Rajiv Das

The British Cardiac Society Working Group definition of myocardial infarction: implications for practice

Objective: To assess the impact on observed mortality of the British Cardiac Society (BCS) definition of myocardial infarction (MI) in 11 UK hospitals. Design: Prospective observational registry. Setting: 11 adjacent hospitals in the West Yorkshire region. Patients: 2484 patients with the acute coronary syndrome (ACS) were identified during a six month period (28 April to 28 October 2003). Demographic, clinical, and treatment variables were collected on all patients. Deaths were monitored through the Office of National Statistics. Patients were categorised into three groups according to the BCS definition of MI: ACS with unstable angina (UA), ACS with myocyte necrosis, and ACS with clinical MI. Results: 30 day mortality was 4.5%, 10.4%, and 12.9% (p < 0.001) in the ACS with UA, ACS with myocyte necrosis, and ACS with clinical MI groups, respectively. At six months the mortality for patients in the groups ACS with clinical MI and ACS with myocyte necrosis was similar (19.2% v 18.7%), being higher than for ACS with UA (8.6%). Same admission percutaneous coronary intervention was similar in groups with clinical MI and myocyte necrosis (11.1% v 10.7%, respectively) as was coronary artery bypass grafting (2.6% v 2.7%, respectively). However, these two groups differed significantly in the prescribing of secondary prevention (aspirin, 79% v 69%; statins, 80% v 68%; β blockers, 66% v 53%; and angiotensin converting enzyme inhibitors, 65% v 53%; p < 0.001). Conclusions: At 30 days the new BCS categories for MI predict three distinct outcomes. However, within a contemporary UK population this was no longer apparent at six months, as mortality for patients with ACS with myocyte necrosis had risen to the same level as those for patients with ACS with clinical MI. One possible explanation for this is the apparent under use of drugs known to improve prognosis after traditionally defined MI.

Early discharge after primary percutaneous coronary intervention for ST-elevation myocardial infarction

Background: To assess safety of early discharge following primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). Methods and results: Retrospective analysis of prospectively collected data of 2448 STEMI patients treated with PPCI surviving to hospital discharge. Post-discharge all-cause mortality was reported at 1, 7, and 30 days and long-term follow up. A total of 1542 patients (63.0%) were discharged within 2 days of admission (early discharge group) and 906 patients (37.0%) after 2 days (late discharge group). In both groups, no deaths were recorded 1 day post discharge. The early and late discharge group mortality figures for 7 days were 0 and 4 patients (0.04%) and between 7 and 30 days were 11 (0.7%) and 11 patients (1.2%), respectively. During a mean follow up of 584 days, 178 patients (7.3%) died: 67 in the early discharge group (4.3%) and 111 in the late discharge group (12.3%). Conclusions: This exploratory, observational study demonstrates that discharging low-risk STEMI patients within 2 days following PPCI is safe. For providers of health care, early discharge can help to allay the cost of providing a 24-hour PPCI service and adds to the recognized benefits arising from PPCI.

T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients

BACKGROUND Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury. METHODS Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI. RESULTS In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8+ T cells decreased more than CD4+ T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r2 = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir. CONCLUSIONS Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells. TRIAL REGISTRATION Not applicable. FUNDING British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.

Myocardial Ischemia and Reperfusion Leads to Transient CD8 Immune Deficiency and Accelerated Immunosenescence in CMV-Seropositive Patients

Rationale: There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals. Objective: The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients. Methods and Results: Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (−192 versus −63 cells/&mgr;L; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8+ cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8+ T cells (2225 versus 3397 bp; P<0.001). Conclusions: Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1–dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients.

Differences in immune responses between CMV‐seronegative and ‐seropositive patients with myocardial ischemia and reperfusion

CMV infection is responsible for acceleration of immune senescence and linked to systemic pathologies, including cardiovascular diseases. In this study, we investigated differences in the immune response between CMV‐seropositive and seronegative patients undergoing primary percutaneous coronary intervention (PPCI) for acute myocardial infarction (MI). Peripheral blood samples were taken at six different time points: pre‐, 15, 30, 90 min, 24 h after PPCI and at 3 months after MI. Absolute counts of lymphocyte subpopulations, immune response to specific and nonspecific stimulation, serum cytokines and levels of CMV‐IgG, cardiolipin‐IgG, and anti‐endothelial cell antibodies were assessed. CMV‐seropositive patients with MI showed a twofold higher IFN‐γ production to PHA‐stimulation, up to 2.5‐fold higher levels of IP‐10 in serum and up to 30% lower serum levels of IL‐16 compared to CMV‐seronegative individuals. CMV‐seropositive patients could be divided into two subgroups with high (IL‐10Hi) and low (IL‐10Lo) IL‐10 serum levels during the acute stage of MI. The IL‐10Hi CMV‐seropositive subgroup showed an increased exit of late‐differentiated T lymphocytes, NK and NKT‐like cells from the circulation, which may potentially enhance cytotoxic damage in the ischemic myocardium. Finally, we did not observe an acceleration of autoimmunity by MI in CMV‐seropositive individuals. The immune response during acute MI showed characteristic differences between CMV seronegative and seropositive patients, with a stronger pro‐inflammatory response in seropositive patients. The effects of IP‐10, IL‐16, and IL‐10 on characteristics of acute immune responses and formation of different immune profiles in CMV‐seropositive individuals require further investigation.

Infarct size and left ventricular remodelling after preventive percutaneous coronary intervention

Objective We hypothesised that, compared with culprit-only primary percutaneous coronary intervention (PCI), additional preventive PCI in selected patients with ST-elevation myocardial infarction with multivessel disease would not be associated with iatrogenic myocardial infarction, and would be associated with reductions in left ventricular (LV) volumes in the longer term. Methods In the preventive angioplasty in myocardial infarction trial (PRAMI; ISRCTN73028481), cardiac magnetic resonance (CMR) was prespecified in two centres and performed (median, IQR) 3 (1, 5) and 209 (189, 957) days after primary PCI. Results From 219 enrolled patients in two sites, 84% underwent CMR. 42 (50%) were randomised to culprit-artery-only PCI and 42 (50%) were randomised to preventive PCI. Follow-up CMR scans were available in 72 (86%) patients. There were two (4.8%) cases of procedure-related myocardial infarction in the preventive PCI group. The culprit-artery-only group had a higher proportion of anterior myocardial infarctions (MIs) (55% vs 24%). Infarct sizes (% LV mass) at baseline and follow-up were similar. At follow-up, there was no difference in LV ejection fraction (%, median (IQR), (culprit-artery-only PCI vs preventive PCI) 51.7 (42.9, 60.2) vs 54.4 (49.3, 62.8), p=0.23), LV end-diastolic volume (mL/m2, 69.3 (59.4, 79.9) vs 66.1 (54.7, 73.7), p=0.48) and LV end-systolic volume (mL/m2, 31.8 (24.4, 43.0) vs 30.7 (23.0, 36.3), p=0.20). Non-culprit angiographic lesions had low-risk Syntax scores and 47% had non-complex characteristics. Conclusions Compared with culprit-only PCI, non-infarct-artery MI in the preventive PCI strategy was uncommon and LV volumes and ejection fraction were similar.

TCT-164 Pressure-Controlled Intermittent Coronary Sinus Occlusion Reduces Infarct Size and Results in Functional Recovery After STEMI; Interim analysis of an ongoing trial

TCT-163 Time to Reperfusion and Infarct Size in Patients With STEMI Undergoing Primary PCI: A Collaborative Patient-Level Pooled Analysis of 10 Randomized Trials Gennaro Giustino, Bjorn Redfors, Ulrich Schaefer, Holger Thiele, Manesh Patel, James Udelson, E. Magnus Ohman, Ingo Eitel, Christopher Granger, Akiko Maehara, Ajay Kirtane, Philippe Généreux, Paul Jenkins, Ori Ben-Yehuda, Gregg Stone The Icahn School of Medicine at Mount Sinai Hospital, New York City, New York, United States; CRF, New York, New York, United States; Asklepios Klinik St. Georg; Medizinische Klinik II (Kardiologie, Angiologie, Intensivmedizin), Lübeck, Germany; Duke University Medical Center, Durham, North Carolina, United States; Tufts Medical Center, Boston, Massachusetts, United States; Duke University Medical Center, Durham, North Carolina, United States; University Heart Center Lübeck, Lübeck, Germany; Duke University Medical Center, Durham, North Carolina, United States; Cardiovascular Research Foundation, New York, New York, United States; NewYorkPresbyterian Hospital/Columbia University Medical Center, New York, New York, United States; Columbia University Medical Center/Hôpital du Sacré-Coeur de Montréal, New York, New York, United States; Loyola; Cardiovascular Research Foundation, New York, New York, United States; Columbia University Medical Center/NewYorkPresbyterian Hospital, New York, New York, United States

5 Major Adverse Cardiovascular Events at 30-days were not Significantly different between Frail and non-frail older (≥75 years) Patients with non ST Elevation Acute Coronary Syndrome Managed by Invasive Strategy: An Analysis from the ICON1 Study

Background Frailty is an independent predictor of major adverse cardiovascular events (MACE) in older patients with Acute Coronary Syndrome (ACS). Evidence based management of ACS involves novel antiplatelets, secondary prevention, revascularisation by percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The impact of frailty status on 30-day MACE (mortality, readmission with ACS, unplanned revascularisation, stroke and major bleeding events) in older patients managed by contemporary treatment is not known. The aim of this study is to evaluate and compare the short-term adverse event rates between frail and non-frail older (≥75 years) patients with non ST elevation ACS (NSTEACS) managed by invasive strategy. Methods Over a period of 20 months (February, 2013 to September, 2014), 196 consecutive patients (≥75 years) with NSTEACS managed by invasive strategy were recruited into an ongoing prospective study (ICON1-A Study to Improve Cardiovascular Outcomes in High Risk PatieNts with Acute Coronary Syndrome, United Kingdom Clinical Research Network ID: 12742). Frailty status was assessed by Fried (Cardiovascular Health Study) frailty assessment tool and patients were grouped as frail (score ≥3) and non-frail (score 0–2) patients. The treating cardiologists were blinded to the frailty status of the patient. MACE were recorded at 30-days. Results The mean age of the patients was 81.3 years (standard deviation [SD] 4.1). Females comprised 40.8% of the patients and 32.1% of patients were frail (Table 1). The diagnosis was non ST elevation myocardial infarction in 80.6% and unstable angina in 19.4% of the patients. Final management strategy after coronary angiography in all patients was PCI in 85.7%, CABG in 3.6% and medical management in 10.7% of the study patients. Mortality data was available for all the patients and other MACE data were available for 92.8% of patients. The rate of MACE between frail and non-frail patients were: mortality 1.6% vs. 0% (p = 0.321), ST elevation myocardial infarction 0% vs. 0%, non ST elevation myocardial infarction 0% vs. 0%, unstable angina 0% vs. 1.7% (p = 1.0), unplanned revascularisation 0% vs. 0.8% (p = 1.0), stroke 1.6% vs. 0.8% (p = 0.551) and major bleeding 3.4% vs. 1.6% (p = 0.596) respectively. The rate of composite adverse outcomes were 5.1% vs. 3.3% (p = 0.684) between the two groups respectively. Conclusion The incidence of MACE at 30-days in frail older (≥75 years) patients with NSTEACS managed by invasive strategy was not significantly different from the non-frail patients. This is likely to be the result of using contemporary treatment strategies and strict adherence to guideline recommended therapy. Given favourable short term outcomes in this high risk cohort, frailty should not deter older patients from receiving invasive treatment and contemporary care in the setting of NSTEACS. Our study consisted of selected patient cohort and will need to be evaluated further in large unselected patient cohort. Abstract 5 Table 1 Baseline characteristics by fried frailty status Baseline variables Total N=196 Frail 63 (32.1) Non-Frail 133 (67.9) p value Age mean (SD) 81.3 (4.1) 81.7 (4.2) 81.1 (4.1) 0.399 BMI mean (SD) 27.4 (4.8) 27.3 (4.8) 27.4 (4.8) 0.875 Hypertension n (%) 150 (76.5) 52 (82.5) 98 (73.7) 0.208 Diabetes n (%) 52 (26.5) 17 (27.0) 35 (26.3) 1.000 Ex-smoker n (%) 97 (49.5) 38 (60.3) 59 (44.4) 0.047* Renal Impairment n (%) 35 (17.9) 17 (27.0) 18 (13.5) 0.028* Previous MI n (%) 69 (35.2) 29 (46.0) 40 (30.1) 0.037* PVD n (%) 13 (6.6) 3 (4.8) 10 (7.5) 0.555 Previous TIA/Stroke n (%) 35 (17.9) 17 (27.0) 18 (13.5) 0.028* BMI Body Mass Index, MI Myocardial Infarction, PVD Peripheral vascular disease, SD Standard Deviation, TIA Transient Ischaemic Attack

Diagnostic yield of early versus late outpatient Cardiac MRI in suspected acute coronary syndrome in patients with normal coronary arteries

Background Cardiac MRI (CMR) is increasingly recognized as a valuable imaging modality for the investigation of patients with suspected acute coronary syndrome found to have non obstructive coronary arteries on angiography. Studies have shown that early CMR within 48 hours can facilitate diagnosis of important differential diagnoses, particularly myocarditis. We attempted to demonstrate whether later scanning, after 6 weeks, would still have a similar pick up rate for these diagnoses, compared with earlier CMR within 6 weeks.

Overcoming Heparin-Associated RT-qPCR Inhibition and Normalization Issues for microRNA Quantification in Patients with Acute Myocardial Infarction

BACKGROUND  Cardiac-enriched micro ribonucleic acids (miRNAs) are released into the circulation following ST-elevation myocardial infarction (STEMI). Lack of standardized approaches for reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) data normalization and presence of RT-qPCR inhibitors (e.g. heparin) in patient blood samples have prevented reproducible miRNA quantification in this cohort and subsequent translation of these biomarkers to clinical practice. MATERIALS AND METHODS  Using a RT-qPCR miRNA screening platform, we identified and validated an endogenous circulating miRNA as a normalization control. In addition, we assessed the effects of in vivo and in vitro anticoagulant drugs administration (heparin and bivalirudin) on three RT-qPCR normalization strategies (global miRNA mean, exogenous spike-in control [cel-miR-39] and endogenous miRNA control). Finally, we evaluated the effect of heparin and its in vitro inhibition with heparinase on the quantification of cardiac-enriched miRNAs in STEMI patients. RESULTS  miR-425-5p was validated as an endogenous miRNA control. Heparin administration in vitro and in vivo inhibited all RT-qPCR normalization strategies. In contrast, bivalirudin had no effects on cel-miR-39 or miR-425-5p quantification. In vitro RNA sample treatment with 0.3 U of heparinase overcame heparin-induced over-estimation of cardiac-enriched miRNA levels and improved their correlation with high-sensitivity troponin T. CONCLUSION  miRNA quantification in STEMI patients receiving heparin is jeopardized by its effect on all RT-qPCR normalization approaches. Use of samples from bivalirudin-treated patients or in vitro treatment of heparin-contaminated samples with heparinase are suitable alternatives for miRNA quantification in this cohort. Finally, we reinforce the evidence that cardiac-enriched miRNAs early after myocardial reperfusion reflect the severity of cardiac injury.