Katrina L. Ellis

Circulating microRNAs as candidate markers to distinguish heart failure in breathless patients

Since their identification in the circulation, microRNAs have received considerable interest as putative biomarkers of cardiovascular disease. We have investigated the diagnostic utility of microRNAs in differentiating between patients with heart failure (HF) and non‐HF‐related breathlessness, and between HF with reduced (HF‐REF) and preserved (HF‐PEF) EF.

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.

Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden: A Collaborative Meta-Analysis

OBJECTIVES This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

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.

Genetic polymorphism rs6922269 in the MTHFD1L gene is associated with survival and baseline active vitamin B12 levels in post-acute coronary syndromes patients.

Background and Aims The methylene-tetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L) gene is involved in mitochondrial tetrahydrofolate metabolism. Polymorphisms in MTHFD1L, including rs6922269, have been implicated in risk for coronary artery disease (CAD). We investigated the association between rs6922269 and known metabolic risk factors and survival in two independent cohorts of coronary heart disease patients. Methods and Results DNA and plasma from 1940 patients with acute coronary syndromes were collected a median of 32 days after index hospital admission (Coronary Disease Cohort Study, CDCS). Samples from a validation cohort of 842 patients post-myocardial infarction (PMI) were taken 24–96 hours after hospitalization. DNA samples were genotyped for rs6922269, using a TaqMan assay. Homocysteine and active vitamin B12 were measured by immunoassay in baseline CDCS plasma samples, but not PMI plasma. All cause mortality was documented over follow-up of 4.1 (CDCS) and 8.8 (PMI) years, respectively. rs6922269 genotype frequencies were AA n = 135, 7.0%; GA n = 785, 40.5% and GG n = 1020, 52.5% in the CDCS and similar in the PMI cohort. CDCS patients with AA genotype for rs6922269 had lower levels of co-variate adjusted baseline plasma active vitamin B12 (p = 0.017) and poorer survival than patients with GG or GA genotype (mortality: AA 19.6%, GA 12.0%, GG 11.6%; p = 0.007). In multivariate analysis, rs6922269 genotype predicted survival, independent of established covariate predictors (p = 0.03). However the association between genotype and survival was not validated in the PMI cohort. Conclusion MTHFD1L rs6922269 genotype is associated with active vitamin B12 levels at baseline and may be a marker of prognostic risk in patients with established coronary heart 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.

Genomic Risk Variants at 1p13.3, 1q41, and 3q22.3 Are Associated With Subsequent Cardiovascular Outcomes in Healthy Controls and in Established Coronary Artery 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.

Progress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism.

Familial hypercholesterolaemia, familial combined hyperlipidaemia (FCH) and elevated lipoprotein(a) are common, inherited disorders of apolipoprotein B metabolism that markedly accelerate the onset of atherosclerotic cardiovascular disease (ASCVD). These disorders are frequently encountered in clinical lipidology and need to be accurately identified and treated in both index patients and their family members, to prevent the development of premature ASCVD. The optimal screening strategies depend on the patterns of heritability for each condition. Established therapies are widely used along with lifestyle interventions to regulate levels of circulating lipoproteins. New therapeutic strategies are becoming available, and could supplement traditional approaches in the most severe cases, but their long-term cost-effectiveness and safety have yet to be confirmed. We review contemporary developments in the understanding, detection and care of these highly atherogenic disorders of apolipoprotein B metabolism.

Genetic variation in the renin-angiotensin-aldosterone system is associated with cardiovascular risk factors and early mortality in established coronary heart disease.

This study examined renin–angiotensin–aldosterone (RAAS) system gene variants for associations with cardiovascular risk factors and outcomes in coronary heart disease. Coronary disease patients (n=1186) were genotyped for 21 single-nucleotide polymorphisms (SNPs) within angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin-II type-1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Associations with all-cause mortality and cardiovascular readmissions were assessed over a median of 3.0 years. The AGT M235T ‘T’ allele was associated with a younger age of clinical coronary disease onset (P=0.006), and the AGT rs2478545 minor allele was associated with lower circulating natriuretic peptides (P=0.0001–P=0.001) and E/E1 (P=0.018). Minor alleles of AGT SNPs rs1926723 and rs11122576 were associated with more frequent history of renal disease (P⩽0.04) and type-2 diabetes (P⩽0.02), higher body mass index (P⩽0.02) and greater mortality (P⩽0.007). AGT rs11568054 minor allele carriers had more frequent history of renal disease (P=0.04) and higher plasma creatinine (P=0.033). AGT rs6687360 minor allele carriers exhibited worse survival (P=0.02). ACE rs4267385 was associated with older clinical coronary disease onset (P=0.008) and hypertension (P=0.013) onset, increased plasma creatinine (P=0.01), yet greater mortality (P=0.044). Less history of hypertension was observed with the AGTR1 rs12685977 minor allele (P=0.039). Genetic variation within the RAAS was associated with cardiovascular risk factors and accordingly poorer survival.

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.