Leonardo P. de Carvalho

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.

Circadian Dependence of Infarct Size and Acute Heart Failure in ST Elevation Myocardial Infarction

Objectives There are conflicting data on the relationship between the time of symptom onset during the 24-hour cycle (circadian dependence) and infarct size in ST-elevation myocardial infarction (STEMI). Moreover, the impact of this circadian pattern of infarct size on clinical outcomes is unknown. We sought to study the circadian dependence of infarct size and its impact on clinical outcomes in STEMI. Methods We studied 6,710 consecutive patients hospitalized for STEMI from 2006 to 2009 in a tropical climate with non-varying day-night cycles. We categorized the time of symptom onset into four 6-hour intervals: midnight–6:00 A.M., 6:00 A.M.–noon, noon–6:00 P.M. and 6:00 P.M.–midnight. We used peak creatine kinase as a surrogate marker of infarct size. Results Midnight–6:00 A.M patients had the highest prevalence of diabetes mellitus (P = 0.03), more commonly presented with anterior MI (P = 0.03) and received percutaneous coronary intervention less frequently, as compared with other time intervals (P = 0.03). Adjusted mean peak creatine kinase was highest among midnight–6:00 A.M. patients and lowest among 6:00 A.M.–noon patients (2,590.8±2,839.1 IU/L and 2,336.3±2,386.6 IU/L, respectively, P = 0.04). Midnight–6:00 A.M patients were at greatest risk of acute heart failure (P<0.001), 30-day mortality (P = 0.03) and 1-year mortality (P = 0.03), while the converse was observed in 6:00 A.M.–noon patients. After adjusting for diabetes, infarct location and performance of percutaneous coronary intervention, circadian variations in acute heart failure incidence remained strongly significant (P = 0.001). Conclusion We observed a circadian peak and nadir in infarct size during STEMI onset from midnight–6:00A.M and 6:00A.M.–noon respectively. The peak and nadir incidence of acute heart failure paralleled this circadian pattern. Differences in diabetes prevalence, infarct location and mechanical reperfusion may account partly for the observed circadian pattern of infarct size and acute heart failure.

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.

Treatment of Mouse Limb Ischemia with an Integrative Hypoxia-Responsive Vector Expressing the Vascular Endothelial Growth Factor Gene

Constitutive vascular endothelial growth factor (VEGF) gene expression systems have been extensively used to treat peripheral arterial diseases, but most of the results have not been satisfactory. In this study, we designed a plasmid vector with a hypoxia-responsive element sequence incorporated into it with the phiC31 integrative system (pVHAVI) to allow long-term VEGF gene expression and to be activated under hypoxia. Repeated activations of VEGF gene expression under hypoxia were confirmed in HEK293 and C2C12 cells transfected with pVHAVI. In limb ischemic mice, the local administration of pVHAVI promoted gastrocnemius mass and force recovery and ameliorated limb necrosis much better than the group treated with hypoxia-insensitive vector, even this last group had produced more VEGF in muscle. Histological analyses carried out after four weeks of gene therapy showed increased capillary density and matured vessels, and reduced number of necrotic cells and fibrosis in pVHAVI treated group. By our study, we demonstrate that the presence of high concentration of VEGF in ischemic tissue is not beneficial or is less beneficial than maintaining a lower but sufficient and long-term concentration of VEGF locally.

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.

Inter-Ethnic Differences in Quantified Coronary Artery Disease Severity and All-Cause Mortality among Dutch and Singaporean Percutaneous Coronary Intervention Patients.

Background Coronary artery disease (CAD) is a global problem with increasing incidence in Asia. Prior studies reported inter-ethnic differences in the prevalence of CAD rather than the severity of CAD. The angiographic “synergy between percutaneous coronary intervention (PCI) with taxus and cardiac surgery” (SYNTAX) score quantifies CAD severity and predicts outcomes. We studied CAD severity and all-cause mortality in four globally populous ethnic groups: Caucasians, Chinese, Indians and Malays. Methods We quantified SYNTAX scores of 1,000 multi-ethnic patients undergoing PCI in two tertiary hospitals in the Netherlands (Caucasians) and Singapore (Chinese, Indians and Malays). Within each ethnicity we studied 150 patients with stable CAD and 100 with ST-elevated myocardial infarction (STEMI). We made inter-ethnic comparisons of SYNTAX scores and all-cause mortality. Results Despite having a younger age (mean age Indians: 56.8 and Malays: 57.7 vs. Caucasians: 63.7 years), multivariable adjusted SYNTAX scores were significantly higher in Indians and Malays than Caucasians with stable CAD: 13.4 [11.9-14.9] and 13.4 [12.0-14.8] vs. 9.4 [8.1-10.8], p<0.001. Among STEMI patients, SYNTAX scores were highest in Chinese and Malays: 17.7 [15.9-19.5] and 18.8 [17.1-20.6] vs. 15.5 [13.5-17.4] and 12.7 [10.9-14.6] in Indians and Caucasians, p<0.001. Over a median follow-up of 709 days, 67 deaths (stable CAD: 37, STEMI: 30) occurred. Among STEMI patients, the SYNTAX score independently predicted all-cause mortality: HR 2.5 [1.7-3.8], p<0.001 for every 10-point increase. All-cause mortality was higher in Indian and Malay STEMI patients than Caucasians, independent of SYNTAX score (adjusted HR 7.2 [1.5-34.7], p=0.01 and 5.8 [1.2-27.2], p=0.02). Conclusion Among stable CAD and STEMI patients requiring PCI, CAD is more severe in Indians and Malays than in Caucasians, despite having a younger age. Moreover, Indian and Malay STEMI patients had a greater adjusted risk of all-cause mortality than Caucasians, independent of SYNTAX score.

P2Y12 platelet receptors: importance in percutaneous coronary intervention

Apart from their role in hemostasis and thrombosis, platelets are involved in many other biological processes such as wound healing and angiogenesis. Percutaneous coronary intervention is a highly thrombogenic procedure inducing platelets and monocytes activation through endothelial trauma and contact activation by intravascular devices. Platelet P2Y12 receptor activation by adenosine diphosphate facilitates non-ADP agonist-mediated platelet aggregation, dense granule secretion, procoagulant activity, and the phosphorylation of several intraplatelet proteins, making it an ideal drug target. However, not all compounds that target the P2Y12 receptor have similar efficacy and safety profiles. Despite targeting the same receptor, the unique pharmacologic properties of each of these P2Y12 receptor-directed compounds can lead to very different clinical effects.

Renal function and anaemia in acute myocardial infarction

BACKGROUND Impaired renal function and anaemia are common among patients with acute myocardial infarction (AMI). While both conditions are known independent risk factors for increased mortality, their interaction as risk factors for increased mortality in AMI is unclear. METHODS We studied 5395 subjects hospitalized for AMI between January 2000 and December 2005. An estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) was defined as impaired GFR and GFR ≥ 60 mL/min/1.73 m(2) was defined as preserved GFR. Anaemia was defined as <13 g/dL (males) and <12 g/dL (females). The odds ratio (OR) for one-year mortality and its 95% confidence interval (CI) were calculated by logistic regression. RESULTS We identified 758 (14%) patients with impaired GFR and anaemia, 1105 (20.5%) patients with impaired GFR without anaemia, 465 (8.6%) patients with preserved GFR and anaemia, and 3012 (55.8%) patients with preserved GFR without anaemia; one-year mortality rates were 56.5%, 41.8%, 31.8% and 10.3% respectively in these 4 groups. Among patients with impaired GFR, anaemia was associated with an adjusted OR of 1.47 (95% CI=1.17-1.85) for one-year mortality, while among patients with preserved GFR, anaemia was associated with a higher adjusted OR of 2.07 (95% CI=1.54-2.76) for one-year mortality, interaction P<0.001. CONCLUSION The combination of impaired GFR and anaemia confers greater than five-fold increased risk of mortality after AMI. The differential effect of anaemia among patients with impaired and preserved GFR on mortality suggests that in patients with preserved GFR anaemia confers a greater relative hazard than in patients with impaired renal function.

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.