Clinical outcomes and health care costs of transferring rural Western Australians for invasive coronary angiography, and a cost-effective alternative care model: a retrospective cross-sectional study.

OBJECTIVES: To examine the severity of coronary artery disease (CAD) in people from rural or remote Western Australia referred for invasive coronary angiography (ICA) in Perth and their subsequent management; to estimate the cost savings were computed tomography coronary angiography (CTCA) offered in rural centres as a first line investigation for people with suspected CAD. DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS: Adults with stable symptoms in rural and remote WA referred to Perth public tertiary hospitals for ICA evaluation during the 2019 calendar year. MAIN OUTCOME MEASURES: Severity and management of CAD (medical management or revascularisation); health care costs by care model (standard care or a proposed alternative model with local CTCA assessment). RESULTS: The mean age of the 1017 people from rural and remote WA who underwent ICA in Perth was 62 years (standard deviation, 13 years); 680 were men (66.9%), 245 were Indigenous people (24.1%). Indications for referral were non-ST elevation myocardial infarction (438, 43.1%), chest pain with normal troponin level (394, 38.7%), and other (185, 18.2%). After ICA assessment, 619 people were medically managed (60.9%) and 398 underwent revascularisation (39.1%). None of the 365 patients (35.9%) without obstructed coronaries (< 50% stenosis) underwent revascularisation; nine patients with moderate CAD (50-69% stenosis; 7%) and 389 with severe CAD (≥ 70% stenosis or occluded vessel; 75.5%) underwent revascularisation. Were CTCA used locally to determine the need for referral, 527 referrals could have been averted (53%), the ICA:revascularisation ratio would have improved from 2.6 to 1.6, and 1757 metropolitan hospital bed-days (43% reduction) and $7.3 million in health care costs (36% reduction) would have been saved. CONCLUSION: Many rural and remote Western Australians transferred for ICA in Perth have non-obstructive CAD and are medically managed. Providing CTCA as a first line investigation in rural centres could avert half of these transfers and be a cost-effective strategy for risk stratification of people with suspected CAD.

Cardiac Complications in Patients Hospitalised With COVID-19 in Australia.

OBJECTIVES: Describe the incidence of cardiac complications in patients admitted to hospital with COVID-19 in Australia. DESIGN: Observational cohort study. SETTING: Twenty-one (21) Australian hospitals. PARTICIPANTS: Consecutive patients aged ≥18 years admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MAIN OUTCOME MEASURES: Incidence of cardiac complications. RESULTS: Six-hundred-and-forty-four (644) hospitalised patients (62.5±20.1 yo, 51.1% male) with COVID-19 were enrolled in the study. Overall in-hospital mortality was 14.3%. Twenty (20) (3.6%) patients developed new atrial fibrillation or flutter during admission and 9 (1.6%) patients were diagnosed with new heart failure or cardiomyopathy. Three (3) (0.5%) patients developed high grade atrioventricular (AV) block. Two (2) (0.3%) patients were clinically diagnosed with pericarditis or myopericarditis. Among the 295 (45.8%) patients with at least one troponin measurement, 99 (33.6%) had a peak troponin above the upper limit of normal (ULN). In-hospital mortality was higher in patients with raised troponin (32.3% vs 6.1%, p<0.001). New onset atrial fibrillation or flutter (6.4% vs 1.0%, p=0.001) and troponin elevation above the ULN (50.3% vs 16.4%, p<0.001) were more common in patients 65 years and older. There was no significant difference in the rate of cardiac complications between males and females. CONCLUSIONS: Among patients with COVID-19 requiring hospitalisation in Australia, troponin elevation was common but clinical cardiac sequelae were uncommon. The incidence of atrial arrhythmias and troponin elevation was greatest in patients 65 years and older.

Lipoprotein(a) and apolipoprotein(a) isoform size: Associations with angiographic extent and severity of coronary artery disease, and carotid artery plaque.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an emerging genetic risk factor for cardiovascular disease (CVD). We examined whether plasma Lp(a) concentration and apolipoprotein(a) [apo(a)] isoform size are associated with extent and severity of coronary artery disease (CAD), and the presence of carotid artery plaque. METHODS: We included in our study male participants (n = 263) from a cohort with angiographically defined premature CAD (Carotid Ultrasound in Patients with Ischemic Heart Disease). The angiographic extent and severity of CAD were determined by the modified Gensini and Coronary Artery Stenosis≥20% (CAGE) scores. Carotid artery plaque was assessed by bilateral carotid B-mode ultrasound. Apo(a) isoform size was determined by LPA Kringle IV-2 copy number (KIV-2 CN). RESULTS: Lp(a) concentration, but not KIV-2 CN, was positively associated with the Gensini score. The association remained significant following adjustment for conventional CVD risk factors (all p < 0.05). Lp(a) concentration and elevated Lp(a) [≥50 mg/dL] were positively associated with the CAGE≥20 score, independent of conventional CVD risk factors. KIV-2 C N Q1 (lowest KIV-2 CN quartile) was associated with CAGE≥20 score and KIV-2 CN, with the CAGE≥20 score in those without diabetes. In multivariate models that included phenotypic familial hypercholesterolemia or low-density lipoprotein cholesterol, Lp(a) concentration, but not KIV-2 CN, was independently associated with the Gensini and CAGE≥20 scores. No significant associations between Lp(a) concentration and KIV-2 CN with carotid artery plaque were observed. CONCLUSIONS: Lp(a) concentration, but not apo(a) isoform size, is independently associated with angiographic extent and severity of CAD. Neither Lp(a) nor apo(a) isoform size is associated with carotid artery plaque.

Management of acute coronary syndrome in special subgroups: female, older, diabetic and Indigenous patients.

While the evidence base for management of acute coronary syndrome (ACS) is extensive, some subgroups have been underrepresented or excluded from relevant clinical trials. These subgroups - such as women, older people, diabetic patients and Indigenous Australians - present clinical challenges for which there is limited evidence to guide optimal therapy. Women may have a different pattern of presentation, with potential for delays in diagnosis and worse outcomes in ST-elevation myocardial infarction, but there is no evidence that treatments affect them differently from men. Older people suffer from a high-risk, low-treatment paradox. This may be due to under-appreciation of the benefits of treatments for older people, or to good clinical judgement in avoiding harm from worsening age-related comorbidities. Patients with diabetes have a high risk of ACS and suffer worse outcomes. Moderate glycaemic control with close monitoring and avoidance of hypoglycaemia are recommended. Coronary artery bypass grafting is preferred to percutaneous coronary intervention for patients with diabetes and multivessel disease, although the latter is reasonable in single-vessel disease. Indigenous patients have a high prevalence of coronary disease, with more frequent coronary events at a young age, a heavy load of risk factors and poor outcomes after ACS. The complex sociocultural barriers to treatment are yet to be addressed adequately.

A comprehensive investigation of variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/R2), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome.

BACKGROUND: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. METHODS: Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. RESULTS: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134). CONCLUSIONS: Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.

Door-to-balloon times are reduced in ST-elevation myocardial infarction by emergency physician activation of the cardiac catheterisation laboratory and immediate patient transfer.

OBJECTIVES: To assess whether a collaborative interdepartmental pathway involving emergency department (ED) physicians activating the cardiac catheterisation laboratory (CCL) with immediate patient transfer to the CCL reduces door-to-balloon (DTB) times for patients with suspected ST-elevation myocardial infarction (STEMI). DESIGN, SETTING AND PARTICIPANTS: A quasi-experimental before-and-after observational study using a prospective database, supplemented by chart review, of consecutive patients transferred from the ED to the CCL for suspected STEMI, from January 2007 to October 2009, at Sir Charles Gairdner Hospital, an adult tertiary-care hospital, Western Australia. MAIN OUTCOMES MEASURES: Median DTB time and proportion of patients with DTB time of < 90 minutes. Secondary outcomes, based on analysis of predefined subgroups, included door-to-activation time, activation-to-balloon time and false-positive activations of the CCL. RESULTS: Two hundred and thirty-four patients underwent emergency coronary angiography for suspected STEMI, with 188 (80%) undergoing percutaneous coronary intervention (118 before and 70 after implementation of the new pathway). Following implementation of the new pathway, median DTB time reduced from 97 to 77 minutes (P < 0.001), median door-to-activation time from 28 to 15 minutes (P = 0.002) and median activation-to-balloon time from 66 to 53 minutes (P < 0.001). The proportion of patients with recommended DTB time of < 90 minutes increased from 41% to 77% (P < 0.001) with no change in false positive CCL activation rates (12% v 11%; P = 0.38). CONCLUSION: ED physician activation of CCL with immediate patient transfer is associated with highly significant improvements in DTB time without increased false positive rates.

Association of PARL rs3732581 genetic variant with insulin levels, metabolic syndrome and coronary artery disease.

PARL (presenilin-associated rhomboid-like) is a mitochondrial protein involved in mitochondrial membrane remodelling, and maps to a quantitative trait locus (3q27) associated with metabolic traits. Recently the rs3732581 (Leu262Val) variant was found to be associated with increased levels of plasma insulin, a finding not replicated in a larger cohort. The aim of the current study was to investigate the associations between rs3732581 and levels of plasma insulin, metabolic syndrome (MetS) and its components, and cardiovascular disease. The CUPID population consisted of 556 subjects with angiographically proven CAD and the CUDAS cohort consisted of 1,109 randomly selected individuals from Perth, Western Australia. Samples were genotyped using mutation-specific PCR. No significant associations were observed between rs3732581 and levels of plasma insulin, glucose, BMI or MetS in either population. However, carriers of the minor allele had significantly lower mean intima-media thickness (IMT) [0.69 mm, 95% CI (0.69, 0.70 mm); P = 0.004], compared with major allele homozygotes [mean IMT = 0.71 mm, 95% CI (0.70, 0.72 mm)] in the CUDAS population. Further analysis using a recessive model showed homozygous carriers of the minor allele were predisposed to CAD [OR 1.55, 95% CI (1.11, 2.16); P = 0.01]. Despite the functional evidence for a role of PARL in regulating insulin levels, no association with rs3732581 was found in the current study. Additionally, there were no associations with glucose levels, BMI or MetS. There were significant effects of the variant on mean IMT and risk of CAD. A role for PARL in metabolic conditions cannot be excluded and more comprehensive genetic studies are warranted.

Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population.

The objective of this study was to determine whether single nucleotide polymorphisms (SNPs) in the Interleukin-1 (IL-1) gene family are associated with central obesity and metabolic syndrome in a coronary heart disease population. The IL-1 alpha C-889T (rs1800587) and IL-1 beta +3954 (rs1143634) SNPs were studied in a Western Australian coronary heart disease (CHD) population (N = 556). Subjects who were TT homozygous at either SNP had larger waist circumference (IL-1 alpha: 1.8 cm greater, P = 0.04; IL-1 beta: 4 cm greater, P = 0.0004) compared with major allele homozygotes. Individuals with two copies of the IL-1 alpha:IL-1 beta T:T haplotype had greater waist circumference (4.7 cm greater, P = 0.0001) compared to other haplotypes. There was a significant interaction between the IL-1 beta SNP and BMI level on waist circumference (P = 0.01). When the cohort was stratified by median BMI, TT carriers for IL-1 beta with above median BMI had greater waist circumference (6.1 cm greater, P = 0.007) compared to baseline carriers, whilst no significant association was seen in the below median group. Similarly, when the cohort was stratified by median fibrinogen level (IL-1 alpha interaction P = 0.01; IL-1 beta interaction P = 0.04), TT carriers for both SNPs in the above median fibrinogen group had greater waist circumference (IL-1 alpha 2.7 cm greater, P = 0.007; IL-1 beta 3.3 cm greater, P = 0.003) compared with major allele homozygotes. This association was not seen in the below median group. Also, we found a trend of increased metabolic syndrome for IL-1 beta TT homozygotes (P = 0.07). In conclusion, our findings suggest that in a CHD population IL-1 gene polymorphisms may be involved in increased central obesity, and the genetic influences are more evident among patients who have a higher level of obesity or inflammatory markers.

Abnormal glucose regulation in an Australian acute coronary syndrome population: a prospective study.

BACKGROUND: Abnormal glucose regulation (AGR) is common and an adverse risk factor in patients presenting with acute coronary syndromes (ACS). METHODS: We prospectively evaluated the prevalence of AGR in 300 ACS patients. Fasting blood glucose (BGL), glycated haemoglobin (HbA1c) and urinary albumin creatinine ratio (ACR) were performed. Patients without diabetes completed an oral glucose tolerance test (OGTT) >or=4 weeks post-discharge. RESULTS: On admission, AGR prevalence was 60%; 32% (n=94) with diabetes and 28% (n=83) with IFG. OGTT completed in 157 patients, detected new diabetes in 5% (n=8), IGT in 24% (n=37), and IFG in 6% (n=10). In 91 patients with normal admission fasting BGL, 25% (n=23) had AGR on OGTT. Conversely, in 62 patients with admission IFG, 50% (n=31) had a normal OGTT. Patients with versus those without AGR on OGTT had higher adjusted geometric mean HbA1c (5.92; 95% CI 5.81-6.02 vs. 5.66; 95% CI, 5.59-5.74, P=0.001) and urinary ACR (1.38; 95% CI, 0.99-1.91 vs. 0.74; 95% CI, 0.58-0.94, P=0.003) levels. CONCLUSIONS: AGR is present in the majority of ACS patients and unrecognised in up to half of cases. OGTT improves the detection of AGR.

15-Lipoxygenase gene variants are associated with carotid plaque but not carotid intima-media thickness.

The major underlying cause of CHD is atherosclerosis, and oxidised LDL is known to play an important role in its development. We examined the role of three single nucleotide polymorphisms (SNPs) in the 15-lipoxygenase gene (ALOX15), in atherosclerosis. We genotyped three SNPs in the ALOX15 promoter in two Western Australian samples-1,111 community-based individuals and 556 with CHD. SNPs and haplotypes were tested for an association with carotid plaque, intima-media thickness and risk of CHD. The -611GG genotype was associated with increased likelihood of carotid plaque in CHD patients (OR = 4.01, 95%CI = 1.39-11.53, P = 0.005) and the C alleles of the G-220C and G-189C SNPs were associated with decreased likelihood of plaque among cases (OR = 0.66, 95%CI = 0.43-0.99, P = 0.05 and OR = 0.51, 95%CI = 0.34-0.78, P = 0.002 respectively). The GGG haplotype was associated with increased risk of carotid plaque in CHD patients (OR = 5.77, 95%CI = 1.82-18.29, P = 0.0007) and in community-based individuals under 53 years (OR = 4.15, 95%CI = 1.23-14.08, P = 0.02). No association was observed between ALOX15 SNPs or haplotypes and intima-media thickness. This study is novel as it is the first to examine the association between 15-lipoxygenase polymorphisms and atherosclerotic indicators. These findings suggest a possible role of ALOX15 polymorphisms in focal plaque formation.

Investigating the association between K198N coding polymorphism in EDN1 and hypertension, lipoprotein levels, the metabolic syndrome and cardiovascular disease.

Endothelin-1 is a potent vasoconstrictor in the body. Previous studies have identified associations between the coding polymorphism K198N and hypertension, systolic blood pressure and HDL levels. We sought to examine the evidence for these associations and, additionally, the association between K198N, insulin resistance, metabolic syndrome and coronary artery disease (CAD). We used generalised linear modelling to test K198N for association with hypertension and systolic blood pressure, lipid levels, insulin resistance scores and metabolic syndrome in a general cross-sectional community sample. Mean carotid intima media thickness and risk of carotid plaque were examined in the general population sample, and Gensini score was examined in a sample of patients with CAD. A case/control sample was used to examine the association of K198N with risk of CAD. There was no significant evidence for association between K198N and hypertension, systolic blood pressure, lipid levels, insulin resistance or metabolic syndrome in either population. The minor allele was marginally associated with increased mean IMT levels (P = 0.02) in the general population sample, although not with CAD in the case/control study or with the severity of disease in patients with CAD. In conclusion, we found no robust evidence for the associations between K198N and hypertension, systolic blood pressure or HDL levels seen in previous studies.

The apolipoprotein AII rs5082 variant is associated with reduced risk of coronary artery disease in an Australian male population.

Serum high density lipoprotein (HDL) levels are inversely related to the development of coronary artery disease (CAD). Apolipoproteins AI and AII are the major protein constituents of HDL particles. APOAI and APOAII genetic polymorphisms have been proposed to affect transcriptional efficiency of their respective genes, thereby altering serum lipid levels and influencing atherosclerotic disease risk. 556 subjects with angiographically proven CAD (>50% stenosis) and 1109 randomly selected individuals from metropolitan Perth, Western Australia, were included in an association study. APOAI -75G/A (rs670) and APOAII -256T/C (rs5082) polymorphisms were both found to be not associated with plasma HDL levels. In a case-control analysis of 484 male CAD patients and 498 male controls, individuals carrying the 'CC' genotype for the APOAII rs5082 polymorphism had significantly lower risk of CAD than the 'T' allele carriers (OR=0.57, 95% CI 0.39-0.84, p=0.004). The minor 'A' allele of the APOAI rs670 polymorphism was found to be not associated with CAD, contrary to previous reports. We conclude that the APOAII rs5082 polymorphism appears to be cardioprotective in this representative Caucasian Australian population.

Carotid intima-medial thickness measured on multiple ultrasound frames: evaluation of a DICOM-based software system.

BACKGROUND: Carotid intima-media thickness (CIMT) measured by B-mode ultrasonography is a marker of atherosclerosis and is commonly used as an outcome in intervention trials. We have developed DICOM-based software that measures CIMT rapidly on multiple end-diastolic image frames. The aims of this study were to compare the performance of our new software with older bitmap-based CIMT measurement software and to determine whether a ten-fold increase in the number of measurements used to calculate mean CIMT would improve reproducibility. METHODS: Two independent sonographers recorded replicate carotid scans in thirty volunteers and two blinded observers measured CIMT off-line using the new DICOM-based software and older bitmap-based software. A Bland-Altman plot was used to compare CIMT results from the two software programs and t-tests were used to compare analysis times. F-tests were used to compare the co-efficients of variation (CVs) from a standard six-frame measurement protocol with CVs from a sixty-frame measurement protocol. Ordinary least products (OLP) regression was used to test for sonographer and observer biases. RESULTS: The new DICOM-based software was much faster than older bitmap-based software (average measurement time for one scan 3.4 +/- 0.6 minutes versus 8.4 +/- 1.8 minutes, p < 0.0001) but CIMT measurements were larger than those made using the alternative software (+0.02 mm, 95%CI 0.01-0.03 mm). The sixty-frame measurement protocol had worse reproducibility than the six-frame protocol (inter-observer CV 5.1% vs 3.5%, p = 0.004) and inter and intra-observer biases were more pronounced in the sixty-frame than the six-frame results. CONCLUSION: While the use of DICOM-based software significantly reduced analysis time, a ten-fold increase in the number of measurements used to calculate CIMT did not improve reproducibility. In addition, we found that observer biases caused differences in mean CIMT of a magnitude commonly reported as significant in intervention trials. Our results highlight the importance of good study design with concurrent controls and the need to ensure that no observer drift occurs between baseline and follow-up measurements when CIMT is used to monitor the effect of an intervention.

Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease.

High-density lipoprotein cholesterol (HDL-C) is a known inverse predictor of coronary heart disease (CHD) and is thus a potential therapeutic target. Cholesteryl ester transfer protein (CETP) is a key protein in HDL-C metabolism such that elevated CETP activity is associated with lower HDL-C. Currently available HDL-C raising drugs are relatively ineffective and evidence suggesting the role of CETP in HDL-C levels has promoted the development of CETP inhibitors as potential therapeutic agents for CHD. We investigated three SNPs in the CETP gene in two cross-sectional community-based populations (n = 1,574 and 1,109) and a population of 556 CHD patients to determine if reduced CETP activity due to genetic variations in the CETP gene would increase HDL-C levels and reduce the risk of CHD. CETP genotypes and haplotypes were tested for association with lipid levels, CETP activity and risk of CHD. Multivariate analysis showed the common AAB2 haplotype defined by the G-2708A, C-629A and TaqIB polymorphisms, was consistently associated with reduced CETP activity and increased HDL-C levels. A mean increase in HDL-C levels of 0.16-0.24 mmol/l was observed in individuals with two copies of the AAB2 haplotype relative to non AAB2 carriers across all three populations (P < 0.001). A case-control study of males indicated no association between single SNPs or haplotypes and the risk of CHD. These results suggest that raising HDL-C via CETP inhibition may not alter risk of CHD. Randomized control trials are needed to determine whether CETP inhibition will in reality reduce risk of CHD by raising HDL-C.

Rapid fatty acid ethyl ester synthesis by porcine myocardium upon ethanol infusion into the left anterior descending coronary artery.

Fatty acid ethyl esters (FAEEs), nonoxidative metabolites of ethanol, have been implicated in ethanol-induced heart injury. To assess the in vivo production of FAEEs by myocardial tissue, we used a modified ethanol ablation procedure in pigs. A controlled 60-minute ethanol infusion was administered into the distal left anterior descending coronary artery in seven swine; serial blood sampling of the coronary sinus and peripheral vein before, during, and after infusion allowed measurement of FAEE production and ethanol levels in the coronary sinus and the peripheral circulation. In a single animal, FAEEs were also quantified from nine different sites within the myocardium. FAEEs were produced by the heart within 5 minutes of exposure to ethanol, with very high concentrations of FAEEs detected in coronary sinus blood. Significant variability in amounts of FAEEs was detected in different regions of the heart tissue. A strong correlation was found between coronary sinus FAEEs and ethanol concentration (r = 0.9241, P < 0.00001). FAEE production by the heart after delivery of ethanol into the left anterior descending coronary artery was rapid, reaching levels in the coronary sinus blood 4 to 10 times greater than that found in peripheral blood after ethanol intake. These data demonstrate that FAEEs may be mediators of ethanol-induced cardiotoxicity.

Interleukin-18 levels are not associated with subclinical carotid atherosclerosis in a community population. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS).

Interleukin (IL)-18 is a novel proinflammatory cytokine that plays a central role in innate and acquired immunity, making it a likely inflammatory candidate in atherosclerosis. We investigated whether circulating IL-18 levels were associated with subclinical atherosclerosis in a community population. Carotid intimal medial thickness (IMT) and carotid plaques were assessed in a cross-sectional study of 1111 randomly selected community subjects, aged 27-77 years. Baseline levels of IL-18, IL-6, high sensitive CRP (hsCRP), fibrinogen and white cell counts were measured along with conventional cardiovascular risk factors. Men had higher mean IL-18 levels than women (P<0.0001). Spearman rank correlations (r(s)) showed that IL-18 was weakly correlated with all inflammatory markers in the whole population (r(s) between 0.11 and 0.23, all P<0.001). IL-18 was also correlated with conventional risk factors including waist-hip ratio, BMI, blood pressure, triglycerides, HDL (inversely) and pack-years smoking (r(s) between 0.18 and 0.39, all P<0.001) but not with LDL-cholesterol. Independent predictors of IL-18 concentrations were waist-hip ratio, HDL, IL-6, hsCRP and hypertension. There was a positive univariate association of IL-18 levels with carotid IMT (P<0.001) and plaque prevalence (P<0.001) but no residual association after adjustment for conventional risk factors (both P>0.05). In a cross-sectional community population, IL-18 levels were related to traditional risk factors and inflammatory markers but were not independently associated with subclinical carotid atherosclerosis.

Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance.

OBJECTIVE: Activated innate immunity is thought to be involved in the pathogenesis of metabolic syndrome and type 2 diabetes. Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine with important regulatory functions in the innate immune response. We sought to determine whether an elevated IL-18 concentration was a risk predictor for metabolic syndrome in a community population independent of obesity and hyperinsulinemia. METHODS AND RESULTS: A representative general population, aged 27 to 77 years, without clinical diabetes was studied for clinical and biochemical risk factors for metabolic syndrome. Serum IL-18 concentration measured in 955 subjects correlated with metabolic syndrome traits including body mass index (BMI), waist circumference, triglyceride, high-density lipoprotein (inversely), and fasting glucose and insulin levels (all P<0.001). Mean IL-18 levels rose progressively with the increasing number of metabolic risk factors (ANOVA P<0.001). After adjusting for age, gender, BMI, and insulin levels, increasing IL-18 tertiles were associated with an odds ratio for metabolic syndrome of 1.0, 1.42, and 2.28, respectively (P trend=0.007). The graded risk relation was even stronger in nonobese subjects and not attenuated when adjusted for C-reactive protein and IL-6 levels. CONCLUSIONS: Our findings support the hypothesis that activation of IL-18 is involved in the pathogenesis of the metabolic syndrome.

Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population.

BACKGROUND AND OBJECTIVES: Arterial remodelling contributes to the development of hypertension. Stromelysin-1 (MMP-3), a member of the matrix metalloproteinase family may contribute to this process. Stromelysin-1 gene expression is partly regulated by a common polymorphism in the promoter region of either five or six consecutive adenosine bases (5A/6A). METHODS AND RESULTS: A cross-sectional study of 1111 randomly selected male and female community subjects (27-77 years), were assessed for conventional cardiovascular risk factors and stromelysin-1 5A-1171-6A genotype. Multivariate analysis showed an independent association between the stromelysin-1 genotype and blood pressure that was recessive for the 5A/5A genotype. Subjects with the 5A/5A genotype had a higher mean systolic blood pressure (SBP) (+4.2 mmHg) and diastolic blood pressure (DBP) (+2.2 mmHg) compared to subjects with 5A/6A and 6A/6A genotypes. Subgroup analysis revealed an independent association of the 5A/5A genotype with SBP (+3.6 mmHg, P = 0.001) and DBP (+2.0 mmHg, P = 0.004) in subjects not on blood pressure medication. Whereas subjects with the 5A/5A genotype and taking medication had a higher mean SBP (+7.4 mmHg, P = 0.02) and DBP (+2.7 mmHg, P = 0.11). Multivariate analysis in the whole population showed there was no association between genotypes and mean intimal-medial wall thickness (IMT) (P = 0.87) or the likelihood of carotid plaque formation. CONCLUSIONS: The stromelysin-1 5A-1171-6A genotype is an important determinant of blood pressure in this general population sample.