Vitamin D levels predict all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome: the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study

OBJECTIVE

Optimal vitamin D levels are associated with reduced cardiovascular and all-cause mortality. We investigated whether optimal 25-hydroxyvitamin D (25[OH]D) is protective in individuals with the metabolic syndrome.

RESEARCH DESIGN AND METHODS

The Ludwigshafen Risk and Cardiovascular Health (LURIC) study is a cohort study of subjects referred for coronary angiography between 1997 and 2000, from which 1,801 with the metabolic syndrome were investigated. Mortality was tracked for a median of 7.7 years. Multivariable survival analysis was used to estimate the association between 25(OH)D levels and mortality.

RESULTS

Most subjects (92%) had suboptimal levels of 25(OH)D (<75 nmol/L), with 22.2% being severely deficient (<25 nmol/L). During follow-up, 462 deaths were recorded, 267 (57.8%) of which were cardiovascular in origin. After full adjustment, including the metabolic syndrome components, those with optimal 25(OH)D levels showed a substantial reduction in all-cause (hazard ratio [HR] 0.25 [95% CI 0.13–0.46]) and cardiovascular disease mortality (0.33 [0.16–0.66]) compared with those with severe vitamin D deficiency. For specific cardiovascular disease mortality, there was a strong reduction for sudden death (0.15 [0.04–0.63]) and congestive heart failure (0.24 [0.06–1.04]), but not for myocardial infarction. The reduction in mortality was dose-dependent for each of these causes.

CONCLUSIONS

Optimal 25(OH)D levels substantially lowered all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome. These observations call for interventional studies that test whether vitamin D supplementation provides a useful adjunct in reducing mortality in these subjects.The cluster of cardiovascular risk factors termed the metabolic syndrome is an important determinant of vascular disease (1–4), which is the major cause of morbidity and mortality worldwide. Available pharmacologic and lifestyle interventions have been shown to attenuate the hazard associated with the syndrome and its components (5,6). However, these treatment modalities still fail to normalize risk, and much research effort is therefore dedicated to exploring additional treatment approaches, for which targeting suboptimal vitamin D levels presents a potentially important option.Studies in the U.S. and Europe show that most of the general population have 25-hydroxyvitamin D (25(OH)D) levels below the target level of 75 nmol/L (7,8), with levels being even lower in those with the metabolic syndrome (9). The high prevalence of a poor vitamin D status has gained much public health interest because of its association with cardiovascular disease conditions, including arterial hypertension, diabetes, and the metabolic syndrome. Moreover, prospective studies have shown that low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality (10–13). Whether these associations are causal remains to be explored, but it is often stressed that vitamin D metabolites regulate a very wide range of genes with significance for overall and cardiovascular health (14), making causality a plausible hypothesis.In light of nascent evidence for a protective effect of optimal vitamin D levels, it is perhaps surprising that no studies have specifically addressed whether vitamin D levels predict mortality and cardiovascular events in subjects with the metabolic syndrome. Such data are needed to assess the potential of supplementation studies in this increased-risk population. We therefore studied a large cohort of subjects referred for coronary angiography, focusing our analyses on 1,801 individuals who fulfilled the criteria for the metabolic syndrome.     

Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study

BACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults. OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals. PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications. RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low. CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.     

Metabolic syndrome as a predictor of all-cause and cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

OBJECTIVE: The aim of this study was to assess in an 11-year survival follow-up of a population-based cohort of type 2 diabetes the predictive role of World Health Organization-defined metabolic syndrome, independent of conventional cardiovascular risk factors. RESEARCH DESIGN AND METHODS: During the follow-up (1991-2001), 1,565 patients were regularly examined with centralized measurements of HbA(1c). The independent role of the metabolic syndrome as a predictor of all-cause and cardiovascular mortality was assessed with multivariate Cox proportional hazards modeling. RESULTS: At baseline, the prevalence of the metabolic syndrome was 75.6% (95% CI 73.6-77.9). Results are based on 685 deaths (520 with the metabolic syndrome and 165 without it) in 10,890.2 person-years of observations. With respect to subjects without the metabolic syndrome, those with the metabolic syndrome had a similar hazard ratio (HR) of cardiovascular mortality after adjustment for age, sex, smoking, total cholesterol level, and coronary heart disease. In contrast, relative to subjects with diabetes only, the HR of subjects with only one component of the syndrome was 2.92 (1.16-7.33), independent of other risk factors. CONCLUSIONS: We found that 1) the prevalence of the metabolic syndrome in a population-based cohort of type 2 diabetes is high (75.6%); 2) the metabolic syndrome is not a predictor of 11-year all-cause and cardiovascular mortality; and 3) more than twofold higher cardiovascular risk, independent of conventional risk factors, is evident in diabetic subjects with only one component of the syndrome compared with those with diabetes only. Categorizing type 2 diabetic subjects as having or not having the metabolic syndrome does not provide further prediction compared with the knowledge of its single components.     

Impact of cardiovascular risk factor control on long-term cardiovascular and all-cause mortality in the general population

Purpose: In clinical trials, lowering cardiovascular risk factors (CVRFs) reduces cardiovascular (CV) morbidity and mortality. We assessed the impact of controlling CVRFs at baseline on long-term all-cause and CV mortality in the general population.

Methods: Analysis was based on the Third French MONICA population-based survey (1994–1997). Vital status was obtained 18 years after inclusion. Statistical analysis was based on Cox-modelling.

Results: About 3402 participants aged 35–64 were included and 569 (17%) presented with 2 or more uncontrolled CVRFs, 1194 (35%) had one uncontrolled CVRF, 770 (23%) had all CVRFs controlled under treatment (or were former smokers) and 869 (25%) exhibited no CVRF. During the follow-up, 389 deaths occurred (76 were due to CV causes). Considering all-cause mortality, the adjusted hazard ratios (aHR) for subjects with one uncontrolled CVRF and for those with two or more were 1.38 [1.03–1.83] (p?=?0.029) and 1.80 [1.33–2.43](p?aHR was 0.66 [0.44–0.98] (p?=?0.042). Considering CV mortality, aHRs for subjects presenting with one and two or more uncontrolled CVRF were 1.70 [0.84–3.42] (p?=?0.138) and 3.67 [1.85–7.29] (p?Conclusions: Failing to control CVRFs significantly increases long-term all-cause and CV mortality in the French general population.

• Key messages

• Only 30% of patients with cardiovascular risk factors were controlled.

• Failing to control cardiovascular risk factors significantly increased long-term cardiovascular and all-cause mortality.

• A residual risk for all-cause mortality remained even when patients were controlled.

     

Impact of diabetes duration and cardiovascular risk factors on mortality in type 2 diabetes: the Hoorn Study

BACKGROUND: Several studies have reported differences in the mortality risk between diabetic subjects detected by screening and known diabetic patients. We studied mortality in relation to diabetes duration, and the contribution of other cardiovascular risk factors to the elevated risk. MATERIALS AND METHODS: Participants were type 2 diabetic subjects (n = 174) of a population-based cohort study. Of these, 95 were diagnosed by screening. Known diabetic subjects were grouped into two categories of diabetes duration, with a median duration of 2.4 and 11.2 years, respectively. We assessed the contribution of classical cardiovascular risk factors (dyslipidaemia, hypertension, and prior myocardial infarction), and of new cardiovascular risk factors (microalbuminuria, von Willebrand factor, sVCAM-1 and C-reactive protein) to the mortality risk during nearly 10 years of follow up. Cox's proportional hazards model was used to study the association of diabetes duration and mortality. RESULTS: The age- and sex-adjusted relative risks of mortality were 2.06 (95% C.I. 1.04-4.10) and 3.19 (1.64-6.20) for the patients with short- and long-term diabetes compared with the screening-detected diabetic subjects, respectively. Adjustment for cardiovascular risk factors resulted in a reduction of mortality risk in both groups: 1.13 (0.51-2.50) and 2.39 (1.18-4.83), respectively. Mortality risk significantly increased with increasing diabetes duration, even after multiple adjustment (P-value for trend ranged from < 0.001-0.018). CONCLUSIONS: Mortality risk increased with increasing diabetes duration. In subjects with short diabetes duration the mortality risk could largely be attributed to other risk factors. In subjects with a longer diabetes duration, however, the elevated mortality risk was independent of these cardiovascular risk factors.     

Associations of prediabetes with all-cause and cardiovascular mortality: A meta-analysis

Abstract

Background. Reports on the association of prediabetes with all-cause mortality and cardiovascular mortality are inconsistent.

Objective. To evaluate the risk of all-cause and cardiovascular mortality in association with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).

Methods. Prospective cohort studies with data on prediabetes and mortality were included. The relative risks (RRs) of all-cause and cardiovascular mortality were calculated and reported with 95% confidence intervals (95% CIs).

Results. Twenty-six studies were included. The risks of all-cause and cardiovascular mortality were increased in participants with prediabetes defined as IFG of 110–125 mg/dL (IFG 110) (RR 1.12, 95% CI 1.05–1.20; and RR 1.19, 95% CI 1.05–1.35, respectively), IGT (RR 1.33, 95% CI 1.24–1.42; RR 1.23, 95% CI 1.11–1.36, respectively), or combined IFG 110 and/or IGT (RR 1.21, 95% CI 1.11–1.32; RR 1.21, 95% CI 1.07–1.36, respectively), but not when IFG was defined as 100–125 mg/dL (RR 1.07, 95% CI 0.92–1.26; and RR 1.16, 95% CI 0.94–1.42, respectively).

Conclusions. Prediabetes, defined as IFG 110, IGT, or combined IFG 110 and/or IGT, was associated with increased all-cause and cardiovascular mortality.     

PROC,PROCR and PROS1 polymorphisms,plasma anticoagulant phenotypes,and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study

Summary. Background and objectives: Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging‐related disorders. Methods: Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow‐up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging. Results: The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all‐cause mortality, and decreased healthy survival during follow‐up. Conclusions: A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging‐related disorders.     

Coronary calcium score and prediction of all-cause mortality in diabetes: the diabetes heart study

OBJECTIVE

In diabetes, it remains unclear whether the coronary artery calcium (CAC) score provides additional information about total mortality risk beyond traditional risk factors.

RESEARCH DESIGN AND METHODS

A total of 1,051 participants, aged 34–86 years, in the Diabetes Heart Study (DHS) were followed for 7.4 years. Subjects were separated into five groups using baseline computed tomography scans and CAC scores (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed adjusting for age, sex, race, smoking, and LDL cholesterol to examine the association between CAC and all-cause mortality. Areas under the curve with and without CAC were compared. Natural splines using continuous measures of CAC were fitted to estimate the relationship between observed CAC and mortality risk.

RESULTS

A total of 17% (178 of 1,051) of participants died during the follow-up. In multivariate analysis, the odds ratios (95% CIs) for all-cause mortality, using CAC 0–9 as the reference group, were CAC 10–99: 1.40 (0.57–3.74); CAC 100–299: 2.87 (1.17–7.77); CAC 300–999: 3.04 (1.32–7.90); and CAC ≥1,000: 6.71 (3.09–16.87). The area under the curve without CAC was 0.68 (95% CI 0.66–0.70), and the area under the curve with CAC was 0.72 (0.70–0.74) (P = 0.0001). Using splines, the estimated risk (95% CI) of mortality for a CAC of 0 was 6.7% (4.6–9.7), and the risk increased nearly linearly, plateauing at CAC ≥1,000 (20.0% [15.7–25.2]).

CONCLUSIONS

In diabetes, CAC was shown to be an independent predictor of mortality. Participants with CAC (0–9) were at lower risk (0.9% annual mortality). The risk of mortality increased with increasing levels of CAC, plateauing at approximately CAC ≥1,000 (2.7% annual mortality). More research is warranted to determine the potential utility of CAC scans in diabetes.Diabetes is a coronary heart disease risk equivalent. The associated high overall mortality is largely attributable to increased cardiovascular deaths (1–3). Most of the morbidity and mortality in this high-risk condition are driven by accelerated atherosclerosis (4), characterized by increased amounts of connective tissue, glycoproteins, and calcified plaque in the blood vessels (5,6). Imaging by computed tomography (CT) reveals that individuals afflicted with diabetes have extensive calcification of their vascular beds (7–9).Several studies have shown that subclinical atherosclerosis, as measured by coronary artery calcium (CAC), predicts future cardiovascular disease (CVD) events and death, independent of conventional risk factors (10–12), in the general population. Whether higher CAC scores are associated with adverse clinical outcomes, in particular all-cause mortality, in diabetes has not been studied extensively. Because individuals with diabetes represent a group at high risk for cardiovascular events and death, risk stratification may be particularly useful in this population. This study examines the risk of death in participants with diabetes across higher levels of CAC scores.     

Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence

OBJECTIVE: In recent years, several major organizations have endorsed the concept of the metabolic syndrome and developed working definitions for it. How well these definitions predict the risk for adverse events in people with the metabolic syndrome is only now being learned. The purpose of this study was to summarize the estimates of relative risk for all-cause mortality, cardiovascular disease, and diabetes reported from prospective studies in samples from the general population using definitions of the metabolic syndrome developed by the National Cholesterol Education Program (NCEP) and World Health Organization (WHO). RESEARCH DESIGN AND METHODS: The author reviewed prospective studies from July 1998 through August 2004. RESULTS: For studies that used the exact NCEP definition of the metabolic syndrome, random-effects estimates of combined relative risk were 1.27 (95% CI 0.90-1.78) for all-cause mortality, 1.65 (1.38-1.99) for cardiovascular disease, and 2.99 (1.96-4.57) for diabetes. For studies that used the most exact WHO definition of the metabolic syndrome, the fixed-effects estimates of relative risk were 1.37 (1.09-1.74) for all-cause mortality and 1.93 (1.39-2.67) for cardiovascular disease; the fixed-effects estimate was 2.60 (1.55-4.38) for coronary heart disease. CONCLUSIONS: These estimates suggest that the population-attributable fraction for the metabolic syndrome, as it is currently conceived, is approximately 6-7% for all-cause mortality, 12-17% for cardiovascular disease, and 30-52% for diabetes. Further research is needed to establish the use of the metabolic syndrome in predicting risk for death, cardiovascular disease, and diabetes in various population subgroups.     

Diabetic retinopathy predicts all-cause mortality and cardiovascular events in both type 1 and 2 diabetes: meta-analysis of observational studies

OBJECTIVE

The prognostic significance of diabetic retinopathy (DR) for death and cardiovascular (CV) outcomes is debated. We investigated the association of DR with all-cause mortality and CV events in patients with diabetes by a systematic review and meta-analysis.

RESEARCH DESIGN AND METHODS

The electronic databases Medline and Embase were searched for cohort studies that evaluated DR in type 2 or type 1 diabetic patients and reported total mortality and/or fatal and nonfatal CV events, including myocardial infarction, angina pectoris, coronary artery bypass graft, ischemic changes on a conventional 12-lead electrocardiogram, transient ischemic attack, nonfatal stroke, or lower leg amputation. Data extraction was performed by two reviewers independently. Pooled effect estimates were obtained by using random-effects meta-analysis.

RESULTS

The analysis included 20 studies that fulfilled the inclusion criteria, providing data from 19,234 patients. In patients with type 2 diabetes (n = 14,896), the presence of any degree of DR increased the chance for all-cause mortality and/or CV events by 2.34 (95% CI 1.96–2.80) compared with patients without DR. In patients with type 1 diabetes (n = 4,438), the corresponding odds ratio was 4.10 (1.50–11.18). These associations remained after adjusting for traditional CV risk factors. DR was also predictive of all-cause mortality in type 2 diabetes (odds ratio 2.41 [1.87–3.10]) and type 1 diabetes (3.65 [1.05–12.66]).

CONCLUSIONS

The presence of DR was associated with an increased risk of all-cause mortality and CV events in both type 2 and type 1 diabetic patients.Diabetic retinopathy (DR) is a common chronic microvascular diabetes complication. Approximately 29% of U.S. adults with type 2 diabetes have DR (1), whereas DR will develop in 95% of type 1 diabetic individuals during their lifetime (2). DR has been associated with increased all-cause and cardiovascular (CV) mortality risk in both type 2 and type 1 diabetes (3–7). Associations with DR have been more extensively evaluated in type 2 diabetes, whereas studies in type 1 diabetes are scarce.Considering these data, identification of DR could possibly add to the diabetic patient’s CV risk stratification. Furthermore, the fundus examination is inexpensive and is routinely performed for the screening of chronic diabetes complications. Therefore, it is worthwhile to comprehensively review data on the predictive role of DR. The aim of the current study was to investigate the association of DR with all-cause mortality and CV events (fatal and nonfatal) in type 2 and type 1 diabetic patients by a systematic review and meta-analysis of cohort studies.     

Relation of lower-extremity amputation to all-cause and cardiovascular disease mortality in American Indians: the Strong Heart Study

OBJECTIVE: To compare risk of all-cause and cardiovascular disease (CVD) mortality in people with a lower-extremity amputation (LEA) attributable to diabetes and people without an LEA. RESEARCH DESIGN AND METHODS: The Strong Heart Study is a study of CVD and its risk factors in 13 American-Indian communities. LEA was ascertained at baseline by direct examination of the legs and feet. Mortality surveillance is complete through 2000. RESULTS: Of 2,108 participants with diabetes at baseline, 134 participants (6.4%) had an LEA. Abnormal ankle-brachial index (53%), albuminuria (87%), and long diabetes duration (mean 19.8 years) were common among diabetic subjects with LEA. Mean diabetes duration among diabetic participants without LEA and in those with toe and below-the-knee amputations was 11.9, 18.6, and 21.1 years, respectively. During 8.7 (+/-2.9) years of follow-up, 102 of the participants with LEA (76%) died from all causes and 35 (26%) died from CVD. Of the 1,974 diabetic participants without LEA at baseline, 604 (31%) died from all causes and 206 (10%) died from CVD. The unadjusted hazard ratios (HRs) for all-cause and CVD mortality in diabetic participants with LEA compared with those without were 4.0 and 4.1, respectively. Adjusting for known and suspected confounders, LEA persisted as a predictor of all-cause (HR 2.2, 95% CI 1.7-2.9) and CVD mortality (HR 1.9, 95% CI 1.3-2.9). We observed a significant interaction between baseline LEA and sex on CVD mortality, with female sex conferring added risk of CVD mortality. CONCLUSIONS: LEA is a potent predictor of all-cause and CVD mortality in diabetic American Indians. The combination of female sex and LEA is associated with greater risk of CVD mortality than either factor alone.     

Aortic and mitral annular calcifications are predictive of all-cause and cardiovascular mortality in patients with type 2 diabetes

OBJECTIVE

To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals.

RESEARCH DESIGN AND METHODS

We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992–2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality.

RESULTS

At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1–4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9–17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality.

CONCLUSIONS

Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.Aortic valve sclerosis (AVS) is a common finding at echocardiography in the elderly population (1). AVS is defined as focal or diffuse calcification and thickening of a trileaflet aortic valve in the absence of obstruction of ventricular outflow. Approximately 30% of adults >65 years of age have AVS in Western countries. Until recently, AVS was considered an incidental echocardiographic finding of no clinical significance, as it does not significantly obstruct left ventricular outflow. However, AVS shows epidemiologic and histopathologic similarities to coronary atherosclerosis (2,3). In addition, recent large prospective studies have suggested a strong association between AVS and cardiovascular disease (CVD) outcomes both in the general population (1,4–6) and in nondiabetic high-risk patient populations such as patients with hypertension (7), coronary artery disease (8), and chronic kidney disease (9).Mitral annulus calcification (MAC) is also a common echocardiographic finding in the elderly (10). Similar to AVS, MAC is strongly associated with an increased risk of CVD morbidity and mortality, mainly in nondiabetic populations (11,12). Notably, a recent large community-based cohort study involving 2,081 German individuals aged ≥45 years (∼11% of patients with diabetes) showed that AVS and MAC were associated with a fourfold to fivefold increased risk of all-cause and CVD mortality and that the combination of AVS and MAC with a heart valve sclerosis score improved the predictability with respect to mortality (5). Similarly, patients with AVS were approximately four times more likely to develop incident coronary heart events than were those without AVS among the 2,279 middle-aged African American participants of the Jackson Atherosclerosis Risk in Community cohort (6), whereas AVS was found to be independently associated with an increase of ~50–60% in the risk of CVD events and death among the 5,621 elderly participants of the Cardiovascular Heart Study (1).To our knowledge, no large observational studies are available on the relationship of AVS and MAC with the risk of all-cause and CVD mortality in patients with type 2 diabetes. The aim of this observational study was to evaluate the association of AVS and MAC, singly or in combination, with the risk of all-cause and CVD mortality in a sample of type 2 diabetic individuals referred for clinically indicated echocardiograms.     

Joint associations of sauna bathing and cardiorespiratory fitness on cardiovascular and all-cause mortality risk: a long-term prospective cohort study

Purpose: We aimed to evaluate the joint impact of cardiorespiratory fitness (CRF) and frequency of sauna bathing (FSB) on the risk of cardiovascular and all-cause mortality.

Design: CRF measured by respiratory gas analyses and sauna exposure were assessed at baseline in a prospective study of 2277 men. CRF was categorized as low and high (median cut-offs) and FSB as low and high (≤2 and 3–7 sessions/week, respectively).

Results: During a median follow-up of 26.1 years, 520 cardiovascular and 1124 all-cause deaths occurred. Comparing high versus low CRF, the multivariate-adjusted hazard ratios (HRs) 95% CIs for cardiovascular and all-cause mortality were 0.51 (0.41–0.63) and 0.65 (0.57–0.75), respectively. Comparing high versus low FSB, the corresponding HRs were 0.74 (0.59–0.94) and 0.84 (0.72–0.97), respectively. Compared to low CRF & low FSB, the HRs of CVD mortality for high CRF & high FSB; high CRF & low FSB; and low CRF & high FSB were 0.42 (0.28–0.62), 0.50 (0.39–0.63) and 0.72 (0.54–0.97), respectively. For all-cause mortality, the corresponding HRs were 0.60 (0.48–0.76), 0.63 (0.54–0.74) and 0.78 (0.64–0.96), respectively.

Conclusions: A combination of high CRF and frequent sauna bathing confers stronger long-term protection on mortality outcomes compared with high CRF or high FSB alone.

• KEY MESSAGES

• Cardiorespiratory fitness (CRF) and frequency of sauna bathing are independently associated with reduced mortality risk; a combination of good CRF and frequent sauna bathing may confer additional survival benefits.

• In a population-based prospective cohort study, a combination of high CRF levels and frequent sauna bathing (3–7 sessions per week) was associated with a substantial risk reduction in fatal cardiovascular and all-cause mortality events compared with good CRF or frequent sauna bathing alone.

• A combination of good fitness levels produced by aerobic exercises and frequent sauna bathing may have added health benefits and confer more protection on the risk of mortality.

     

Plasma insulin and all-cause, cardiovascular, and noncardiovascular mortality: the 22-year follow-up results of the Helsinki Policemen Study

OBJECTIVE: To investigate the association of plasma insulin with all-cause, cardiovascular, and noncardiovascular mortality. RESEARCH DESIGN AND METHODS: We studied 22-year mortality data from the Helsinki Policemen Study The study population comprised 970 men, 34-64 years of age, who were free of coronary heart disease, other cardiovascular disease, and diabetes. Area under the insulin response curve (AUC insulin) during an oral glucose tolerance test was used to reflect plasma insulin levels. RESULTS: During the follow-up period, 276 men died: 130 from cardiovascular and 146 from noncardiovascular causes. The hazard ratio (HR) for hyperinsulinemia (highest AUC insulin quintile vs. combined lower quintiles) with regard to all-cause mortality adjusting for age, was 1.94 (95% CI 1.20-3.13) during the first 10 years of the follow-up period and 1.51 (1.15-1.97) during the entire 22 years; adjusting for other risk factors, the HR was 1.88 (1.08-3.30) and 1.37 (1.00-1.87) during 10 and 22 years, respectively The corresponding HRs for cardiovascular mortality during 10 and 22 years were 2.67 (1.35-5.29) and 1.73 (1.19-2.53), respectively, for age-adjusted and 2.30 (1.03-5.12) and 1.39 (0.90-2.15), respectively, for multiple-adjusted HRs. A U-shaped association was observed between insulin and noncardiovascular mortality, multiple-adjusted HRs for lowest and highest versus middle AUC insulin quintiles were 1.85 (1.20-2.86) and 1.43 (0.91-2.24), respectively CONCLUSIONS: Hyperinsulinemia was associated with increased all-cause and cardiovascular mortality in Helsinki policemen independent of other risk factors, although these associations weakened with the lengthening of the follow-up period. The association of insulin with noncardiovascular mortality was U-shaped.     

Proinsulin concentration is an independent predictor of all-cause and cardiovascular mortality: an 11-year follow-up of the Hoorn Study

OBJECTIVE: High proinsulin concentration may be a better predictor for cardiovascular disease (CVD) mortality than insulin concentration. Previous observations may have been confounded by glucose tolerance status or lack of precision because of high intraindividual variability. We investigated the longitudinal relation of means of duplicate measurements of insulin and proinsulin with all-cause and CVD mortality in a population-based cohort taking glucose tolerance status into account. RESEARCH DESIGN AND METHODS: Fasting and post-75-g glucose-load (2-h) glucose, insulin, and proinsulin values were determined in duplicate on separate days in 277 participants with normal glucose metabolism, 208 participants with impaired glucose metabolism, and 119 newly detected patients with type 2 diabetes of the Hoorn Study. Insulin resistance and beta-cell function were estimated by homeostasis model assessment (HOMA-IR and HOMA-B, respectively), and the fasting proinsulin-to-insulin ratio was calculated. Subjects were followed with respect to mortality until January 2003. RESULTS: Fasting proinsulin levels were significantly associated with all-cause and CVD mortality. The hazard ratios (HRs) per increase in interquartile range adjusted for age and sex were 1.21 (95% CI 1.04-1.42) for all-cause mortality and 1.33 (1.06-1.66) for CVD mortality. Adjustment for glucose tolerance status and HOMA-IR did not substantially change the associations. CONCLUSIONS: Fasting proinsulin was associated with all-cause and CVD mortality, independent of glucose tolerance status and insulin resistance and largely independent of other CVD risk factors. Proinsulin might play a role in the relationship between insulin resistance and CVD.