Additional improvement in regional myocardial ischemia after intracardiac injection of bone marrow cells during CABG surgery.

Background: Post-procedure residual ischemia is associated with worse prognosis in patients with coronary artery diasease (CAD). Objective: We evaluated whether autologous bone marrow-derived cells (BMC) contribute to additional reduction in regional stress-induced myocardial ischemia (SIMI) in patients undergoing incomplete coronary artery bypass graft surgery (CABG). Methods: In a double-blind, randomized, placebo-controlled trial, we enrolled 143 patients (82% men, 58 ± 11 years) with stable CAD and not candidates for complete CABG. They received 100 million BMC (n = 77) or placebo (n = 66) injected into ischemic non-revascularized segments during CABG. The primary outcome was improvement on SIMI quantified as the area at risk in injected segments assessed by cardiovascular magnetic resonance (CMR) 1, 6, and 12 months after CABG. Results: The reduction in global SIMI after CABG was comparable (p = 0.491) in both groups indicating sustained beneficial effects of the surgical procedure over 12 month period. In contrast, we observed additional improvement in regional SIMI in BMC treated group (p = 0.047). Baseline regional SIMI values were comparable [18.5 (16.2-21.0) vs. 18.5 (16.5-20.7)] and reached the lowest values at 1 month [9.74 (8.25; 11.49) vs. 12.69 (10.84; 14.85)] for BMC and placebo groups, respectively. The ischemia's improvement from baseline represented a 50% difference in regional SIMI in favor of the BMC transplanted group at 30 days. We found no differences in clinical and LVEF% between groups during the 12 month follow-up period. The 1 month rate of major adverse cerebral and cardiovascular events (MACCE) (p = 0.34) and all-cause mortality (p = 0.08) did not differ between groups 1 month post intervention. Conclusion: We provided evidence that BMC leads to additional reduction in regional SIMI in chronic ischemic patients when injected in segments not subjected to direct surgical revascularization. This adjuvant therapy deserves further assessment in patients with advanced CAD especially in those with microcirculation dysfunction. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT01727063.

Plasma Ceramides as Prognostic Biomarkers and Their Arterial and Myocardial Tissue Correlates in Acute Myocardial Infarction.

We identified a plasma signature of 11 C14 to C26 ceramides and 1 C16 dihydroceramide predictive of major adverse cardiovascular events in patients with acute myocardial infarction (AMI). Among patients undergoing coronary artery bypass surgery, those with recent AMI, compared with those without recent AMI, showed a significant increase in 5 of the signature's 12 ceramides in plasma but not simultaneously-biopsied aortic tissue. In contrast, a rat AMI model, compared with sham control, showed a significant increase in myocardial concentrations of all 12 ceramides and up-regulation of 3 ceramide-producing enzymes, suggesting ischemic myocardium as a possible source of this ceramide signature.

Prognostic Implications of Dual Platelet Reactivity Testing in Acute Coronary Syndrome.

Studies on platelet reactivity (PR) testing commonly test PR only after percutaneous coronary intervention (PCI) has been performed. There are few data on pre- and post-PCI testing. Data on simultaneous testing of aspirin and adenosine diphosphate antagonist response are conflicting. We investigated the prognostic value of combined serial assessments of high on-aspirin PR (HASPR) and high on-adenosine diphosphate receptor antagonist PR (HADPR) in patients with acute coronary syndrome (ACS). HASPR and HADPR were assessed in 928 ACS patients before (initial test) and 24 hours after (final test) coronary angiography, with or without revascularization. Patients with HASPR on the initial test, compared with those without, had significantly higher intraprocedural thrombotic events (IPTE) (8.6 vs. 1.2%, p ≤ 0.001) and higher 30-day major adverse cardiovascular and cerebrovascular events (MACCE; 5.2 vs. 2.3%, p = 0.05), but not 12-month MACCE (13.0 vs. 15.1%, p = 0.50). Patients with initial HADPR, compared with those without, had significantly higher IPTE (4.4 vs. 0.9%, p = 0.004), but not 30-day (3.5 vs. 2.3%, p = 0.32) or 12-month MACCE (14.0 vs. 12.5%, p = 0.54). The c-statistic of the Global Registry of Acute Coronary Events (GRACE) score alone, GRACE score + ASPR test and GRACE score + ADPR test for discriminating 30-day MACCE was 0.649, 0.803 and 0.757, respectively. Final ADPR was associated with 30-day MACCE among patients with intermediate-to-high GRACE score (adjusted odds ratio [OR]: 4.50, 95% confidence interval [CI]: 1.14-17.66), but not low GRACE score (adjusted OR: 1.19, 95% CI: 0.13-10.79). In conclusion, both HASPR and HADPR predict ischaemic events in ACS. This predictive utility is time-dependent and risk-dependent.

Influence of Ethnicity, Age, and Time on Sex Disparities in Long-Term Cause-Specific Mortality After Acute Myocardial Infarction.

BACKGROUND: We examined the influence of sex, ethnicity, and time on competing cardiovascular and noncardiovascular causes of death following acute myocardial infarction in a multiethnic Asian cohort. METHODS AND RESULTS: For 12 years, we followed a prospective nationwide cohort of 15 151 patients (aged 22-101 years, median age 63 years; 72.3% male; 66.7% Chinese, 19.8% Malay, 13.5% Indian) who were hospitalized for acute myocardial infarction between 2000 and 2005. There were 6463 deaths (4534 cardiovascular, 1929 noncardiovascular). Compared with men, women had a higher risk of cardiovascular death (age-adjusted hazard ratio [HR] 1.3, 95% CI 1.2-1.4) but a similar risk of noncardiovascular death (HR 0.9, 95% CI 0.8-1.0). Sex differences in cardiovascular death varied by ethnicity, age, and time. Compared with Chinese women, Malay women had the greatest increased hazard of cardiovascular death (HR 1.4, 95% CI 1.2-1.6) and a marked imbalance in death due to heart failure or cardiomyopathy (HR 3.4 [95% CI 1.9-6.0] versus HR 1.5 [95% CI 0.6-3.6] for Indian women). Compared with same-age Malay men, Malay women aged 22 to 49 years had a 2.5-fold (95% CI 1.6-3.8) increased hazard of cardiovascular death. Sex disparities in cardiovascular death tapered over time, least among Chinese patients and most among Indian patients; the HR comparing cardiovascular death of Indian women and men decreased from 1.9 (95% CI 1.5-2.4) at 30 days to 0.9 (95% CI 0.5-1.6) at 10 years. CONCLUSION: Age, ethnicity, and time strongly influence the association between sex and specific cardiovascular causes of mortality, suggesting that health care policy to reduce sex disparities in acute myocardial infarction outcomes must consider the complex interplay of these 3 major modifying factors.

Comparison of Long-Term Mortality of Patients Aged ≤40 Versus >40 Years With Acute Myocardial Infarction.

Young patients with acute myocardial infarction (MI) have a more favorable prognosis than older patients with MI. However, there are limited data comparing the prognosis of young patients with MI with young population controls. Comparison with an age-matched background population could unmask residual mortality risk in young patients with MI that would otherwise not be apparent when merely comparing the mortality risk of young and older patients with MI. We studied 15,151 patients with AMI from 2000 to 2005, of which 601 patients were ≤40 years (young MI). The relative survival ratio (RSR) was calculated as the ratio of the observed survival of patients with MI divided by the expected survival, estimated from the background population (n = 3,771,700) matched for age, gender, and follow-up year. An RSR of <1.0 or >1.0 indicates poorer or better survival, respectively, than the background population. The 12-year all-cause and cardiovascular mortality of young versus older patients was 12.8% versus 50.7% (p <0.001) and 9.2% versus 34.5% (p <0.001), respectively. The adjusted hazard ratio (95% confidence interval) for all-cause and cardiovascular mortality comparing young with older patients was 0.20 (0.16 to 0.27) and 0.27 (0.20 to 0.36), respectively. The RSR (95% confidence interval) of young and older patients was, respectively, 0.969 (0.950 to 0.980) and 0.804 (0.797 to 0.811) at 1 year, 0.942 (0.918 to 0.960) and 0.716 (0.707 to 0.726) at 5 years, and 0.908 (0.878 to 0.938) and 0.638 (0.620 to 0.654) at 9 years. In conclusion, despite a fivefold lower long-term mortality than older patients with MI, young patients with MI remain at significantly greater risk of long-term mortality than an age-matched background population.

Ethnicity Modifies Associations between Cardiovascular Risk Factors and Disease Severity in Parallel Dutch and Singapore Coronary Cohorts.

BACKGROUND: In 2020 the largest number of patients with coronary artery disease (CAD) will be found in Asia. Published epidemiological and clinical reports are overwhelmingly derived from western (White) cohorts and data from Asia are scant. We compared CAD severity and all-cause mortality among 4 of the world's most populous ethnicities: Whites, Chinese, Indians and Malays. METHODS: The UNIted CORoNary cohort (UNICORN) simultaneously enrolled parallel populations of consecutive patients undergoing coronary angiography or intervention for suspected CAD in the Netherlands and Singapore. Using multivariable ordinal regression, we investigated the independent association of ethnicity with CAD severity and interactions between risk factors and ethnicity on CAD severity. Also, we compared all-cause mortality among the ethnic groups using multivariable Cox regression analysis. RESULTS: We included 1,759 White, 685 Chinese, 201 Indian and 224 Malay patients undergoing coronary angiography. We found distinct inter-ethnic differences in cardiovascular risk factors. Furthermore, the associations of gender and diabetes with severity of CAD were significantly stronger in Chinese than Whites. Chinese (OR 1.3 [1.1-1.7], p = 0.008) and Malay (OR 1.9 [1.4-2.6], p<0.001) ethnicity were independently associated with more severe CAD as compared to White ethnicity. Strikingly, when stratified for diabetes status, we found a significant association of all three Asian ethnic groups as compared to White ethnicity with more severe CAD among diabetics, but not in non-diabetics. Crude all-cause mortality did not differ, but when adjusted for covariates mortality was higher in Malays than the other ethnic groups. CONCLUSION: In this population of individuals undergoing coronary angiography, ethnicity is independently associated with the severity of CAD and modifies the strength of association between certain risk factors and CAD severity. Furthermore, mortality differs among ethnic groups. Our data provide insight in inter-ethnic differences in CAD risk factors, CAD severity and mortality.

Long-term prognosis and risk heterogeneity of heart failure complicating acute myocardial infarction.

The Killip classification of acute heart failure was developed decades ago to predict short-term mortality in patients with acute myocardial infarction (AMI). The aim of this study was to determine the long-term prognosis of acute heart failure graded according to the Killip classification in 15,235 unselected patients hospitalized for AMI from 2000 to 2005. Vital status for each patient was ascertained, through to March 1, 2012, from linkage with national death records. A stepwise gradient in the adjusted hazard ratio (HR) for 12-year mortality was observed with increasing Killip class: class I (n = 10,123), HR 1.00 (reference group); class II (n = 2,913), HR 1.13 (95% confidence interval [CI] 1.06 to 1.21); class III (n = 1,217) HR 1.49 (95% CI 1.37 to 1.62); and class IV (n = 898), HR 2.80 (95% CI 2.53 to 3.10). Unexpectedly, in a landmark analysis excluding deaths <30 days after admission, patients in Killip class IV had lower adjusted long-term mortality than those in class III. The adjusted HR for 12-year mortality comparing Killip class IV with Killip class III in patients <60 years of age was 1.71 (95% CI 1.33 to 2.19, p <0.001) and in patients >60 years of age was 2.30 (95% CI 2.07 to 2.56, p <0.001). In conclusion, on the basis of simple clinical features, the Killip classification robustly predicted 12-year mortality after AMI. The heterogeneity in early versus late risk in patients with Killip class IV heart failure underscores the importance of appropriate early treatment in cardiogenic shock.

Differences in late cardiovascular mortality following acute myocardial infarction in three major Asian ethnic groups.

AIM: the purpose of this study was to investigate differences in long-term mortality following acute myocardial infarction (AMI) in patients from three major ethnicities of Asia. METHODS AND RESULTS: We studied 15,151 patients hospitalized for AMI with a median follow-up of 7.3 years (maximum 12 years) in six publicly-funded hospitals in Singapore from 2000-2005. Overall and cause-specific cardiovascular (CV) mortality until 2012 were compared among three major ethnic groups that represent large parts of Asia: Chinese, Malay and Indian. Relative survival of all three ethnic groups was compared with a contemporaneous background reference population using the relative survival ratio (RSR) method. The median global registry of acute coronary events score was highest among Chinese, followed by Malay and Indians: 144 (25th percentile 119, 75th percentile 173), 138 (115, 167), and 131 (109, 160), respectively, p<0.0001; similarly, in-hospital mortality was highest among Chinese (9.8%) followed by Malay (7.6%) and Indian (6.4%) patients. In contrast, 12-year overall and cause-specific CV mortality was highest among Malay (46.2 and 32.0%) followed by Chinese (43.0 and 27.0%) and Indian (35.9 and 25.2%) patients, p<0.0001. The five-year RSR was lowest among Malay (RSR 0.69) followed by Chinese (RSR 0.73) and Indian (RSR 0.79) patients, compared with a background reference population (RSR 1.00). CONCLUSIONS: We observed strong inter-Asian ethnic disparities in long-term mortality after AMI. Malay patients had the most discordant relationship between baseline risk and long-term mortality. Intensified interventions targeting Malay patients as a high-risk group are necessary to reduce disparities in long-term outcomes.