Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study

Aims/hypothesis. The degree of glycaemia has been shown to be associated with all-cause and cardiovascular mortality in diabetic subjects. Whether this association also exists in the general population is still controversial. We studied the predictive value of fasting plasma glucose, 2-hour post-load glucose and HbA_{1 c} in a population-based cohort of 2363 older (50–75 years) subjects, without known diabetes. Methods. Relative risks (RR) of all-cause and cardiovascular mortality were estimated by Cox proportional hazards model, adjusting for age and sex, and additionally for known cardiovascular risk factors. Results. During 8 years of follow-up, 185 subjects died; 98 of cardiovascular causes. Fasting plasma glucose was only predictive in the diabetic range, although the risks started to increase at about 6.1 mmol/l. Post-load glucose and HbA_{1 c} values were, even within the non-diabetic range, associated with an increased risk (p for linear trend < 0.05). These increased risks were mostly, but not completely, attributable to known cardiovascular risk factors. After exclusion of subjects with newly diagnosed diabetes or with pre-existent cardiovascular disease (n = 551), a 5.8 mmol/l increase of post-load glucose (corresponding to two standard deviations of the population distribution) was associated with a higher age-adjusted and sex-adjusted risk of all-cause (RR 2.24) and cardiovascular mortality (RR 3.40) (p < 0.05). After additional adjustment for known cardiovascular risk factors, these relative risks were still statistically significant, with values of 2.20 and 3.00 respectively (p < 0.05). Conclusion/interpretation. High glycaemic variables, especially 2-h post-load glucose concentrations and to a lesser extent HbA_{1 c} values, indicate a risk of all-cause and cardiovascular mortality in a general population without known diabetes. [Diabetologia (1999) 42: 926–931] Received: 18 January 1999 and in revised form: 22 April 1999     

Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study

BACKGROUND: Small, short-term, intervention studies indicate that cocoa-containing foods improve endothelial function and reduce blood pressure. We studied whether habitual cocoa intake was cross-sectionally related to blood pressure and prospectively related with cardiovascular mortality. METHODS: Data used were of 470 elderly men participating in the Zutphen Elderly Study and free of chronic diseases at baseline. Blood pressure was measured at baseline and 5 years later, and causes of death were ascertained during 15 years of follow-up. Habitual food consumption was assessed by the cross-check dietary history method in 1985, 1990, and 1995. Cocoa intake was estimated from the consumption of cocoa-containing foods. RESULTS: One third of the men did not use cocoa at baseline. The median cocoa intake among users was 2.11 g/d. After adjustment, the mean systolic blood pressure in the highest tertile of cocoa intake was 3.7 mm Hg lower (95% confidence interval [CI], -7.1 to -0.3 mm Hg; P = .03 for trend) and the mean diastolic blood pressure was 2.1 mm Hg lower (95% CI, -4.0 to -0.2 mm Hg; P = .03 for trend) compared with the lowest tertile. During follow-up, 314 men died, 152 of cardiovascular diseases. Compared with the lowest tertile of cocoa intake, the adjusted relative risk for men in the highest tertile was 0.50 (95% CI, 0.32-0.78; P = .004 for trend) for cardiovascular mortality and 0.53 (95% CI, 0.39-0.72; P < .001) for all-cause mortality. CONCLUSION: In a cohort of elderly men, cocoa intake is inversely associated with blood pressure and 15-year cardiovascular and all-cause mortality.     

Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study

Microalbuminuria (MA) is associated with increased cardiovascular and all-cause mortality. It has been proposed that MA reflects generalized atherosclerosis and may thus predict mortality. To investigate this hypothesis, we studied the associations between, on the one hand, MA and peripheral arterial disease (PAD), a generally accepted marker of generalized atherosclerosis, and, on the other hand, cardiovascular and all-cause mortality in an age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years followed prospectively for 5 years. At baseline, the albumin-to-creatinine ratio (ACR) was measured in an overnight spot urine sample; MA was defined as ACR >2.0 mg/mmol. PAD was defined as an ankle-brachial pressure index below 0.90 and/or a history of a peripheral arterial bypass or amputation. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). Both MA and PAD were associated with a 4-fold increase in cardiovascular mortality. After adjusting for age, sex, diabetes mellitus, hypertension, levels of total and HDL-cholesterol and triglyceride, body mass index, smoking habits, and preexistent ischemic heart disease, the relative risks (RR) (95% confidence intervals) were 3.2 (1.3 to 8.1) for MA and 2.4 (0.9 to 6.1) for PAD. When both MA and PAD were included in the multivariate analysis, the RRs were 2.9 (1.1 to 7.3) for MA and 2.0 (0.7 to 5.7) for PAD. MA and PAD were both associated with an about 2-fold increase in all-cause mortality. The RRs of all-cause mortality associated with MA and PAD were about 4 times higher among hypertensive than among normotensive subjects. We conclude that both MA and PAD are associated with an increased risk of cardiovascular mortality. MA and PAD are mutually independent risk indicators. The associations of MA and PAD with all-cause mortality are somewhat weaker. They are more pronounced in the presence of hypertension than in its absence. These data suggest that MA affects mortality risk through a mechanism different from generalized atherosclerosis.     

Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study

Aims/hypothesis. Currently, three categories of measures are used to assess cardiovascular autonomic dysfunction: measures of the Ewing-test, measures of heart-rate variability, and measures of baroreflex sensitivity. We studied the determinants of these measures obtained from cardiovascular autonomic function tests in the Hoorn Study. Methods. The study group (n = 631) consisted of a glucose-tolerance-stratified sample from a 50- to 75-year-old group of people. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (a) spontaneous breathing, (b) six deep breaths over one minute, and (c) an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (three Ewing, six heart-rate variability and one baroreflex sensitivity). As possible determinants we considered age, sex, glucose tolerance, cardiovascular disease, use of anti-hypertensive drugs, anthropometric factors, metabolic factors and lifestyle factors. Results. Multivariate analysis showed that eight of ten cardiovascular autonomic function measures were most strongly associated with glucose tolerance. Furthermore, measures were moderately associated with age, sex, waist-to-hip ratio, use of anti-hypertensive drugs, and insulin. The measures were weakly associated with coronary artery disease but not with lipids. The strongest determinants seemed to differ between subjects with and without diabetes: in the non-diabetic subjects the most strongly associated were age and use of anti-hypertensive drugs and in subjects with diabetes, insulin. No consistent differences in association between the three categories of measures were observed. Conclusion/interpretation. The strongest determinants of autonomic function were age, presence of diabetes and use of anti-hypertensive drugs. [Diabetologia (2000) 43: 561–570] Received: 25 October 1999 and in revised form: 3 January 2000     

Combined effects of heart rate and pulse pressure on cardiovascular mortality according to age

OBJECTIVES: The aim of the study was to assess the combined effects of pulse pressure (PP) and heart rate (HR) on cardiovascular mortality in a large French population. DESIGN: The study population was composed of 125,513 men and 96,301 women aged 16-95 years who had a health check-up at the IPC Center between January 1978 and December 1988. Subjects taking antihypertensive treatment were excluded. Mortality was assessed for an 8-year period. HR and PP were classified into three groups. HR groups were: < 60, 60-79 and > or = 80 beats per minute (bpm). PP groups were: < 50, 50-64 and > or = 65 mmHg. RESULTS: In men, PP and HR were both positively associated with cardiovascular mortality risk. In women, mean arterial pressure (MAP) but not PP or HR was associated with cardiovascular mortality. In men, a combined elevation of PP and HR was associated with an important increase of cardiovascular mortality risk. The group with the highest PP and the highest HR had a 4.8-fold increase in cardiovascular mortality risk as compared to the reference group (PP < 50 mmHg and HR < 60 bpm). This effect was more pronounced in younger men (5.4-fold increase) than in older men (3.7-fold increase), as compared to the reference groups of the same age. In women, the combined effects of PP and HR on cardiovascular mortality were not significant. CONCLUSION: A combined elevation of the two components of pulsatile arterial stress is associated with an important increase in cardiovascular mortality in men, especially in younger men. In women, steady-state stress (evaluated primarily by MAP), but not pulsatile stress, is an important determinant of cardiovascular mortality.     

Systolic and diastolic blood pressure, mean arterial pressure and pulse pressure for prediction of cardiovascular events and mortality in a Middle Eastern population

We compared systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure (PP) as independent predictors of cardiovascular disease (CVD), total and CVD mortality among an Iranian population. The study conducted among 5991 subjects aged ≥ 30 years without baseline CVD and antihypertensive medication. The mean of two measurements of SBP and DBP, in sitting position, was considered the subject's blood pressure. During a median follow-up of 8.7 years, 346 CVD and 157 deaths, 63 attributed to CVD, occurred. Hazard ratios (HRs) of each outcome were calculated for a one standard deviation (SD) increase in each blood pressure (BP) measures. In multivariate models, all BP measures were associated with increased risk of CVD regardless of age. In those aged < 60 years, SBP, DBP, PP and MAP were associated with total mortality (p < 0.05), but in subjects aged ≥ 60 years, only SBP and PP increased risk of total mortality significantly. In multivariate analyses, a 1SD increase in SBP, PP and MAP were associated with 35%, 31% and 28% increased risk of CVD mortality (p < 0.05). In terms of fitness and discrimination of models, DBP, PP and MAP were not superior to SBP. In conclusion, our findings provided further evidence from a Middle Eastern population, in support of SBP predictability for CVD events and CVD and all-cause mortality compared with other BP measures.     

Wide pulse pressure is an independent predictor of cardiovascular mortality in Puerto Rican men

BACKGROUND AND AIM: Emerging evidence suggests that pulse pressure is an independent predictor of risk for cardiovascular mortality. New studies in diverse populations are needed to further establish the applicability of this finding. Thus, the purpose of this study is to examine the relationship between pulse pressure and cardiovascular mortality in a cohort of Puerto Rican men after 12 years of follow-up. METHODS AND RESULTS: The Puerto Rico Heart Health Program is a study of coronary disease risk factors in men aged 35-79 years at baseline who had an initial examination during the years 1962-1965. It was attended by 9824 subjects representing 80% of the total age-specific male residents in 4 rural and 3 urban areas of Puerto Rico. Cardiovascular risk factors including systolic and diastolic blood pressures were monitored prospectively. This study includes 9106 men free of overt CHD at baseline who were stratified by quartiles of pulse pressure in mmHg: quartile 1, or=57. The odds ratio of cardiovascular mortality was calculated using logistic regression analysis. After adjusting for age, education, smoking status, hypercholesterolemic status, physical activity, diabetic status and mean arterial pressure, we found that those in the highest quartile of pulse pressure (pulse pressure>=57) had significantly higher cardiovascular mortality than those in the lowest quartile (reference group) (OR=1.38 95% CI=1.01-1.88). CONCLUSION: Our findings showed that a wide pulse pressure is independently associated with cardiovascular mortality in this group of Puerto Rican men.     

von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study

Increased levels of von Willebrand factor (vWf) and C-reactive protein (CRP) predict cardiovascular mortality in selected populations. It is uncertain whether vWf and CRP predict mortality in a general population and whether vWf and CRP predict mortality through similar pathways. This study investigated the association of vWf and CRP with cardiovascular and all-cause mortality among diabetic and nondiabetic subjects. An age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years was followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). vWf (>1.56 IU/mL) and CRP (>2.84 mg/L) levels in the upper tertile were associated with, respectively, a 3- and 2-fold increase in cardiovascular mortality after adjustment for age, sex, and glucose tolerance status. Analyses in nondiabetic and diabetic subjects separately gave similar results. After further adjustment for hypertension, levels of HDL cholesterol and triglyceride, smoking habits, ischemic heart disease, and peripheral arterial disease, the relative risks (RRs) were 3.0 (95% CI 1.2 to 7.9) for vWf and 1.4 (95% CI 0.6 to 3.5) for CRP. When both vWf and CRP were included in the latter multivariate analysis, the RRs were 3.0 (95% CI 1.1 to 7.9) for vWf and 1.3 (95% CI 0.5 to 3.4) for CRP. The association between vWf and risk of cardiovascular mortality was independent of blood group (O versus non-O) and, moreover, similar among subjects with different blood groups. Repeating the analyses for all-cause mortality gave similar results for CRP. For vWf, the RR was 2.0 (95% CI 1.1 to 3.5) after adjustment for all other risk factors. Increased levels of vWf are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects. The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors. Mutual adjustment of vWf and CRP did not markedly change the results, favoring the hypothesis that vWf and CRP predict mortality through different pathways.     

Impaired fasting glucose,blood pressure and cardiovascular disease mortality

Impaired fasting glucose (fasting plasma glucose 6.1 to 6.9 mmol/L [110 to 125 mg/dL]) is a common glycemic disorder which usually progress to diabetes mellitus. The relationships between impaired fasting glucose, other risk factors including blood pressure, and mortality have never been clearly investigated. We studied 63 443 consecutive men (ages 21 to 60 years), each of whom had a routine health examination with a fasting plasma glucose measurement. Men with known ischemic cardiac disease and treatment for diabetes or hypertension were excluded. Impaired fasting glucose was found in 10 773 (17.0%) of these men. Mean body mass index, serum triglyceride and cholesterol levels, and systolic, diastolic, and pulse blood pressure were significantly higher for men with impaired fasting glucose compared with those men with normal fasting glucose (fasting plasma glucose 3.9 to 6.0 mmol/L). When adjusted for confounding variables, relative risk of 8-year cardiovascular mortality associated with impaired fasting glucose was dependent on systolic blood pressure level (1.02 [95% CI: 0.62 to 1.70] when <140 mm Hg and 2.10 [95% CI: 1.16 to 3.80] between 140 and 160 mm Hg). Inversely, relative risk of 8-year cardiovascular mortality associated with moderate systolic hypertension (140 to 159 mm Hg) compared with normal systolic blood pressure (<140 mm Hg) was highly dependent on the glycemic status (2.97 [95% CI: 1.58 to 5.55] for men with impaired fasting glucose compared with 1.35 [95% CI: 0.84 to 2.18] in those with normal fasting glucose). Similar results were found concerning overall mortality. In conclusion, the presence of moderate systolic hypertension can identify subjects with impaired fasting glucose who are at risk of cardiovascular and overall mortality, and vice versa, probably through the metabolic syndrome.     

Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality

Previously diagnosed diabetes mellitus, newly diagnosed diabetes mellitus, and impaired glucose tolerance are important determinants of the risk of clinical cardiovascular disease (CVD). We have evaluated the relation of patients with subclinical CVD, diabetes, and impaired glucose tolerance and "normal" subjects and the risk of clinical CVD in the Cardiovascular Health Study. Diabetes (1343), impaired glucose tolerance (1433), and normal (2421) were defined by World Health Organization criteria at baseline in 1989 to 1990. The average follow-up was 6.4 years (mean age 73 years). Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. Compared with diabetes in the absence of subclinical disease, the presence of subclinical CVD and diabetes was associated with significant increased adjusted relative risk of death (1.5, CI 0.93 to 2.41), relative risk of incident coronary heart disease (1.99, CI 1.25 to 3.19), and incident myocardial infarction (1.93, CI 0.96 to 3.91). The risk of clinical events was greater for participants with a history of diabetes compared with newly diagnosed diabetics at baseline. Compared with nondiabetic nonhypertensive subjects without subclinical disease, patients with a combination of diabetes, hypertension, and subclinical disease had a 12-fold increased risk of stroke. Fasting blood glucose levels were a weak predictor of incident coronary heart disease as were most other risk factors. Subclinical CVD was the primary determinant of clinical CVD among diabetics in the Cardiovascular Health Study.     

Sulphonylurea–metformin combination therapy,cardiovascular disease and all‐cause mortality: the Fremantle Diabetes Study

Aim: To determine whether combination of metformin–sulphonylurea is associated with an increased risk of cardiovascular disease (CVD) and mortality in an urban community‐based cohort of type 2 patients. Methods: We studied 1271 (98.2%) of 1294 type 2 participants in the observational Fremantle Diabetes Study (mean age 64.2 years, 48.8% males) who had detailed diabetes‐specific therapy recorded at baseline and complete follow‐up data. Mortality and hospital discharge data were collected over 13 174 patient‐years (mean ± SD: 10.4 ± 3.9 years). Cox proportional hazards modelling was used to determine whether baseline diabetes treatments were independently associated with cardiovascular mortality, hospitalization for/death from CVD or all‐cause mortality after adjustment for other explanatory variables. Results: During follow‐up, 523 deaths occurred (41.1%) of which 269 (51.4%) were attributed to CVD. Hospitalization for CVD as principal diagnosis occurred at least once for 481 (37.8%) participants. In Kaplan–Meier analyses, there were significant differences in cardiovascular mortality, hospitalization for/death from CVD and all‐cause mortality between diabetes therapy groups (p < 0.001). Compared with diet and metformin monotherapy, those treated with metformin–sulphonylurea had higher cardiovascular and all‐cause mortality (p ≤ 0.024). Insulin users had significantly higher cardiovascular mortality, hospitalization for/death from CVD and all‐cause mortality than those on combination therapy (p ≤ 0.016). After adjustment for significant variables in the most parsimonious models, diabetes treatment was not independently associated with any of the three study endpoints (p ≥ 0.49). Conclusions: Combination metformin–sulphonylurea appears as safe as other blood glucose‐lowering therapies used for type 2 diabetes.     

Association of double product and pulse pressure with cardiovascular and all‐cause mortality in the LURIC study

Systolic (SBP) and diastolic blood pressure (DBP) and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is considered as an easily available marker of vascular stiffness and the double product (DP) as a marker of cardiac workload. Therefore, we have examined the predictive value of PP and DP in the Ludwigshafen Risk and Cardiovascular Health study, a monocentric cohort study of 3316 patients referred to coronary angiography. An increase of SBP or PP by 1mmHg increased the risk of CVM with hazard ratios of 1.009 (95% CI, 1.005‐1.012) and 1.016 (1.012‐1.020), respectively. Increasing DP by 100 mm Hg/min was associated with a 1.010 (1.007‐1.013) higher risk of CVM. In patient subgroups with coronary artery disease (CAD) and heart failure (HF), PP and DP predicted CVM better than SBP or MAP. In a multivariate analysis adjusted for sex, BMI, diabetes, eGFR, hazard ratios for CVM for z‐standardized PP, DP, SBP, and HR were 1.20, 1.16, 1.12, and 1.14. After adding age to the multivariate analysis, only DP and HR remained significant. We provide evidence that PP and DP are powerful predictors of CVM and all‐cause mortality in a CV medium‐ to high‐risk population, especially in patients with CAD and HF. While DP proved to be an independent predictor of cardiovascular and all‐cause mortality also in multivariate analysis, PP was no independent predictor in our cohort with widespread antihypertensive treatment (>85%). PP is associated with age, presence of diabetes, obesity, and impaired renal function.     

Heart rate and cardiovascular mortality: the Framingham Study

The relation of resting heart rate on biennial ECG examinations to mortality rates over 30 years of follow-up of the Framingham cohort was examined based on 1876 total deaths and 894 cardiovascular deaths, evolving out of 5070 subjects free of cardiovascular disease at entry into the study. In both sexes, at all ages, all-cause, cardiovascular, and coronary mortality rates increased progressively in relation to antecedent heart rates determined biennially. A more impressive association to cardiovascular disease was observed in men than in women, which was independent of associated cardiovascular risk factors. Case fatality rates following coronary events also increased with antecedent heart rate and the fraction of coronary deaths as sudden death increased strikingly with heart rate in men 35 to 64 years of age. There was also a substantial excess of noncardiovascular deaths at high heart rates, and the proportion of all deaths resulting from cardiovascular disease did not increase with heart rate. The excess cardiovascular deaths with more rapid heart rates were also noted, excluding those with interim overt cardiovascular disease, suggesting an effect independent of preexisting cardiac damage.