally, May AMI admissions to non-teaching hospitals had higher rates of cardiogenic shock (4.6% vs 4.3%) and cardiac arrest (5.2% vs 5.0%) compared to July admissions ( all p&lt;0.001). July AMI admissions had lower in-hospital mortality compared to May admissions in both teaching (5.6% vs 5.8%; adjusted OR (aOR) 0.94 [95% confidence interval {CI} 0.92-0.97]; p&lt;0.001) and non-teaching (5.9% vs 6.3%, p&lt;0.001; aOR 0.97 [95% CI 0.95-0.99]; p=0.02) hospitals. When we analyzed the July effect using the difference-in-difference model for in-hospital mortality, we did not identify a July effect for in-hospital mortality in AMI admissions (p=0.14). Conclusions: Unlike prior reports, we did not identify a July effect for in-hospital mortality in this large contemporary AMI population in the United States. Greater care and support for new incoming trainees and/or awareness of a potential July effect among hospitals may have resulted in improved outcomes in July when compared to May.

Abstract 10944: Cardiac Magnetic Resonance Derived Left Atrioventricular Coupling Index and Major Adverse Cardiac Events in Patients Following Myocardial Infarction

Introduction: Recently a novel left atrioventricular coupling index (LACI) has been introduced providing prognostic value to predict cardiovascular events beyond common risk factors in patients without cardiovascular disease. Since data on cardiovascular magnetic resonance (CMR)-derived LACI in patients following acute myocardial infarction (AMI) are scare we aimed to assess and validate the diagnostic and prognostic implications of LACI in a large AMI patient cohort. Methods: 1044 patients following AMI were included. After primary percutaneous coronary intervention CMR imaging and subsequent functional analyses were performed in median 3 days after AMI. LACI was defined by the ratio of the left atrial end-diastolic volume divided by the left ventricular end-diastolic volume. Major adverse cardiac events (MACE) including death, reinfarction or congestive heart failure within 12 months after the index event were defined as primary clinical endpoint. Results: LACI was significantly higher in patients with MACE compared to those without MACE (p &lt; 0.001). Youden Index identified an optimal LACI cut-off of 34.7% to classify patients at high-risk (p &lt; 0.001 on log-rank testing). Greater LACI was independently associated with MACE on univariate regression modeling (HR 8.1, 95% CI 3.4% - 14.9 %, p &lt; 0.001) and maintained independence after adjusting for baseline confounders and left ventricular ejection fraction (LVEF) on multivariate regression analyses (HR 3.1 95% CI 1.0 - 9., p = 0.049). Furthermore, LACI assessment enabled further risk stratification in high-risk patients according to traditionally utilized reduced LVEF ≤ 35 % (p &lt; 0.001 on log-rank testing). Conclusions: Atrial-ventricular interaction using CMR-derived LACI is a superior measure of outcome beyond sole LA or LV volume analyses and EF especially in high-risk patients following AMI.

Acute myocardial infarction reparation/regeneration strategy using Wharton's jelly multipotent stem cells as an 'unlimited' therapeutic agent: 3-year outcomes in a pilot cohort of the CIRCULATE-AMI trial.

CIRCULATE-AMI (NCT03404063), a cardiac magnetic resonance imaging (cMRI) infarct size-reduction-powered double-blind randomized controlled trial (RCT) of standardized Wharton jelly multipotent stem cells (WJMSCs, CardioCell Investigational Medical Product) vs. placebo (2 : 1) transcoronary transfer on acute myocardial infarction (AMI) day ~5-7, is preceded by safety and feasibility evaluation in a pilot study cohort (CIRCULATE-AMI PSC). To evaluate WJMSC transplantation safety and evolution of left ventricular (LV) remodeling in CIRCULATE-AMI PSC. In 10 consecutive patients (32-65 years, peak CK-MB 533 ±89 U/l, cMRI-LVEF 40.3 ±2.7%, cMRI-infarct size 20.1 ±2.8%), 30 × 106 WJMSCs were administered using a novel cell delivery-dedicated, coronary-non-occlusive method (CIRCULATE catheter). Other treatment was guideline-based. WJMSC transfer was safe and occurred in the absence of coronary (TIMI-3 in all) or myocardial (corrected TIMI frame count (cTFC) 45 ±8 vs. 44 ±9, p = 0.51) flow deterioration or troponin elevation. By 3 years, 1 patient died from a new, non-index territory AMI; there were no other major adverse cardiovascular and cerebrovascular events (MACCE) and no adverse events that might be related to WJMSCs. cMRI infarct size was reduced from 33.2 ±7.6 g to 25.5 ±6.4 g at 1 year and 23.1 ±5.6 g at 3 years (p = 0.03 vs. baseline). cMRI, SPECT, and echo showed a consistent, statistically significant increase in LVEF at 6-12 months (41.9 ±2.6% vs. 51.0 ±3.3%, 36.0 ±3.9% vs. 44.9 ±5.0%, and 38.4 ±2.5% vs. 48.0 ±2.1% respectively, p < 0.01 for all); the effect was sustained at 3 years. CIRCULATE-AMI PSC data suggest that WJMSC transcoronary application ~5-7 days after large AMI in humans is feasible and safe and it may be associated with a durable LVEF improvement. CIRCULATE-AMI RCT will quantify the magnitude of LV adverse remodeling attenuation with CardioCell/placebo administration.

Cardiogenic shock without hypotension in acute myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiogenic Shock(CS)complicates 10%of Acute Myocardial Infarction(AMI), being the main cause for intra-hospital death in these patients.Although early revascularization has contributed to increase survival,mortality still presents high, being 40-50%.CS usually presents with inadequate cardiac output and persistent hypotension.However,after large AMI,peripheral hypoperfusion can occur with sustained or borderline systolic blood pressure(SBP). Purpose Characterize patients(pts)with CS after AMI in the absence of hypotension(defined as SBP &amp;lt; 90mmHg),and assess impact in mortality. Methods We evaluated 528pts presenting with CS in context of AMI.We considered 2groups:Group 1-Pts who had SBP ≥90mmHg,without any inotropic drug or assist device and 2-Pts with SBP &amp;lt; 90mmHg.We registered age,gender,co-morbidities,presentation,coronary anatomy and treatment strategies.We evaluated in-hospital mortality and complications:re-infarction,mechanical complications,high-grade atrioventricular block(AVB),sustained ventricular tachycardia,atrial fibrillation,resuscitated cardiac arrest and stroke. Results AMI presenting as Cardiogenic Shock without hypotension(CSWH)was found in 51%of pts(n = 272),of whom 69%were male.They were younger(between age of 45-64years old in 34%of cases vs 25%,p = 0.040)and had higher body mass index (27.3 ± 4.5vs 26 ± 4.1,p = 0.001).Hypertension was a similarly distributed comorbidity.In group 1,pts were previously more frequently under beta blocker medication (25.2%vs 17.7%,p = 0.047).In this group,mean left ventricular (LV)ejection fraction was 39 ± 13%,a quarter having severely depressed LV function(&amp;lt;30%).Although STEMI was the most common presentation in both sets(73.5% vs 87.1%,p &amp;lt; 0.001),NSTEMI was more prevalent in CSWH(23.9%vs12.1%,p &amp;lt; 0.001).Those pts presented more,at admission,with dyspnea(14.9%vs5.5%,p &amp;lt; 0.001)and in sinus rhythm(81.9%vs69%,p &amp;lt; 0.001).In this group,ICU admission was less frequent(19.4%vs27.2%,p = 0.036),and only about half of pts were medicated with inotropic drugs(vs 78.1%,p &amp;lt; 0.001).However,difference in intra-aortic balloon use wasn’t found.CSWH presented with multivessel disease in 63.8%of pts,being LAD more frequently the culprit vessel(42.4% vs 30.7%,p = 0.030),but fewer left main artery(LM)(4.2%vs14.0%,p = 0.003).Group 1 had fewer prevalence of vessel occlusion,which was particularly true for LM(3.8%vs11.5%,p = 0.015) and circumflex(12.4%vs20.7%,p = 0.047),and were less often submitted to revascularization.Group 1 had fewer AVB(9.8%vs22.4%,p &amp;lt; 0.001).Rates of other complications were similar.In-hospital mortality was higher in classic CS(33.1% vs 43.8%, p= 0.012). Conclusion Cardiogenic Shock without hypotension was found in about half of pts with CS due to AMI.A majority of these were younger and globally had a less severe event and complications.Even though CSWH was associated with one third of in-hospital mortality,it was lower than in pts with hypotension.

Sex differences in heart failure hospitalisation risk following acute myocardial infarction

ObjectiveWe evaluated the sex differences in 6-month heart failure (HF) hospitalisation risk in acute myocardial infarction (AMI) survivors.MethodsFor this retrospective cohort analysis, adult survivors of an AMI between January and...

Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study.

Background: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods: Adult pigs (30–40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.

Symptoms Predictive of Acute Myocardial Infarction in the Troponin Era: Analysis From the TRAPID-AMI Study.

The TRAPID-AMI (High Sensitivity Cardiac Troponin T assay for rapid Rule-out of Acute Myocardial Infarction) study evaluated a rapid "rule-out" acute myocardial infarction (AMI). We evaluated what symptoms were associated with AMI as part of a substudy of TRAPID-AMI. There were 1282 patients evaluated from 12 centers in Europe, the United States of America, and Australia from 2011 to 2013. Multiple symptom variables were prospectively obtained and evaluated for association with the final diagnosis of AMI. Multivariate logistic regression analysis was done, and odds ratios (OR) were calculated. There were 213/1282 (17%) AMIs. Four independent predictors for the diagnosis of AMI were identified: radiation to right arm or shoulder [OR = 3.0; confidence interval (CI): 1.8-5.0], chest pressure (OR = 2.5; CI: 1.3-4.6), worsened by physical activity (OR = 1.7; CI: 1.2-2.5), and radiation to left arm or shoulder (OR = 1.7; CI: 1.1-2.4). In the entire group, 131 (10%) had radiation to right arm or shoulder, 897 (70%) had chest pressure, 385 (30%) worsened with physical activity, and 448 (35%) had radiation to left arm or shoulder. Duration of symptoms was not predictive of AMI. There were no symptoms predictive of non-AMI. Relationship between AMI size and symptoms was also studied. For 213 AMI patients, cardiac troponins I values were divided into 4 quartiles. Symptoms including pulling chest pain, supramammillary right location, and right arm/shoulder radiation were significantly more likely to occur in patients with larger AMIs. In a large multicenter trial, only 4 symptoms were associated with the diagnosis of AMI, and no symptoms that were associated with a non-AMI diagnosis.

Bivalirudin infusion to reduce ventricular infarction: the open-label, randomised Bivalirudin Infusion for Ventricular InfArction Limitation (BIVAL) study.

The aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial infarction (AMI). This multicentre open-label trial randomised 78 patients undergoing PPCI for large AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR-assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and cell injury. No difference was observed in mean IS at five days (25.0±19.7g for bivalirudin vs. 27.1±20.7g for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3±5.8g vs. 7.7±6.3g; p=0.17), with no significant difference in ejection fraction at 90 days (54.6±12.0% vs. 49.1±12.1%; p=0.11). In the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivalirudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5±21.6 vs. 68.7±35.8 mmHg×s, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction in IS was observed with bivalirudin; the trial was discontinued for futility. This study did not achieve its primary endpoint of significant infarct size reduction in PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure.

Clinical and electrocardiographic characteristics of infarctional ventricular ectopic beats: An observational study.

The purpose of this study was to explore the clinical and electrocardiographic characteristics of infarctional ventricular ectopic beats (IVEBs).Thirty-eight acute myocardial infarction (AMI) patients with IVEB and 109 AMI patients without IVEB were analyzed. The morphological changes of QRS complex, ST segment, and T wave were compared to IVEB with sinus rhythm from the same period and fully evolved phase.An IVEB QRS complex often revealed the right bundle branch block morphology, in addition to Q wave AMI; no-Q wave AMI also had IVEB. Single-factor analysis found that IVEB often appeared in early AMI (<6 hours), and they were more frequent in inferoposterior with/without right ventricular involvement, large area AMI and thrombolytic reperfusion than in anterior or anteroseptal myocardial infarction, small area AMI, and unthrombolytic nonreperfusion. Multifactors no conditional logistic regression analysis revealed a positive correlation between IVEB and early AMI, AMI size, Killip heart function degree, inferoposterior with/without right ventricular involvement, and thrombolytic reperfusion. The Q wave of IVEB was wider, and the ST segment elevation was higher than those of the same period in sinus rhythms. The infarctional morphological changes of IVEB could be found before the same period in sinus rhythm and elevated myocardial enzymes.IVEBs were not rare. They were useful for early diagnosis and location of AMI.

ESC working group position paper on myocardial infarction with non-obstructive coronary arteries.

The management of acute myocardial infarction (AMI)1 has evolved over the past century and particularly in the past 50 years. Important milestones include the development of the electrocardiogram, coronary care units, coronary angiography, reperfusion therapies, and troponin assays. These innovations are the foundation of contemporary AMI management strategies that include a diagnosis centred on elevated troponin values associated with corroborative clinical evidence,1 early use of coronary angiography, and reperfusion therapies.2–4 Pivotal in the evolution of these contemporary strategies were the early AMI coronary angiography studies undertaken by DeWood et al. These pioneering studies demonstrated that, in patients presenting with ST elevation myocardial infarction (STEMI), almost 90% had an occluded coronary artery provided that angiography was undertaken within 4 h of chest pain onset.5 In contrast, in AMI patients who did not present with ST elevation (non-ST elevation myocardial infarction or NSTEMI), only 26% had an occluded coronary artery when angiography was performed within 24 h of symptom onset.6 In both of these landmark studies,5,6 >90% of the acute MI patients had angiographic evidence of obstructive coronary artery disease (CAD), underscoring the importance of the atherosclerotic process in the pathogenesis of AMI. Although DeWood's studies underscore the importance of obstructive CAD in AMI, it is fascinating that ∼10% had no significant CAD on coronary angiography. This is confirmed in several large AMI registries7–9 where 1–13% of AMI's occurred in the absence of obstructive CAD thereby eliciting an important set of questions—what is the mechanism of the myocardial damage in these patients? Do these patients differ from those with obstructive CAD? Should they be …

Myocardial regeneration strategy using Wharton’s jelly mesenchymal stem cells as an off-the-shelf ‘unlimited’ therapeutic agent: results from the Acute Myocardial Infarction First-in-Man Study

IntroductionIn large-animal acute myocardial infarction (AMI) models, Wharton's jelly (umbilical cord matrix) mesenchymal stem cells (WJMSCs) effectively promote angiogenesis and drive functional myocardial regeneration. Human data are lacking.AimTo evaluate the feasibility and safety of a novel myocardial regeneration strategy using human WJMSCs as a unique, allogenic but immuno-privileged, off-the-shelf cellular therapeutic agent.Material and methodsThe inclusion criterion was first, large (LVEF ≤ 45%, CK-MB > 100 U/l) AMI with successful infarct-related artery primary percutaneous coronary intervention reperfusion (TIMI ≥ 2). Ten consecutive patients (age 32–65 years, peak hs-troponin T 17.3 ±9.1 ng/ml and peak CK-MB 533 ±89 U/l, sustained echo LVEF reduction to 37.6 ±2.6%, cMRI LVEF 40.3 ±2.7% and infarct size 20.1 ±2.8%) were enrolled.Results30 × 106 WJMSCs were administered (LAD/Cx/RCA in 6/3/1) per protocol at ≈ 5–7 days using a cell delivery-dedicated, coronary-non-occlusive method. No clinical symptoms or ECG signs of myocardial ischemia occurred. There was no epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45 ±8 vs. 44 ±9, p = 0.51), and no patient showed hs-troponin T elevation (0.92 ±0.29 ≤ 24 h before vs. 0.89 ±0.28 ≤ 24 h after; decrease, p = 0.04). One subject experienced, 2 days after cell transfer, a transient temperature rise (38.9°C); this was reactive to paracetamol with no sequel. No other adverse events and no significant arrhythmias (ECG Holter) occurred. Up to 12 months there was one new, non-index territory lethal AMI but no adverse events that might be attributable to WJMSC treatment.ConclusionsThis study demonstrated the feasibility and procedural safety of WJMSC use as off-the-shelf cellular therapy in human AMI and suggested further clinical safety of WJMSC cardiac transfer, providing a basis for randomized placebo-controlled endpoint-powered evaluation.

Shenyuan, an extract of American Ginseng and Corydalis Tuber formula, attenuates cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and oxidative stress in a porcine model of acute myocardial infarction

Ethnopharmacological relevanceThe decoction of American Ginseng and Corydalis Tuber has been widely used for treatment of cardiovascular diseases due to their anti-ischemic and anti-arrhythmic effects. The aim of this study is to evaluate the anti-apoptotic effect of Shenyuan, which is composed of the bioactive components extracted from the mixture of American Ginseng and Corydalis Tuber, and to explore potential mechanisms involved in the regulation of apoptosis. Materials and methodsA porcine model of acute myocardial infarction (AMI) was established by ligation of the left anterior descending coronary artery. Thirty-eight pigs were randomized into six groups: Group S, sham (n=6); Group C, AMI controls (n=8); Group L, AMI+low-dose Shenyuan (240mg/kgd, n=6); Group M, AMI+moderate-dose Shenyuan (320mg/kgd, n=6); Group H, AMI+high-dose Shenyuan (400mg/kgd, n=6); Group B, AMI+Metoprolol Tartrate (1mg/kgd, n=6). The treatment of Shenyuan or Metoprolol started one week before AMI and continued for another two weeks after AMI. ResultsTreatment with all doses of Shenyuan as well as Metoprolol produced a significant decrease of apoptotic index (P<0.05), which was confirmed by TUNEL staining method. This anti-apoptotic effect was accompanied by less release of cardiac enzymes and limit of infarct size. In Group H, levels of MDA, 8-iso-prostaglandin F2α, GRP78/bip, calregulin, CHOP/GADD153, Bax, caspase-3, cleaved caspase-3 and activity of caspase-3 were reduced, while GSH, SOD, Bcl-2 and the Bcl-2/Bax ratio were significantly increased (P<0.05). In groups M and L, some results did not show statistical difference. There was no statistical difference in cardiac function between treatment groups and Group C. ConclusionShenyuan treatment significantly inhibited ERS and oxidative stress, balanced the Bcl-2/Bax ratio, suppressed activation of caspase-3, and finally exerted an anti-apoptotic effect in pigs with a large anterior wall AMI. This was accompanied by less release of cardiac enzymes and limit of infarct size. Shenyuan treatment inhibited apoptosis and may have a therapeutic role in improving the natural process of AMI.

Relevance of gender in patients with acute myocardial infarction undergoing coronary interventions

To evaluate whether gender differences in terms of up to 4-year outcome still persist within patients with acute myocardial infarction (AMI) who uniformly underwent coronary revascularization, we performed a gender comparison in a large contemporary multicentre percutaneous intervention (PCI) registry. We retrospectively analyzed data from 18,351 patients with AMI, who underwent percutaneous coronary interventions (5093 women and 13,258 men) in the Emilia Romagna region of Italy between July 2002 and December 2007. Median follow-up was 1174 days. After propensity score adjustment, differences in gender-related mortality were not temporarily homogeneous: 30-day adjusted mortality was higher in women than in men [hazard ratio (HR): 1.40, P < 0.0001], whereas thereafter female gender showed a significantly lower mortality risk (HR: 0.84, P = 0.01). Notably, younger women (<50 years old) both in the acute and postacute period had more than 3.6 higher risk of mortality when compared with men, whereas older women, particularly after the first 30-day post AMI, had similar (50-80 years old) or even better (≥ 80 years old) survival compared with men. Finally 1-month adjusted risk of heart failure and post PCI vascular complications requiring surgical treatment was higher in women while there was no detectable difference in terms of early and late AMI/unstable angina, stroke and angiographic stent thrombosis. In a contemporary large real-world AMI population treated with PCI, we found gender-related temporal and age-dependent adjusted differences in mortality. Our data suggest the hypothesis that biological gender-related differences could, in part, explain these findings.

Support for Cardiovascular Cell Therapy Research at the National Heart, Lung, and Blood Institute

Heart failure (HF) exerts an enormous burden both in the United States and worldwide, compounded by the lack of effective therapies for patients with end-stage HF. Current options other than medical management are limited to cardiac transplantation, severely limited by the lack of donor availability, and ventricular assist device (VAD) implantation. Although the introduction of newer VADs has reduced complications such as thrombosis and infection, mortality in patients with VADs is still significant (≈25% in the first year1). Since the capacity of the heart to repair itself after myocardial infarction (MI) is very limited, effective regenerative therapies for patients with large acute MI to prevent progression to HF would be highly beneficial in decreasing the morbidity and mortality associated with end-stage HF. Regenerative therapies to repair failing hearts have the potential to provide new options for patients with advanced HF who currently face low quality of life as well as poor prognosis. ### National Heart, Lung, and Blood Institute Cardiovascular Cell Therapy Research Network Clinical trials to test the ability of cell therapy to treat patients after MI were initiated a decade ago in Europe with injection of autologous skeletal myoblasts in patients undergoing coronary artery bypass surgery,2 followed rapidly by trials using other cell types and delivery routes. In response to the proliferation of non-US cell therapy trials, the National Heart, Lung, and Blood Institute (NHLBI) held a working group in August 2004 to assess the status of clinical studies of cell-based therapies for cardiovascular disease, to determine the gaps in knowledge and barriers that prevent the implementation of well-designed and safe clinical studies. Another charge to the working group was to identify the areas of opportunity to apply cell-based therapies for cardiovascular disease.3 The primary recommendation of the working group was the formation of a cardiovascular cell therapy research network, consisting of a clinical research network component …

Relation Between Red Blood Cell Omega-3 Fatty Acid Index and Bleeding During Acute Myocardial Infarction

Omega-3 fatty acids have multiple cardiovascular benefits but may also inhibit platelet aggregation and increase bleeding risk. If this platelet inhibition is clinically meaningful, patients with the highest omega-3 indexes (red blood cell eicosapentaenoic acid plus docosahexaenoic acid), which reflect long-term omega-3 fatty acid intake, should be at the risk for bleeding. In this study, 1,523 patients from 24 United States centers who had their omega-3 indexes assessed at the time of acute myocardial infarction were studied. The rates of serious bleeding (Thrombolysis In Myocardial Infarction [TIMI] major or minor) and mild to moderate bleeding (TIMI minimal) were identified in patients with low (<4%), intermediate (4% to 8%), and high (>8%) omega-3 indices. There were no differences in bleeding across omega-3 index categories. After multivariate adjustment, there remained no association between the omega-3 index and either serious (per 2% increase, relative risk 1.03, 95% confidence interval 0.90 to 1.19) or mild to moderate bleeding (per 2% increase, relative risk 1.02, 95% confidence interval 0.85 to 1.23). In conclusion, no relation was found between the omega-3 index and bleeding in this large, multicenter cohort of patients with acute myocardial infarction, suggesting that concerns about bleeding should not preclude the use of omega-3 supplements or increased fish consumption when clinically indicated.

Improving myocardial viability: clinical implications for the use of bone marrow-derived stem cell infusion after acute myocardial infarction

The treatment of acute myocardial infarction (AMI) has evolved substantially over the past three decades, after an improvement in the mortality rate of AMI due to thrombolytics [1,2] and primary percu taneous intervention for coronary reperfusion [3]. Less than a decade ago, initial reports on the clinical application of mono nucleated bone marrow-derived stem cells (BMCs) in patients with AMI opened up a new era of regenerative cardiology and brought with it great enthusiasm [4]. Since then, numerous clinical trials have been carried out, with the aim of assessing the efficacy and safety of bone marrow stem cell therapy. Randomized Phase II trials have demonstrated contradictory results, but finally a significant improvement in cardiac function assessed by left ventricular ejection fraction (LVEF) after cell therapy was highlighted in meta-analyses [5–7]. Some of the discrepancies between some trials may be explained by differences in cell isolation and storage procedures [8]. Nevertheless, there was some evidence to suggest that BMC-based therapy is effective at improving LVEF in certain subpopulations, such as patients with large AMI and decreased LVEF [7,9]. Improvement of LVEF is of clinical relevance, since an increased LVEF achieved with cell transplantation is within an intriguingly similar range compared with established therapeutic strategies [10]. Several mechanisms of action have been suggested, but improvement in myocardial viability had never been assessed before the Bone Marrow in Acute Myocardial Infarction (BONAMI) trial [11].