Decreased levels of stem cell factor in subjects with incident coronary events.

BACKGROUND: It has been proposed that vascular progenitor cells play an important role in vascular repair, but their possible clinical importance in cardiovascular disease has not been fully characterized. Vascular endothelial growth factor A, placental growth factor and stem cell factor (SCF) are three growth factors that are important in recruiting vascular progenitor cells. In this study, we investigated the association between the plasma levels of these growth factors and incident coronary events (CEs). METHODS: Levels of the three growth factors were measured using the proximity extension assay technique in baseline plasma samples from 384 subjects with a first CE (mean follow-up 14.0 ± 4.3 years) and 409 event-free control subjects matched by sex and age, as well as in homogenates from 201 endarterectomy specimens. RESULTS: After controlling for known cardiovascular disease risk factors in a Cox regression model, subjects in the lowest SCF tertile had a hazard ratio of 1.70 (95% confidence interval 1.14-2.54) compared with subjects in the highest SCF tertile. Lower SCF levels were also associated with more severe carotid disease, less fibrous atherosclerotic plaques and an increased incidence of heart failure. Expression of the SCF receptor c-kit was demonstrated in the subendothelial layer and fibrous cap of human atherosclerotic plaques. Smokers and subjects with diabetes had decreased levels of SCF compared with control subjects. CONCLUSION: To our knowledge, this is the first clinical study to provide evidence to support a key role for SCF and progenitor cells in vascular repair. We suggest that the SCF-c-kit pathway may be a promising biomarker and therapeutic target in cardiovascular disease.

Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers.

BACKGROUND: Genetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking-related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and lung cancer. OBJECTIVES: To test whether rs1051730 (C/T), a tag for multiple variants in the CHRNA5-CHRNA3-CHRNB3 cluster, is associated with a change in risk of smoking-related mortality and morbidity in the Malmö Diet and Cancer study, a population-based prospective cohort study. METHODS: At baseline participants were classified as current (n = 6951), previous (n = 8426) or never (n = 9417) smokers. Cox-proportional hazards models were used to determine the correlation between rs1051730 and incidence of first COPD, tobacco-related cancer, other cancer and cardiovascular disease (CVD), and total mortality due to these causes, during approximately 14 years of follow-up. RESULTS: Amongst current smokers there were 480 first incident COPD events, 852 tobacco-related cancers, 810 other cancers and 1022 CVD events. A total of 1508 deaths occurred, including 500 due to CVD, 102 due to respiratory diseases and 677 due to cancer. In adjusted additive models, an increasing number of T alleles were associated with a gradual increase in total mortality, incident COPD and tobacco-related cancer, even after adjustment for smoking quantity. No significant associations were observed amongst never smokers. CONCLUSION: Our data suggest that gene variance in the CHRNA5-CHRNA3-CHRNB4 cluster is associated with an increased risk of death, incidence of COPD and tobacco-related cancer in smokers. These findings indicate an individual susceptibility to tobacco use and its complications; this may be important when targeting and designing smoking cessation therapies.

CD4+ CD56+ natural killer T-like cells secreting interferon-γ are associated with incident coronary events.

BACKGROUND: CD3(+) CD56(+) natural killer T (NKT)-like cells are a subset of T cells characterized by expression of NK receptors and potent antitumour activity. It has also been suggested that they have a role in autoimmune disease, and levels of NKT-like cells are elevated in patients with coronary disease. OBJECTIVES: To investigate whether high levels of CD3(+) CD56(+) NKT-like cells are associated with an increased incidence of cardiovascular disease and a lower incidence of cancer. METHODS: This was a prospective study including 700 subjects participating in the baseline investigation of the Malmö Diet and Cancer study between 1991 and 1994. Leucocytes obtained at the baseline investigation and stored at -140 °C were thawed and CD3(+) CD56(+) cells analysed by flow cytometry. The incidence rates of cancer and coronary events during a mean follow-up of 15 years were determined through national registers. RESULTS: Subjects in the lowest tertile of interferon (IFN)-γ-expressing CD4(+) CD56(+) cells were found to have an increased risk of incidence of coronary events (log-rank test: P < 0.05). This association remained significant after controlling for age, sex, smoking, body mass index, hypertension, diabetes and the Th1/Th2 and Th1/Treg cell ratios in a Cox proportional hazards regression model (hazard ratio 1.98, 95% confidence interval 1.24-3.16), but not when the LDL/HDL ratio was included in the model. There were no associations between CD3(+) CD56(+) NKT-like cells and incident cancer. CONCLUSIONS: The present results could not confirm the hypothesis that low levels of CD3(+) CD56(+) NKT-like cells are associated with a higher incidence of cancer and a lower incidence of cardiovascular disease. However, we found that low levels of IFN-γ-expressing CD3(+) CD4(+) CD56(+) NKT-like cells were associated with an increased incidence of coronary events and that this association may be dependent on lipoproteins.

The Swedish CArdioPulmonary BioImage Study: objectives and design.

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Risk factors for the progression of carotid intima-media thickness over a 16-year follow-up period: the Malmö Diet and Cancer Study.

OBJECTIVE: To evaluate the progression of carotid intima-media thickness (IMT) in the common carotid artery (CCA) and the bifurcation over a mean follow-up of 16 years in relation to cardiovascular risk factors. METHODS: The study population included 3426 middle-aged Swedish men and women participating in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the cardiovascular cohort of the Malmö Diet and Cancer Study (MDCS). RESULTS: There were differences in risk factor patterns in arterial segments in that diabetes and male sex were associated with the progression of IMT in the bifurcation, but not in the CCA, and high-density lipoprotein cholesterol (HDL) was associated with the progression of IMT in the CCA, but not in the bifurcation. Favourable changes in systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL) and HDL during follow-up decreased the IMT progression rate in the CCA. There was a cumulative relationship between traditional cardiovascular risk factors (i.e., regular smoking, LDL/HDL-ratio ≥ 3, hypertension) and IMT progression rates. The odds ratio (OR) of high IMT CCA progression rate (>75th percentile) was 1.0 (reference), 1.4 (95% CI: 1.1, 1.7), 1.7 (95% CI: 1.3, 2.2) and 2.1 (95% CI: 1.4, 3.1), respectively, for individuals with none, one, two, and three risk factors. CONCLUSION: There were differences in the associations between risk factors and progression rate in different arterial segments. Favourable changes in SBP and lipids during the follow-up period were associated with reduced IMT progression rates in the CCA.

Snus (Swedish smokeless tobacco) use and risk of stroke: pooled analyses of incidence and survival.

BACKGROUND: Snus is a moist smokeless tobacco product with high nicotine content. Its use has a short-term effect on the cardiovascular system, but the relationship between snus use and stroke is unclear. OBJECTIVE: The aim of this study was to assess the associations between use of snus and incidence of and survival after stroke, both overall and according to subtypes. METHODS: Pooled analyses of eight Swedish prospective cohort studies were conducted, including 130 485 men who never smoked. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of incidence and death after diagnosis using Cox proportional hazard regression models and case fatality and survival using logistic regression and Kaplan-Meier methods, respectively. RESULTS: No associations were observed between the use of snus and the risk of overall stroke (HR 1.04, 95% CI 0.92-1.17) or of any of the stroke subtypes. The odds ratio (OR) of 28-day case fatality was 1.42 (95% CI 0.99-2.04) amongst users of snus who had experienced a stroke, and the HR of death during the follow-up period was 1.32 (95% CI 1.08-1.61). CONCLUSION: Use of snus was not associated with the risk of stroke. Hence, nicotine is unlikely to contribute importantly to the pathophysiology of stroke. However, case fatality was increased in snus users, compared with nonusers, but further studies are needed to determine any possible causal mechanisms.

Red cell distribution width, haemoglobin A1c and incidence of diabetes mellitus.

OBJECTIVE: Hyperglycaemia has multiple effects on the red blood cell (RBC), including glycation of haemoglobin, reduced deformability and reduced lifespan. Red cell distribution width (RDW) is a measure of the heterogeneity of erythrocyte volumes. The aim of this study was to explore the relationships between RDW and glucose, haemoglobin A1c (HbA1c) and incidence of diabetes mellitus (DM). DESIGN, SETTING AND SUBJECTS: RDW and mean corpuscular volume were measured in 26 709 non-diabetic participants (aged 45-73 years) from the population-based Malmö Diet and Cancer cohort. HbA1c and fasting venous blood glucose levels were measured in 4845 subjects. MAIN OUTCOME MEASURE: Incidence of DM (n = 2944) over 14 years of follow-up was studied by linkage with national and local DM registers. RESULTS: Individuals with low RDW had significantly higher risk of developing DM [adjusted hazard ratio (HR) 1.48, 95% confidence interval (CI) 1.29-1.70, for 1st vs. 4th quartile], especially in subjects with impaired fasting glucose (n = 416) (HR 2.15, 95% CI 1.12-4.14). Low RDW was also associated with significantly higher waist circumference and glucose, insulin and triglyceride concentrations. By contrast, RDW was significantly and positively associated with HbA1c, corresponding an increase in HbA1c of 0.10% per 1 SD increase in RDW. CONCLUSION: Low RDW is associated with increased incidence of DM independently of other risk factors. We propose that low RDW could be a surrogate marker of reduced RBC survival, with lower HbA1c due to shorter duration of glucose exposure. RDW is a biomarker that could improve risk assessment for individuals at risk of developing DM.

Cystatin C identifies cardiovascular risk better than creatinine-based estimates of glomerular filtration in middle-aged individuals without a history of cardiovascular disease.

OBJECTIVES: Creatinine- and cystatin C-based estimates of renal function are considered to be cardiovascular disease (CVD) risk factors, but the clinical utility in middle-aged subjects without a history of CVD is controversial. DESIGN: We related plasma cystatin C and creatinine-based glomerular filtration rate (GFR) [MDRD, CKD-EPI-2009, and CKD-EPI-comb (a combination of creatinine and cystatin C)] to incident CVD, CVD mortality, all-cause mortality, and heart failure in 4650 middle-aged subjects without CVD. RESULTS: The hazard ratio (HR) per standard deviation increment (95% CI) of cystatin C predicted incident CVD (1.22, 1.11-1.33; P < 0.0001), CVD mortality (1.44, 1.24-1.66; P < 0.0001), all-cause mortality (1.15, 1.05-1.26; P = 0.002), and heart failure (1.27, 1.05-1.55; P = 0.02), whereas MDRD and CKD-EPI-2009 only predicted CVD mortality (0.79, 0.66-0.93; P = 0.006 and 0.78, 0.66-0.92; P = 0.003, respectively). Cystatin C led to a significant increase in the net reclassification improvement for all endpoints, except heart failure. Only within the quartile with the worst renal function were all measures related to all-cause and CVD mortality. The top 25% of cystatin C in the population significantly predicted risk of incident CVD and CVD mortality, whereas MDRD and CKD-EPI-2009 were predictors of CVD mortality only at a GFR < 60 mL/min/1.73 m(2) (11-13% of the population) and of incident CVD only at a GFR < 45 mL/min/1.73 m(2) (<1% of the population). CONCLUSION: Cystatin C is a better risk marker for CVD morbidity and mortality than creatinine-based GFR. Whether this is explained by cystatin C being a better marker for true GFR or through other effects of cystatin C remains to be shown.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Ceruloplasmin and atrial fibrillation: evidence of causality from a population-based Mendelian randomization study.

OBJECTIVES: Inflammatory diseases and inflammatory markers secreted by the liver, including C-reactive protein (CRP) and ceruloplasmin, have been associated with incident atrial fibrillation (AF). Genetic studies have not supported a causal relationship between CRP and AF, but the relationship between ceruloplasmin and AF has not been studied. The purpose of this Mendelian randomization study was to explore whether genetic polymorphisms in the gene encoding ceruloplasmin are associated with elevated ceruloplasmin levels, and whether such genetic polymorphisms are also associated with the incidence of AF. DESIGN: Genetic polymorphisms in the ceruloplasmin gene (CP) were genotyped in a population-based cohort study of men from southern Sweden (Malmö Preventive Project; n = 3900). Genetic polymorphisms associated with plasma ceruloplasmin concentration were also investigated for association with incident AF (n = 520) during a mean follow-up of 29 years in the same cohort. Findings were replicated in an independent case-control sample (The Malmö AF cohort; n = 2247 cases, 2208 controls). RESULTS: A single nucleotide polymorphism (rs11708215, minor allele frequency 0.12) located in the CP gene promoter was strongly associated with increased levels of plasma ceruloplasmin (P = 9 × 10(-10) ) and with AF in both the discovery cohort [hazard ratio 1.24 per risk allele, 95% confidence interval (CI) 1.06-1.44, P = 0.006] and the replication cohort (odds ratio 1.13, 95% CI 1.02-1.26, P = 0.02). CONCLUSIONS: Our findings indicate a causal role of ceruloplasmin in AF pathophysiology and suggest that ceruloplasmin might be a mediator in a specific inflammatory pathway that causally links inflammatory diseases and incidence of AF.

Red blood cell distribution width is associated with incidence of atrial fibrillation.

OBJECTIVES: Red blood cell distribution width (RDW), a measure of variation in erythrocyte volume, has been associated with several cardiovascular disorders, but the relationship with atrial fibrillation (AF) remains unclear. We investigated the association between RDW and incidence of first hospitalization due to AF in a population-based cohort. DESIGN: Red blood cell distribution width was measured in 27,124 subjects from the general population (age 45-73 years, 62% women) with no history of AF, heart failure, myocardial infarction or stroke. The association between baseline RDW and incidence of AF identified from the Swedish Hospital Discharge Register was evaluated. RESULTS: During a mean follow-up of 13.6 years, 1894 subjects (53% men) were hospitalized with a diagnosis of AF. After adjustment for potential confounding factors, including cardiovascular disease risk factors, nutrient intake (iron, vitamin B12 and folate) and several haematological parameters (haemoglobin concentration, mean corpuscular volume and corpuscular haemoglobin content), the hazard ratio (HR) for incidence of AF was 1.33 [95% confidence interval (CI) 1.16-1.53] for the fourth versus first quartile of RDW (P for trend <0.001). The results were essentially unchanged when subjects with incident myocardial infarction or hospitalizations because of heart failure were censored from the analysis (HR 1.30, 95% CI 1.13-1.51; P for trend = 0.001). CONCLUSION: Red blood cell distribution width was associated with incidence of AF independently of several cardiovascular, nutritional and haematological factors in this study of middle-aged subjects from the general population.

Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke?

BACKGROUND AND PURPOSE: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. METHODS: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. RESULTS: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. CONCLUSIONS: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants.

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

Chromosome 9p21 genetic variation explains 13% of cardiovascular disease incidence but does not improve risk prediction.

OBJECTIVES: To evaluate the proportion of cardiovascular disease (CVD) incidence that is explained by genetic variation at chromosome 9p21 and to test whether such variation adds incremental information with regard to CVD prediction, beyond traditional risk factors. DESIGN, SETTING AND PARTICIPANTS: rs4977574 on chromosome 9p21 was genotyped in 24 777 subjects from the Malmö Diet and Cancer study who were free from CVD prior to the baseline examination. Association between genotype and incident CVD (n = 2668) during a median follow-up of 11.7 years was evaluated in multivariate Cox proportional hazard models. Analyses were performed in quartiles of baseline age, and linear trends in effect size across age groups were estimated in logistic regression models. RESULTS: In additive models, chromosome 9p21 significantly predicted CVD in the entire population (hazard ratio 1.17 per G allele, 95% confidence interval 1.11-1.23, P < 0.001). Effect estimates increased from the highest (Q4) to the lowest quartile (Q1) of baseline age, but this trend was not significant. The overall population attributable risk conferred by chromosome 9p21 in fully adjusted models was 13%, ranging from 17% in Q1 to 11% in Q4. Addition of chromosome 9p21 to traditional risk factors only marginally improved predictive accuracy. CONCLUSION: The high population attributable risk conferred by chromosome 9p21 suggests that future interventions interfering with downstream mechanisms of the genetic variation may affect CVD incidence over a broad range of ages. However, variation of chromosome 9p21 alone does not add clinically meaningful information in terms of CVD prediction beyond traditional risk factors at any age.

High levels of cystatin C predict the metabolic syndrome: the prospective Malmö Diet and Cancer Study.

OBJECTIVE: Cystatin C is a novel marker of cardiovascular disease (CVD); however, the underlying mechanisms remain unclear. Here, we prospectively investigated whether plasma levels of cystatin C predict new-onset metabolic syndrome (MetS) as well as long-term progression and incidence of the different components of the MetS. METHODS: Cystatin C was measured in 1502 individuals included in the Malmö Diet and Cancer cardiovascular cohort (mean age 56 years, 59% women) who were free from the MetS at baseline and subsequently underwent a follow-up examination after a median of 16 years. MetS was defined according to the NCEP-ATP-III guidelines. Logistic regression was used to adjust for covariates. MAIN OUTCOME MEASURES: Metabolic syndrome and long-term progression as well as incidence of the different components of the MetS. RESULTS: During follow-up, 428 subjects developed new-onset MetS. In age- and sex-adjusted analysis, compared with the lowest quartile of cystatin C, the odds ratios (95% confidence interval) for incident MetS in subjects with cystatin C levels in quartiles 2, 3 and 4 were 1.00 (0.71-1.40), 1.48 (1.06-2.07) and 1.91 (1.37-2.68), respectively (Ptrend  < 0.001); this linear association remained significant even after full multivariate adjustment (Ptrend  = 0.041). Interestingly, in this fully adjusted model, long-term progression of abdominal obesity was the only component of the MetS significantly associated with increasing quartiles of baseline cystatin C levels (Ptrend  = 0.008). CONCLUSION: These findings suggest that cystatin C may adversely affect metabolic factors, particularly abdominal obesity, thus contributing to development of the MetS. Our results may help to explain the link between cystatin C and development of CVD.

Association between CD8+ T-cell subsets and cardiovascular disease.

BACKGROUND: The findings of experimental studies suggest that the immune system plays a key role in atherosclerosis, but the clinical importance of different immune cells in cardiovascular disease remains poorly characterized. In this study we investigated the association between CD8(+) T cells and carotid disease as well as development of cardiovascular disease events. METHODS: The study cohort comprised 700 subjects from the cardiovascular arm of the Malmö Diet and Cancer Study. Peripheral blood mononuclear cells, obtained at the 1991-1994 baseline investigation and stored at -140 °C, were thawed and the different CD8(+) T-cell populations analysed by flow cytometry. Baseline carotid intima-media thickness and stenosis were assessed by ultrasonography and clinical events were monitored through validated national registers. RESULTS: Subjects with a high fraction of CD8(+) T cells were characterized by decreased cytokine release from activated leucocytes, metabolic signs of insulin resistance and increased incidence of coronary events; hazard ratios (95% confidence intervals) for the second and third tertiles of CD8(+) T cells were 2.57 (1.16, 5.67) and 2.61 (1.19, 5,71), respectively, in a Cox proportional hazards regression model. Correlations were found between the fraction of CD8(+) CD25(+) T cells and the degree of carotid stenosis (r = 0.11, P < 0.01), and between the CD8(+) CD56(-) IFN-γ(+) T-cell fraction and the degree of stenosis (r = -0.18, P < 0.005). The association between CD8(+) CD56(-) IFN-γ(+) T cells and carotid stenosis remained significant after controlling for major cardiovascular disease risk factors. CONCLUSION: This study provides prospective clinical evidence for a role of CD8(+) T cells in cardiovascular disease and suggests the existence of CD8(+) T-cell subsets with different pathological functions.

Copeptin, a marker of vasopressin, in abdominal obesity, diabetes and microalbuminuria: the prospective Malmö Diet and Cancer Study cardiovascular cohort.

BACKGROUND: High plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin pro-hormone, has been associated with the metabolic syndrome (MetS), diabetes mellitus (DM) development and nephropathy. Here we tested whether elevated copeptin level is associated with later development of the MetS, its individual components and microalbuminuria. METHODS: We analysed copeptin at baseline (1991-1994) in the population-based Malmö Diet and Cancer Study cardiovasular cohort and re-examined 2064 subjects 15.8 years later (mean age 72.8 years, 59% women) with oral glucose tolerance test and measurement of MetS and its individual components. RESULTS: After age and sex adjustment, increasing quartiles of copeptin at baseline (the lowest quartile as reference) were associated with MetS (P for trend=0.008), incident abdominal obesity (P for trend=0.002), DM (P for trend=0.001) and microalbuminuria (P for trend=0.002). After additional adjustment for all the MetS components at baseline, increasing copeptin quartiles predicted incident abdominal obesity (odds ratios 1.55, 1.30 and 1.59; P for trend=0.04), DM (odds ratios 1.18, 1.32 and 1.46; P for trend=0.04) and microalbuminuria (odds ratios 1.05, 1.08 and 1.65; P for trend=0.02) but not MetS (P for trend=0.19) at the reexamination. Further, the relationship between copeptin and microalbuminuria was independent of baseline C-reactive protein, incident DM and incident hypertension. CONCLUSION: Copeptin independently predicts DM and abdominal obesity but not the cluster of MetS. Apart from predicting DM and abdominal obesity, elevated copeptin signals increased risk of microalbuminuria. Interestingly, the association between copeptin and later microalbuminuria was independent of both prevalent and incident DM and hypertension. Our findings suggest a relationship between a dysregulated vasopressin system and cardiometabolic risk, which could have implications for risk assessment and novel preventive treatments.