Vascular endothelial growth factor-A promoter polymorphisms, circulating VEGF-A and survival in acute coronary syndromes.

BACKGROUND: Development of a competent collateral circulation in established coronary artery disease is cardio-protective. The vascular endothelial growth factor (VEGF) system plays a key role in this process. We investigated the prognostic performance of circulating VEGF-A and three genetic variants in the VEGFA gene in a clinical coronary cohort. METHODS AND RESULTS: The Coronary Disease Cohort Study (CDCS) recruited 2,140 patients, with a diagnosis of acute coronary syndrome (ACS), after admission to Christchurch or Auckland City Hospitals between July 2002 and January 2009. We present data for 1927 patients from the cohort genotyped for three SNPs in the VEGF-A gene, rs699947 (C-2578A), rs2010963 (C405G) and rs3025039 (C936T). Plasma VEGF-A concentrations were assayed in a subgroup (n = 550) of CDCS patients (geometric mean 36.6 [34.7-38.5] pg/ml). VEGF-A levels correlated with patient heart rate at baseline (p = 0.034). None of rs699947, rs3025039, nor rs2010963 genotypes were significantly associated with VEGF-A levels, but rs3025039 genotype was positively associated with collateral vessels perfusion according to the Rentrop classification (p = 0.01) and baseline natriuretic peptide levels (p<0.05). Survival in the CDCS cohort was independently associated with baseline VEGF-A levels and (in males) with rs699947 genotype. CONCLUSIONS: This study is strongly suggestive that VEGF-A levels have value as a prognostic biomarker in coronary heart disease patients and SNPs in VEGF-A deserve further investigation as prognostic markers and indicators of angiogenic potential influencing the formation of collateral circulation.

Long term survival after acute myocardial infarction in Australia and New Zealand, 2009-2015: a population cohort study.

OBJECTIVE: To assess long term survival and patient characteristics associated with survival following acute myocardial infarction (AMI) in Australia and New Zealand. DESIGN: Cohort study. SETTING, PARTICIPANTS: All patients admitted with AMI (ICD-10-AM codes I21.0-I21.4) to all public and most private hospitals in Australia and New Zealand during 2009-2015. MAIN OUTCOME MEASURE: All-cause mortality up to seven years after an AMI. RESULTS: 239 402 initial admissions with AMI were identified; the mean age of the patients was 69.3 years (SD, 14.3 years), 154 287 were men (64.5%), and 64 335 had ST-elevation myocardial infarction (STEMI; 26.9%). 7-year survival after AMI was 62.3% (STEMI, 70.8%; non-ST-elevation myocardial infarction [NSTEMI], 59.2%); survival exceeded 85% for people under 65 years of age, but was 17.4% for those aged 85 years or more. 120 155 patients (50.2%) underwent revascularisation (STEMI, 72.2%; NSTEMI, 42.1%); 7-year survival exceeded 80% for patients in each group who underwent revascularisation, and was lower than 45% for those who did not. Being older (85 years or older v 18-54 years: adjusted hazard ratio [aHR], 10.6; 95% CI, 10.1-11.1) or a woman (aHR, 1.15; 95% CI, 1.13-1.17) were each associated with greater long term mortality during the study period, as was prior heart failure (aHR, 1.79; 95% CI, 1.76-1.83). Several non-cardiac conditions and geriatric syndromes common in these patients were independently associated with lower long term survival, including major and metastatic cancer, cirrhosis and end-stage liver disease, and dementia. CONCLUSION: AMI care in Australia and New Zealand is associated with high rates of long term survival; 7-year rates exceed 80% for patients under 65 years of age and for those who undergo revascularisation. Efforts to further improve survival should target patients with NSTEMI, who are often older and have several comorbid conditions, for whom revascularisation rates are low and survival after AMI poor.

All-Cause Mortality Following an Acute Coronary Syndrome: 12-Year Follow-Up of the Comprehensive 2002 New Zealand Acute Coronary Syndrome Audit.

BACKGROUND: To describe the long-term mortality of a complete national cohort of acute coronary syndrome (ACS) patients enrolled in 2002, to compare this with a national age, sex and Maori ethnicity matched population, and to assess the influence of baseline factors on the 12-year mortality. METHODS: We reviewed 721 patients with a discharge diagnosis of an ACS who were enrolled in the first New Zealand ACS audit group cohort over 14days in May 2002. We matched the cohort to the national mortality database using each patient's unique national identity number. RESULTS: Over a median follow-up of 12.7 years of 721 patients discharged with an ACS, overall mortality was 52%: ST-elevation myocardial infarction (STEMI) (58%), non-ST-elevation myocardial infarction (NSTEMI) (61%) and unstable angina pectoris (UAP) (42%) patients, p<0.0001. In an age-adjusted survival model, males had a 29% increased mortality rate compared to females with a hazard ratio of 1.29 (95% CI 1.04, 1.61, p=0.019). Over 12 years there were 339 (47%) deaths, compared to 284 (39%) deaths observed in the matched population. The standardised mortality ratio for patients admitted with an ACS in New Zealand is 1.3 (95% CI 1.2, 1.5) with eight patients per 100 not surviving to 12 years compared to this matched population. CONCLUSIONS: The high mortality rate in this ACS cohort is a stark reminder of the prognostic implications of a presentation with an ACS. It emphasises the on-going need for optimal management of these patients throughout every stage of their initial treatment and subsequent on-going care.

Plasma levels of soluble VEGF receptor isoforms, circulating pterins and VEGF system SNPs as prognostic biomarkers in patients with acute coronary syndromes.

BACKGROUND: Development of collateral circulation in coronary artery disease is cardio-protective. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. In patients from a prospectively recruited post-acute coronary syndromes cohort we investigated the prognostic performance of three products of activated macrophages, soluble vascular endothelial growth factor (VEGF) receptors (sFlt-1 and sKDR) and pterins, alongside genetic variants in VEGF receptor genes, VEGFR-1 and VEGFR-2. METHODS: Baseline levels of sFlt-1 (VEGFR1), sKDR (VEGFR2) and pterins were measured in plasma samples from subgroups (n = 513; 211; 144, respectively) of the Coronary Disease Cohort Study (CDCS, n = 2067). DNA samples from the cohort were genotyped for polymorphisms from the VEGFR-1 gene SNPs (rs748252 n = 2027, rs9513070 n = 2048) and VEGFR-2 gene SNPs (rs2071559 n = 2050, rs2305948 n = 2066, rs1870377 n = 2042). RESULTS: At baseline, levels of sFlt-1 were significantly correlated with age, alcohol consumption, NTproBNP, BNP and other covariates relevant to cardiovascular pathophysiology. Total neopterin levels were associated with alcohol consumption at baseline. 7,8 dihydroneopterin was associated with BMI. The A allele of VEGFR-2 variant rs1870377 was associated with higher plasma sFlt-1 and lower levels of sKDR at baseline. Baseline plasma sFlt-1 was univariately associated with all cause mortality with (p < 0.001) and in a Cox's proportional hazards regression model sFlt-1 and pterins were both associated with mortality independent of established predictors (p < 0.027). CONCLUSIONS: sFlt-1 and pterins may have potential as prognostic biomarkers in acute coronary syndromes patients. Genetic markers from VEGF system genes warrant further investigation as markers of levels of VEGF system components in these patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. ACTRN12605000431628 . 16 September 2005, Retrospectively registered.

Expertise and infrastructure capacity impacts acute coronary syndrome outcomes.

Objective Effective translation of evidence to practice may depend on systems of care characteristics within the health service. The present study evaluated associations between hospital expertise and infrastructure capacity and acute coronary syndrome (ACS) care as part of the SNAPSHOT ACS registry. Methods A survey collected hospital systems and process data and our analysis developed a score to assess hospital infrastructure and expertise capacity. Patient-level data from a registry of 4387 suspected ACS patients enrolled over a 2-week period were used and associations with guideline care and in-hospital and 6-, 12- and 18-month outcomes were measured. Results Of 375 participating hospitals, 348 (92.8%) were included in the analysis. Higher expertise was associated with increased coronary angiograms (440/1329; 33.1%), 580/1656 (35.0%) and 609/1402 (43.4%) for low, intermediate and high expertise capacity respectively; P<0.001) and the prescription of guideline therapies observed a tendency for an association with (531/1329 (40.0%), 733/1656 (44.3%) and 603/1402 (43.0%) for low, intermediate and high expertise capacity respectively; P=0.056), but not rehabilitation (474/1329 (35.7%), 603/1656 (36.4%) and 535/1402 (38.2%) for low, intermediate and high expertise capacity respectively; P=0.377). Higher expertise capacity was associated with a lower incidence of major adverse events (152/1329 (11.4%), 142/1656 (8.6%) and 149/149 (10.6%) for low, intermediate and high expertise capacity respectively; P=0.026), as well as adjusted mortality within 18 months (low vs intermediate expertise capacity: odds ratio (OR) 0.79, 95% confidence interval (CI) 0.58-1.08, P=0.153; intermediate vs high expertise capacity: OR 0.64, 95% CI 0.48-0.86, P=0.003). Conclusions Both higher-level expertise in decision making and infrastructure capacity are associated with improved evidence translation and survival over 18 months of an ACS event and have clear healthcare design and policy implications. What is known about the topic? There are comprehensive guidelines for treating ACS patients, but Australia and New Zealand registry data reveal substantial gaps in delivery of best practice care across metropolitan, regional, rural and remote health services, raising questions of equity of access and outcome. Greater mortality and morbidity gains can be achieved by increasing the application of current evidence-based therapies than by developing new therapy innovations. Health service system characteristics may be barriers or enablers to the delivery of best practice care and need to be identified and evaluated for correlations with performance indicators and outcomes in order to improve health service design. What does this paper add? This study measures two system characteristics, namely expertise and infrastructure, evaluating the relationship with ACS guideline application and clinical outcomes in a large and diverse cohort of Australian and New Zealand hospitals. The study identifies decision-making expertise and infrastructure capacity, to a lesser degree, as enabling characteristics to help improve patient outcomes. What are the implications for practitioners? In the design of health services to improve access and equity, expertise must be preserved. However, it is difficult to have experienced personnel at the bedside no matter where the health service, and engineering innovative systems and processes of care to facilitate delivery of expertise should be considered.

A decade of improvement in the management of New Zealand ST-elevation myocardial infarction (STEMI) patients: results from the New Zealand Acute Coronary Syndrome (ACS) Audit Group national audits of 2002, 2007 and 2012.

AIMS: To audit the management of ST-segment elevation myocardial infarction (STEMI) patients admitted to a New Zealand Hospital over three 14-day periods to review their number, characteristics, management and outcome changes over a decade. METHODS: The acute coronary syndrome (ACS) audits were conducted over 14 days in May of 2002, 2007 and 2012 at New Zealand Hospitals admitting patients with a suspected or definite ACS. Longitudinal analyses of the STEMI subgroup are reported. RESULTS: From 2002 to 2012, the largest change in management was the proportion of patients undergoing reperfusion by primary PCI from 3% to 15% and 41%; P<0.001, and the rates of second antiplatelet agent use in addition to aspirin from 14% to 62% and 98%; P<0.001. The use of proven secondary prevention medications at discharge also increased during the decade. There were also significant increases in cardiac investigations for patients, especially echocardiograms (35%, 62% and 70%, P<0.001) and invasive coronary angiograms (31%, 58% and 87%, P<0.001). Notably even in 2012, one in four patients presenting with STEMI did not receive any reperfusion therapy. CONCLUSIONS: Substantial improvements have been seen in the management of STEMI patients in New Zealand over the last decade, in accordance with evidenced-based guideline recommendations. However, there appears to be considerable room to optimise management, particularly with the use of timely reperfusion therapy for more patients.

C-Type Natriuretic Peptides in Coronary Disease.

AIMS: C-type natriuretic peptide (CNP) is a paracrine growth factor expressed in the vascular endothelium. Although upregulated in atheromatous arteries, the predictive value of plasma CNP products for outcome in coronary disease is unknown. This study aimed to compare the prognostic value of plasma CNP products with those of other natriuretic peptides in individuals with coronary artery disease, and investigate their associations with cardiac and renal function. METHODS AND RESULTS: Plasma concentrations of CNP and amino-terminal proCNP (NT-proCNP) were measured at baseline in 2129 individuals after an index acute coronary syndrome admission and related to cardiac and renal function, other natriuretic peptides [atrial NP (ANP) and B-type NP (BNP)] and prognosis (primary end point, mortality; secondary end point, cardiac readmission). Median follow-up was 4 years. At baseline, and in contrast to CNP, ANP, and BNP, plasma NT-proCNP was higher in males and weakly related to cardiac function but strongly correlated to plasma creatinine. All NPs were univariately associated with mortality. Resampling at 4 and 12 months in survivors showed stable concentrations of NT-proCNP whereas all other peptides declined. When studied by diagnosis (myocardial infarction, unstable angina) at index admission using a multivariate model, NT-proBNP predicted mortality and readmission in myocardial infarction. In unstable angina, only NT-proCNP predicted both mortality and cardiac readmission. CONCLUSIONS: In contrast to the close association of NT-proBNP with cardiac function, and predictive value for outcome after myocardial infarction, plasma NT-proCNP is highly correlated with renal function and is an independent predictor of mortality and cardiac readmission in individuals with unstable angina.

A review of a regional primary percutaneous coronary intervention service, with a focus on door to reperfusion times: the 2012 Auckland/Northland experience.

AIMS: Primary percutaneous coronary intervention (PCI) is the optimal management for ST segment elevation myocardial infarction (STEMI) patients. We reviewed the largest primary PCI regional service in New Zealand: the Auckland/Northland service based at Auckland City Hospital, to assess patient management, in particular the door to reperfusion times (DTRTs), and predictors of death in hospital. METHODS: We obtained patient details from a comprehensive prospective database of all primary PCI patients admitted with STEMI from 1/1/12 to 31/12/12 to the Auckland City Hospital cardiac catheterisation laboratory. Of four District Health Boards (DHBs) within the region, two accessed this regional service at all times, and two accessed the Auckland City Hospital cardiac catheterisation laboratory 'after hours': all times except for 08:00 to 16:00 hours on Monday to Friday. RESULTS: A total of 401 adult patients underwent a primary PCI at the Auckland City Hospital Regional centre for a STEMI presentation, over the 12 months period. The median patient age was 61 years, 77% were male. Overall 183 (46%) (95% CI 41, 51) patients achieved a DTRT of < 90 mins, and 266 (66%) (95% CI 61, 71) a DTRT of < 120 mins, with a clear geographical influence to these times. Of 27 patients with direct transfer to the catheter laboratory from the community, the DTRT was < 120 mins in 24 (92%) (95% CI 72, 96) patients. In-hospital mortality was 24 (6%) patients (95% CI 4, 9). CONCLUSIONS: The 2012 Auckland/Northland primary PCI service delivers good outcomes consistent with current Australasian standards. Although geographical isolation complicates door to reperfusion times, these may potentially be improved by more focus on direct transfer to the cardiac catheterisation laboratory, especially directly from the community.

Circulating miR-323-3p and miR-652: candidate markers for the presence and progression of acute coronary syndromes.

BACKGROUND: The prognostic utility of circulating plasma microRNA in patients with acute coronary syndromes (ACS) has been proposed but not yet demonstrated. We set out to investigate circulating microRNA levels in patients incurring recent ACS and examined associations with neurohormones, cardiac structure and function, and survival over 5 years of follow-up. METHODS: An initial screen of 375 microRNAs was performed in 35 ACS patients and 16 healthy controls. Candidates identified from the initial screen (miR-323-3p, miR-652, miR-27b, miR-103 and miR-208a) were validated in a further cohort of 200 patients at baseline (~ 30 days post-ACS) and at 4 and 12 months post-ACS, and compared with 100 controls. RESULTS: In the validation cohort, significantly higher levels in patients were replicated for miR-323-3p, miR-652 and miR-27b (10-fold, 2.3-fold and 2.3-fold, respectively, adjusted p<0.05). Lower levels of miR-103 were not replicated and miR-208a was undetectable. From baseline to 4 months post-admission, miR-323-3p and miR-652 remained elevated in patients compared to controls (adjusted p<0.01), with no further change in levels between 4 and 12 months; whereas miR-27b fell to control levels by 4 months. Baseline levels of miR-652 in the lowest tertile were significantly associated with readmission for heart failure (log-rank p<0.001). In combination with NT-proBNP and LVEF, miR-652 significantly improved risk stratification (p<0.001). CONCLUSIONS: Our study identifies miR-652 as a novel candidate biomarker for post-ACS prognosis beyond existing biomarkers of LVEF and NT-proBNP. Moreover circulating miR-323-3p was markedly elevated in patients for at least a year post-ACS and may be a stable biomarker for ACS.

Prescription of secondary prevention medications, lifestyle advice, and referral to rehabilitation among acute coronary syndrome inpatients: results from a large prospective audit in Australia and New Zealand.

OBJECTIVE: To evaluate the proportion of patients hospitalised with acute coronary syndrome (ACS) in Australia and New Zealand who received optimal inpatient preventive care and to identify factors associated with preventive care. METHODS: All patients hospitalised bi-nationally with ACS were identified between 14-27 May 2012. Optimal in-hospital preventive care was defined as having received lifestyle advice, referral to rehabilitation, and prescription of secondary prevention pharmacotherapies. Multilevel multivariable logistic regression was used to determine factors associated with receipt of optimal preventive care. RESULTS: For the 2299 ACS survivors, mean (SD) age was 69 (13) years, 46% were referred to rehabilitation, 65% were discharged on sufficient preventive medications, and 27% received optimal preventive care. Diagnosis of ST elevation myocardial infarction (OR: 2.64 [95% CI: 1.88-3.71]; p<0.001) and non-ST elevation myocardial infarction (OR: 1.99 [95% CI: 1.52-2.61]; p<0.001) compared with a diagnosis of unstable angina, having a percutaneous coronary intervention (PCI) (OR: 4.71 [95% CI: 3.67-6.11]; p<0.001) or coronary bypass (OR: 2.10 [95% CI: 1.21-3.60]; p=0.011) during the admission or history of hypertension (OR:1.36 [95% CI: 1.06-1.75]; p=0.017) were associated with greater exposure to preventive care. Age over 70 years (OR:0.53 [95% CI: 0.35-0.79]; p=0.002) or admission to a private hospital (OR:0.59 [95% CI: 0.42-0.84]; p=0.003) were associated with lower exposure to preventive care. CONCLUSIONS: Only one-quarter of ACS patients received optimal secondary prevention in-hospital. Patients with UA, who did not have PCI, were over 70 years or were admitted to a private hospital, were less likely to receive optimal care.

Cardiovascular investigations of airline pilots with excessive cardiovascular risk.

BACKGROUND: This study examined the prevalence of airline pilots who have an excessive cardiovascular disease (CVD) risk score according to the New Zealand Guideline Group (NZGG) Framingham-based Risk Chart and describes their cardiovascular risk assessment and investigations. METHODS: A cross-sectional study was performed among 856 pilots employed in an Oceania based airline. Pilots with elevated CVD risk that had been previously evaluated at various times over the previous 19 yr were reviewed retrospectively from the airline's medical records, and the subsequent cardiovascular investigations were then described. RESULTS: There were 30 (3.5%) pilots who were found to have 5-yr CVD risk score of 10-15% or higher. Of the 29 pilots who had complete cardiac investigations data, 26 pilots underwent exercise electrocardiography (ECG), 2 pilots progressed directly to coronary angiograms and 1 pilot with abnormal echocardiogram was not examined further. Of the 26 pilots, 7 had positive or borderline exercise tests, all of whom subsequently had angiograms. One patient with a negative exercise test also had a coronary angiogram. Of the 9 patients who had coronary angiograms as a consequence of screening, 5 had significant disease that required treatment and 4 had either trivial disease or normal coronary arteries. CONCLUSION: The current approach to investigate excessive cardiovascular risk in pilots relies heavily on exercise electrocardiograms as a diagnostic test, and may not be optimal either to detect disease or to protect pilots from unnecessary invasive procedures. A more comprehensive and accurate cardiac investigation algorithm to assess excessive CVD risk in pilots is required.

Cardiovascular risk score and cardiovascular events among airline pilots: a case-control study.

BACKGROUND: A cardiovascular risk prediction score is routinely applied by aviation authorities worldwide. We examined the accuracy of the Framingham-based risk chart used by the New Zealand Civil Aviation Authority in predicting cardiovascular events among airline pilots. METHODS: A matched case-control design was applied to assess the association of 5-yr cardiovascular risk score and cardiovascular events in Oceania-based airline pilots. Cases were pilots with cardiovascular events as recorded on their medical records. Each case was age and gender matched with four controls that were randomly selected from the pilot population. To collect data before the events, 5-yr retrospective evaluations were conducted. RESULTS: Over a 16-yr study period we identified 15 cases of cardiovascular events, 9 (60%) of which were sudden clinical presentations and only 6 (40%) of which were detected using cardiovascular screening. There were 8 cases (53%) and 16 controls (27%) who had a 5-yr risk of > or = 10-15%. Almost half of the events (7/15) occurred in pilots whose highest 5-yr risk was in the 5-10% range. Cases were 3.91 times more likely to have highest 5-yr risk score of > or =10-15% than controls (OR = 3.91, 95% CI 1.04-16.35). The accuracy of the highest risk scores were moderate (AUC = 0.723, 95% CI 0.583-0.863). The cutoff point of 10% is valid, with a specificity of 0.73, but low sensitivity (0.53). CONCLUSION: Despite a valid and appropriate cutoff point, the tool had low sensitivity and was unable to predict almost half of the cardiovascular events.

KCNE5 polymorphism rs697829 is associated with QT interval and survival in acute coronary syndromes patients.

INTRODUCTION: The KCNE family is a group of small transmembrane channel proteins involved in potassium ion (K(+)) conductance. The X-linked KCNE5 gene encodes a regulator of the K(+) current mediated by the potassium channel KCNQ1. Polymorphisms in KCNE5 have been associated with altered cardiac electrophysiological properties in human studies. We investigated associations of the common rs697829 polymorphism from KCNE5 with baseline characteristics, baseline electrocardiographic (ECG) measurements, and patient survival in a cohort of post-acute coronary syndromes (ACS) patients (the Coronary Disease Cohort Study cohort). METHODS AND RESULTS: DNA samples (n = 1,740) were genotyped for rs697829 using a TaqMan assay. Baseline ECG data revealed corrected QT (QTc) interval was associated with rs697829 in male, but not female, patients, being extended in the G genotype group (A 416 ± 1.71; G 431 ± 4.25 ms, P = 0.002). Covariate-adjusted survival was poorest in G genotype patients in Cox proportional hazard modeling of mortality data of males (P(overall) = 0.020). Male patients with G genotype had a hazard ratio of 1.44 (1.11-2.33) for death when compared to the A genotype male patients (P = 0.048) after adjustment for age, baseline log-transformed N-terminal pro-B-type natriuretic peptide (NTproBNP), ß-blocker and insulin treatment, QTc interval, history of myocardial infarction, and physical activity score. CONCLUSION: This study suggests an association between rs697829, a common single nucleotide polymorphism (SNP) from KCNE5, and ECG measurements and survival in postacute ACS patients. Prolonged subclinical QT interval may be a marker of adverse outcome in this group of patients.

Association between endothelin type A receptor haplotypes and mortality in coronary heart disease.

AIMS: The endothelin type A receptor, encoded by EDNRA, mediates the effects of endothelin-1 to promote vasoconstriction, vascular cell growth, adhesion, fibrosis and thrombosis. We investigated the association between EDNRA haplotype and cardiovascular outcomes in patients with coronary artery disease. METHODS: Coronary disease patients (n = 1007) were genotyped for the His323His (rs5333) variant and one tag SNP from each of the major EDNRA haplotype blocks (rs6537484, rs1568136, rs5335 and rs10003447). EDNRA haplotype associations with clinical history, natriuretic peptides cardiac function and cardiovascular outcomes were tested over a median 3.8 years. RESULTS: Univariate analysis identified a 'low-risk' EDNRA haplotype associated with later age of Type 2 diabetes onset (p = 0.004) smaller BMI (p = 0.021), and reduced mortality (log rank p = 0.001). Cox proportional hazards analysis including established cardiovascular risk factors revealed an independent association between haplotype and mortality (p < 0.0001). CONCLUSION: These data highlight the potential importance of the endothelin system, and in particular EDNRA in coronary disease.

Genomic risk variants at 1p13.3, 1q41, and 3q22.3 are associated with subsequent cardiovascular outcomes in healthy controls and in established coronary artery disease.

BACKGROUND: Genome-wide association studies have identified gene variants associated with coronary artery disease risk; however, whether they affect disease progression is largely unknown. This study investigated associations between polymorphisms at 1p13.3 (rs599839), 1q41 (rs17465637), and 3q22.3 (rs9818870) and cardiovascular outcomes in healthy volunteers and in patients with established heart disease. METHODS AND RESULTS: Canterbury Healthy Volunteer study (HV) (n=1649), Coronary Disease Cohort Study (CDCS) (n=1797), and Post-Myocardial Infarction study (PMI) (n=906) participants (New Zealand), were genotyped for rs599839, rs9818870, and rs17465637. Associations between genotype and anthropometric characteristics, neurohormonal analysis, echocardiography, and clinical outcomes over medium-long-term follow-up (median HV, 5.9 years; CDCS, 3.7 years; PMI, 11.3 years) were tested. At 1p13.3, HV and CDCS participants carrying 1 or more rs599839 G allele had a lower prevalence of dyslipidemia (P ≤ 0.005) or lower levels of low-density lipoprotein (P=0.031) and total (P=0.004) cholesterol and/or less history of myocardial infarction (P ≤ 0.04) compared with AA participants. Moreover, CDCS and PMI AG/GG participants had better cardiac function as indicated by echocardiography (P ≤ 0.026), and fewer CDCS AG/GG participants were readmitted for a non-ST-segment elevation MI (P=0.012) during follow-up. The polymorphism at 1q41 (rs17465637) was associated with better cardiovascular outcomes in the HV (P=0.028) and PMI (P=0.008) cohorts, and 3q22.3 (rs9818870) was a predictor of death/admission in the HV cohort (P=0.045). CONCLUSIONS: These data suggest that coronary artery disease genomic risk variants at 1p13.3 and 1q41 are associated with subsequent clinical outcome in heart patients and confirm rs9818870 at 3q22.3 as a predictor of cardiovascular risk in individuals free of overt heart disease.

High calcium scores in patients with a low Framingham risk of cardiovascular (CVS) disease: implications for more accurate CVS risk assessment in New Zealand.

AIMS: New Zealand (NZ) patients are recommended to undergo an 'adjusted' Framingham score to assess their cardiovascular (CVS) risk. The current (2009) NZ CVS Risk Guideline does not recommend the use of a 'calcium score' as an additional risk tool, although it has been shown to be powerfully predictive of CVS events above the predictive power of traditional Framingham risk factors. Calcium scores of >400 are very strongly predictive of a future CVS event and give direct evidence of atheromatous disease in the coronary circulation. Identification of people with advanced, premature coronary atheroma would allow early treatment of those who may benefit from more vigorous preventative strategies, including statin therapy. METHODS: Using a prospectively acquired, comprehensive database we audited the first 1000 patients (7 August 2006 to 28 November 2008) to undergo a 64-slice computed tomographic (CT) cardiac angiogram (GE Light Speed), which included a scan for a 'calcium score', at the Mercy Hospital, Auckland. We excluded 58 patients who had experienced one or more of a previous myocardial infarction (MI) (n=21), coronary artery bypass graft (CABG) surgery (n=15), percutaneous coronary intervention (PCI) (n=13) or stroke (n=21) and who therefore already had definite evidence of vascular disease and would be automatically placed in a high risk strata. We calculated each patient's Framingham risk from the original 'Anderson' equation, used by the 1996 NZ CVS risk Guideline, and the 'adjusted' Framingham 5-year CVS risk using the NZ Guidelines Group 2003/2009 recommendations, and then compared this with the observed calcium scores. RESULTS: The mean patient age was 56 (SD 9) years; 364 (39%) patients were female, 82% patients were Caucasian. 41% were current (4.6%) or previous (36%) cigarette smokers, 35% had a history of hypertension, 44% hyperlipidaemia and 5.6% had diabetes mellitus. The percentage of patients at 'low' 5-Year CVS risk (0-10% 5-year risk), using the 1996 and 2003/2009 guideline methods, was 78% and 58% respectively. Of patients in these Framingham 'low-risk' groups, 10% and 8.8% had a calcium score of >400 Agatston units, indicating that they were actually at very high CVS risk, and 203 (28%) and 147 (27%) respectively had a calcium score of >100 Agatston units, indicating that they were actually at 'high risk' and not 'low risk'. CONCLUSION: Approximately 10% to 27% of patients with a low CVS risk as assessed by the established Framingham equation have a markedly increased calcium score and hence a significantly increased risk of a CVS event. Currently promoted methods of risk assessment may be inadvertently, falsely re-assuring these patients. Clinicians managing patients may consider a calcium score as an additional tool to the standard risk assessment strategies.

Association of genetic variation in the natriuretic peptide system with cardiovascular outcomes.

Polymorphisms within individual natriuretic peptide genes have been associated with risk factors for cardiovascular disease, but their association with clinical outcomes was previously unknown. This study aimed to investigate the association between genetic variants in key genes of the natriuretic peptide system with cardiovascular outcomes in patients with coronary artery disease. Coronary disease patients (n=1810) were genotyped for polymorphisms within NPPA, NPPB, NPPC, NPR1 and NPR2. Clinical history, natriuretic peptide concentrations, echocardiography, all-cause mortality and cardiovascular hospital readmissions were recorded over a median 2.8 years. Minor alleles of NPPA rs5068, rs5065 and rs198358 were associated with less history of hypertension; minor alleles of NPPA rs5068 and rs198358 was also associated with higher circulating natriuretic peptide levels (p=0.003 to p=0.04). Minor alleles of NPPB rs198388, rs198389, and rs632793 were associated with higher circulating BNP and NT-proBNP (p=0.001 to p=0.03), and reduced E/E(1) (p=0.011), or LVESVI (p=0.001) and LVEDVI (p=0.004). Within NPPC, both rs11079028 and rs479651 were associated with higher NT-proBNP and CNP (p=0.01 to p=0.03), and rs479651 was associated with lower LVESVI (p=0.008) and LVEDVI (p=0.018). NPR2 rs10758325 was associated with smaller LVMI (p<0.02). A reduced rate of cardiovascular readmission was observed for minor alleles of NPPA rs5065 (p<0.0001), NPPB rs632793 (p<0.0001), rs198388 (p<0.0001), rs198389 (p<0.0001), and NPR2 rs10758325 (p<0.0001). There were no associations with all-cause mortality. In established cardiovascular disease, natriuretic peptide system polymorphisms were associated with natriuretic peptide levels, hypertension, echocardiographic indices and the incidence of hospital readmission for cardiovascular events.

A common variant at chromosome 9P21.3 is associated with age of onset of coronary disease but not subsequent mortality.

BACKGROUND: Chromosome 9p21.3 (chr9p21.3) recently was identified by several genome-wide association studies as the genomic region most strongly associated with the risk of coronary artery disease. Within the chr9p21.3 locus, the single-nucleotide polymorphism rs1333049 has been demonstrated to be most strongly associated with susceptibility to developing coronary artery disease. However, the effect of rs1333049 on clinical outcomes in patients with established coronary disease has yet to be determined. METHODS AND RESULTS: Coronary Disease Cohort Study (CDCS) (n=1054) and Post-Myocardial Infarction (PMI) (n=816) study participants were genotyped for rs1333049. Clinical history, circulating lipids, neurohormones, cardiac function, and discharge medications were documented. All-cause mortality and cardiovascular hospital readmissions were recorded over a median follow-up period of 4.0 years for the CDCS cohort and 9.1 years for the PMI cohort. The CDCS patients homozygous for the high-risk C allele had an age of onset 2 to 5 years earlier for coronary disease (P=.005), angina (P=.025), myocardial infarction (P=.022), and percutaneous transluminal coronary angioplasty (P=.009). Patients with the CC genotype also had higher levels of total cholesterol (P=.033) and triglycerides (P=.003). The PMI participants with the CC genotype were 3 years younger on admission (P=.009). Cox proportional hazards analysis adjusting for established predictors of increased risk showed no significant association between rs1333049 genotype and mortality in either the CDCS (P=.214) or the PMI (P=.696) cohorts. CONCLUSIONS: The chr9p21.3 polymorphism rs1333049 was associated with an earlier age of disease onset in 2 coronary disease cohorts but not with poorer clinical outcome in either cohort.

CYP1A1 MSPI (T6235C) gene polymorphism is associated with mortality in acute coronary syndrome patients.

1. The CYP1A1 T6235C polymorphism (rs4646903) gene polymorphism has been linked to the development of coronary heart disease and cigarette smoking-related lung cancer. The present study investigated associations between survival in acute coronary syndromes (ACS), smoking and the CYP1A1 T6235C polymorphism. 2. Patients with ACS (n = 1251) were genotyped for the CYP1A1 T6235C polymorphism. Patients had a mean age of 67.0 years, 69.8% were male and follow up occurred over a median of 1.9 years. 3. Overall genotype frequencies were CC 2.2%, TC 21.7% and TT 76.1%. The CC genotype was associated with baseline characteristics of a higher incidence of Type 2 diabetes (P = 0.017), elevated body mass index (P = 0.001) and younger age (P = 0.045). Patients with the CC genotype had significantly worse survival than TT/TC patients (P = 0.014), independent of ethnicity and established clinical risk factors. When survival was stratified by smoking history, the T6235C genotype was particularly associated with mortality in past or current smokers (mortality 23.5 vs 9.4% in CC and TT/TC patients, respectively; P = 0.019) compared with those who had never smoked (mortality 11.1 vs 11.5% in CC and TT/TC patients, respectively; P = 0.853). 4. The results indicate that the homozygous CYP1A1 6235C genotype is associated with greater mortality following the onset of ACS, independent of ethnicity and clinical risk factors, but related to smoking history.

Can an illness perception intervention reduce illness anxiety in spouses of myocardial infarction patients? A randomized controlled trial.

OBJECTIVE: To investigate whether a brief in-hospital illness perception intervention for myocardial infarction (MI) patients and their spouses could change spouses' illness perceptions and reduce spouses' anxiety about the illness. METHODS: Fifty-seven spouses participated in a randomized controlled trial of an illness perception intervention for MI patients. Spouses of patients randomized to the intervention attended one half-hour patient-and-spouse session with a psychologist in addition to standard care. Spouses completed measures of illness perceptions, expectations, and illness anxiety at admission and at 1 week following discharge, and spouses' illness worry was rated by the patients at 3 months. The main outcome for spouses was differences in anxiety between intervention and control groups. RESULTS: One week following discharge, spouses in the intervention group had higher illness understanding, lower concern, stronger causal attributions to hereditary factors, and fewer questions about their partner's heart condition compared to the control group. Intervention group spouses reported more positive expectations about the ability of the patient's heart to recover, and lower perceived likelihood of another MI. They had lower anxiety about the patient doing physical activity and about the patient's medications, and lower distress about the patient's symptoms. Spouses in the intervention group were rated as less worried about the illness at 3 months. CONCLUSION: Spouses of patients represent a new target for illness perception interventions and these results demonstrate that a brief illness perception intervention can change illness perceptions and reduce anxiety about the illness in spouses of MI patients.