Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy.

BACKGROUND: Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. OBJECTIVE: We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. METHODS: A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. RESULTS: The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. CONCLUSIONS: For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.

Cardiorespiratory fitness and risk of dementia: a prospective population-based cohort study.

Dementia is considered to be one of the major public health problems in light of the ageing population. Little is known about directly measured cardiorespiratory fitness as measured by maximal oxygen uptake and the risk of dementia. Our aim was to examine the relationship of cardiorespiratory fitness, as indicated by maximal oxygen uptake, with subsequent incidence of dementia. This was a population-based cohort study with an average follow-up of 22 (range 0.22-29.8) years from eastern Finland. About 2,031 men with a mean age of 52.8 years of age and no history of dementia or pulmonary disease at baseline participated in the study. Among these men, 208 cases of dementia occurred. Maximal oxygen uptake (ml/kg/min) was measured during exercise testing at baseline. One standard deviation increase in VO2max was associated with a 20% decrease in dementia. Cardiorespiratory fitness was inversely related to the risk of dementia. Men with low cardiorespiratory fitness (VO2max < 23.7 ml/kg/min, lowest quintile) had a 1.92-fold (1.24-2.967, P = 0.003), risk of dementia as compared with men who had high cardiorespiratory fitness (VO2max >36.5 ml/kg/min, highest quintile) after adjusting for age and examination years. In a multivariate model, low cardiorespiratory fitness was associated with a 1.95-fold (1.24-3.05, P = 0.003) risk of dementia. Our findings show that low cardiorespiratory fitness was associated with an increased risk of dementia.

The joint impact of prediagnostic inflammatory markers and cardiorespiratory fitness on the risk of cancer mortality.

Independently, cardiorespiratory fitness (CRF), C-reactive protein (CRP), and leukocyte count have been shown to predict cancer death. Little is known about the joint impact of CRF and prediagnostic markers of inflammation, particularly leukocyte count and CRP, and their prognostic value with cancer death. The aim of this study was to explore the association between prediagnostic inflammatory markers and CRF with cancer mortality. A population-based cohort of 2270 men from Eastern Finland with no cancer history at baseline participated in the study. CRP, leukocyte count, and CRF data were among the measures collected at baseline. Blood leukocyte count was measured with a cell counter, and serum CRP concentrations were measured using an immunometric assay. The highest value or plateau of directly measured oxygen consumption by a respiratory gas analyzer during an incremental exercise test to exhaustion was used to describe CRF. Over an average follow-up of 22 years, 272 cases of cancer mortality occurred. In a multivariate model, the joint impact of high leukocyte count (>5.40 × 109 /L) and low CRF (VO2 max < 30.08 mL kg-1  min-1 ) had a 1.85-fold (95% CI 1.30-2.63, P < .01) increased risk for cancer death compared to men with low leukocyte count (<5.40 × 109 /L) and high CRF (VO2 max > 30.08 mL kg-1  min-1 ). The joint impact of CRP and CRF shared no association with cancer mortality in a multivariate model. The joint impact of high leukocyte count and low CRF increases risk for cancer death, suggesting it is a better predictor of cancer death compared to the joint impact of CRP and CRF.

Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke.

BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

Associations of serum n-3 and n-6 polyunsaturated fatty acids with plasma natriuretic peptides.

BACKGROUND/OBJECTIVES: The n-3 and n-6 polyunsaturated fatty acids (PUFAs) have been associated with lower risk of cardiovascular disease (CVD), but little is known about their association with natriuretic peptides (NPs), a marker for CVD risk. The aim of this study was to investigate the association of serum n-3 and n-6 PUFAs with NPs. SUBJECTS/METHODS: A cross-sectional analysis of the association between serum n-3 and n-6 PUFAs with plasma N-terminal atrial (NT-proANP) and brain (NT-proBNP) NPs in a population-based sample of 985 men aged 46-65 years from Eastern Finland. RESULTS: After adjustment for age and examination year, only serum n-6 PUFA arachidonic acid (ARA) was inversely associated with NT-proANP (P-trend across quartiles=0.02), but further adjustments for conventional risk factors (body mass index, smoking, alcohol intake, systolic blood pressure, low-density lipoprotein cholesterol and history of CVD) attenuated the association (P-trend=0.10). The associations with the other PUFAs were not statistically significant. Among the PUFAs, only serum n-3 PUFA docosapentaenoic acid (DPA; P-trend=0.03) and ARA (P-trend=0.02) had inverse associations with NT-proBNP after adjustment for age and examination years. The associations were again attenuated after further adjustments but remained statistically significant for DPA (P-trend=0.05). Our results also suggested that the inverse associations may be more evident among those using beta-blockers. CONCLUSIONS: Our study suggests little overall impact of serum n-3 or n-6 PUFAs on plasma NPs.

Association between direct measurement of active serum calcium and risk of type 2 diabetes mellitus: A prospective study.

BACKGROUND AND AIMS: Previous prospective studies showing a positive association between serum calcium and incidence of type 2 diabetes mellitus (T2DM) have relied on total calcium or an indirect estimate of active, ionized calcium (iCa). We aimed to assess this relationship using a direct measurement of iCa. METHODS AND RESULTS: iCa and cardiometabolic risk factors were measured in a population-based sample of 2350 men without a known history of T2DM at baseline. Associations between iCa levels and incident cases of T2DM (self-reported, ascertained with a glucose tolerance test, or determined by record linkage to national registers) were estimated using Cox regression analyses adjusted for potential confounders. At baseline, mean (standard deviation) age was 53 (5) years and mean iCa 1.18 (0.05) mmol/L. During a median follow-up of 23.1 years, 140 new cases of T2DM were recorded. In a multivariable analysis adjusted for age, body mass index, systolic blood pressure, serum HDL-cholesterol, and family history of T2DM, there was no association comparing second (hazard ratio 0.84; 95% confidence interval 0.59-1.18), third (0.77; 0.52-1.14), or fourth (0.98; 0.69-1.39) vs first quartile of iCa (p for trend 0.538); further adjustment for C-reactive protein, physical activity level, and triglycerides did not change the estimates (p for trend 0.389). CONCLUSION: In this study, we did not find evidence of an association between direct measurement of active calcium and risk of T2DM. Further studies are needed to confirm our findings and define the relationship between factors influencing indirect calcium estimation and incident T2DM.

Serum fructosamine and risk of cardiovascular and all-cause mortality: a 24-year prospective population-based study.

BACKGROUND AND AIMS: The association between fructosamine and cardiovascular complications is not well established. We sought to evaluate whether serum fructosamine may be a risk factor for cardiovascular and all-cause mortality in nondiabetic subjects. METHODS AND RESULTS: Fructosamine and other cardiovascular risk factors were measured in a sample of 1909 nondiabetic middle-aged men without a known history of coronary heart disease (CHD) at baseline. Associations between baseline fructosamine levels and fatal CHD and cardiovascular disease (CVD) events, and all-cause mortality were estimated using a Cox regression analysis, progressively adjusted for potential confounders. Mean baseline age was 52 years and 30% were smokers. During a median follow-up of 24 years (interquartile range: 18-26 years), 177 (9%) fatal CHD, 289 (15%) fatal CVD, and 728 (38%) all-cause mortality events occurred. In analyses adjusted for several conventional risk factors (i.e., age, systolic blood pressure, smoking, LDL- and HDL-cholesterol), the hazard ratios (HRs) comparing top vs bottom quartile of serum fructosamine levels resulted: 1.33 (95% CI: 0.97, 1.82; p = 0.078) for CHD death and 0.93 (0.72, 1.19; p = 0.567) for CVD death, and 1.04 (0.89, 1.22; p = 0.617) for all-cause mortality. In similar comparisons, further adjustments for body mass index, alcohol consumption, C-reactive protein, and fasting plasma glucose did not materially change these estimates. The exclusion of participants with prevalent CVD at baseline yielded similar results. CONCLUSION: In our cohort of nondiabetic men without known CHD, baseline fructosamine levels were not independently associated with cardiovascular and all-cause mortality. Further studies are warranted to confirm these results in other populations.

The frequency of alcohol consumption is associated with the stroke mortality.

OBJECTIVES: The purpose of this study was to examine the association between the frequency of alcohol consumption and stroke mortality among eastern Finnish men. MATERIAL AND METHODS: This study is a population-based sample of men with an average follow-up of 20.2 years. A total of 2609 men with no history of stroke at baseline participated in the study. During the follow-up, 66 deaths from stroke occurred. RESULTS: After adjustment for systolic blood pressure, smoking, BMI, diabetes, and socioeconomic status, the relative risk (RR) among men who consumed alcohol <0.5 times per week was 0.70 (95% CI, 0.30-1.66; P = 0.419) compared with nondrinkers. Respective RR was 1.08 (95% CI, 0.51-2.27; P = 0.846) for men with alcohol consumption of 0.5-2.5 times per week and 2.44 (95% CI, 1.11-5.40; P = 0.027) for men who consumed alcohol >2.5 times per week after adjustment for risk factors. When the total amount of alcohol consumption (g/week) was taken into account with other covariates, RR was 0.71 (95% CI, 0.30-1.68; P = 0.437) for men with alcohol consumption <0.5 times per week and 1.16 (95% CI, 0.54-2.50; P = 0.704) among men who consumed alcohol 0.5-2.5 times per week. Among men who consumed alcohol >2.5 times per week compared with nondrinkers, RR was 3.03 (95% CI, 1.19-7.72; P = 0.020). CONCLUSIONS: This study shows a strong association between the frequency of alcohol consumption and stroke mortality, independent of total amount of alcohol consumption. The risk of stroke death was the highest among men who consumed alcohol >2.5 times per week.

Hangover and the risk of stroke in middle-aged men.

OBJECTIVES: The aim of this study was to examine the association between hangover and the risk of stroke. MATERIAL AND METHODS: A population-based sample of men with an average follow-up of 15.7 years. 2466 men with no history of stroke at baseline participated. Two hundred and six strokes occurred, of which 167 were ischemic strokes. RESULTS: The age-adjusted, relative risk (RR) for any stroke among men with ≥1 hangover per year was 2.33-fold (95% confidence interval (CI), 1.19-4.56; P = 0.013) relative to men without hangover, and 2.99-fold (95% CI, 1.52-5.86; P = 0.001) for ischemic stroke, respectively. After adjustment for age, smoking, high density lipoprotein (HDL)-cholesterol, LDL-cholesterol, BMI, SBP, myocardial ischemia during exercise, symptomatic coronary heart disease (CHD) and CHD in family, C-reactive protein, diabetes, and total alcohol consumption, the RR for any stroke was 1.94-fold (95% CI, 0.95-3.96; P = 0.070) and 2.58-fold (95% CI, 1.24-5.36; P = 0.011) for ischemic stroke among men with hangovers. Additional adjustment of atrial fibrillation and cardiac failure and risk was 2.45-fold (95% CI, 1.18-5.12; P = 0.017) for ischemic strokes. CONCLUSION: This study shows that at least one hangover a year is related to an increased risk of ischemic stroke in men.

LDL oxidative modification and carotid atherosclerosis: results of a multicenter study.

OBJECTIVE: Serum LDL conjugated diene concentration is a marker of oxidative modification of LDL. We investigated the relationship between LDL conjugated dienes and cross-sectional subclinical atherosclerosis assessed by carotid IMT in high-risk subjects of a multicenter study. METHODS: Serum LDL conjugated dienes and ultrasonographically assessed carotid intima-media thickness (IMT(mean), IMT(max) and IMT(mean-max)) were available for 553 subjects from Finland, France, Italy, the Netherlands, and Sweden. RESULTS: In multivariate regression analysis, gender (p < 0.001), age (p < 0.001), systolic blood pressure (IMT(mean), p = 0.01; IMT(mean-max), p = 0.05) and serum LDL conjugated dienes (p = 0.02 for both IMT(mean) and IMT(mean-max)) were the strongest determinants of IMT variation, adjusted for study center, ultrasound videotape reader and serum LDL cholesterol. Pack-years of smoking, added into the regression model, did not destroy the significant association between increased serum LDL conjugated dienes and IMT. Ratio of LDL conjugated dienes to LDL particle cholesterol was higher in subjects of Northern recruiting centers than of Southern centers (r = 0.39, p < 0.0001). CONCLUSIONS: There was a cross-sectional association between in vivo increased LDL oxidative modification and subclinical atherosclerosis after adjustment for traditional risk factors. The subjects in Northern countries of Europe had more oxidatively modified lipids per cholesterol in LDL particle than subjects in Southern countries.

Low ß-carotene concentrations increase the risk of cardiovascular disease mortality among Finnish men with risk factors.

BACKGROUND & AIMS: Healthy diet rich in fruits and vegetables is an important factor in prevention of cardiovascular diseases (CVD). Some previous epidemiological studies have suggested that dietary and serum carotenoids are associated with decreased CVD mortality, but the results have been inconsistent. We assessed relations between the concentrations of serum carotenoids and CVD mortality among Eastern Finnish men. METHODS & RESULTS: The study population consisted of 1031 Eastern Finnish men aged 46-65 years in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) cohort. Subjects were classified quartiles according to concentrations of carotenoids and subgroups according to risk factors. Hazard ratios of serum lycopene, α-carotene and ß-carotene were estimated by the Cox proportional hazard model after adjusting for potential confounding factors. During the median 15.9-year follow-up, 122 deaths from CVDs, were identified among the cohort subjects. Low serum concentrations of ß-carotene were strongly related to an increased CVD mortality risk after adjustment for confounders. For ß-carotene, the hazard ratio (95% confidence interval) for the lowest versus highest quartile was 2.23 (1.26-3.93; P=0.006). However, the strongest risk of CVD mortality was observed among smokers with lowest levels of ß-carotene (HR=3.15, 95%, CI: 1.19-8.33; P=0.020). Other carotenoids and the sum of carotenoids were not significantly related to increased risk of CVD mortality. CONCLUSIONS: Low concentrations of serum ß-carotene concentrations may increase the risk for CVD mortality among Eastern Finnish men; thus elevated serum concentrations of ß-carotene may have clinical and public health relevance.

Plasma carotenoids are related to intima--media thickness of the carotid artery wall in men from eastern Finland.

BACKGROUND: Several previous epidemiological studies have suggested that high plasma concentrations of carotenoids may slow the development of early atherosclerosis, but results have been inconclusive. METHODS: We examined the effect of carotenoids on early atherosclerosis in a population-based study. The association between plasma carotenoid concentrations and intima-media thickness of the common carotid artery (CCA-IMT) was investigated in 1212 elderly men (aged 61-80 years) in Eastern Finland. They were examined by B-mode ultrasound to detect early signs of carotid atherosclerosis, and plasma concentrations of carotenoids were measured by high-performance liquid chromatography. RESULTS: Men in the lowest quartile of CCA-IMT had significantly higher concentrations of plasma ß-cryptoxanthin, lycopene and α-carotene than men in the highest quartile (P for the differences: 0.043, 0.045 and 0.046, respectively), after adjustment for age, examination year, body mass index, smoking, alcohol intake, years of education, symptomatic coronary heart disease (CHD) or CHD history, diabetes, low-density lipoprotein cholesterol, medications and season. The concentrations of plasma ß-cryptoxanthin, lycopene and α-carotene decreased linearly with increasing CCA-IMT. CONCLUSIONS: The results of this study suggest that high plasma concentrations of ß-cryptoxanthin, lycopene and α-carotene may be associated with decreased carotid atherosclerosis in elderly men from eastern Finland.

Intensity of leisure-time physical activity and cancer mortality in men.

OBJECTIVE: there is a lack of evidence to show the role of exercise intensity in the prevention of cancer mortality because no previous studies have shown this relation. The relationship of leisure-time physical activity with cancer mortality was therefore assessed. METHODS: participants were from a population-based sample of 2560 men from eastern Finland with no history of cancer at baseline. Physical activity was assessed using the 12-month leisure-time physical activity questionnaire. During an average follow-up of 16.7 years, a total of 181 cancer related deaths occurred. RESULTS: an increase of 1.2 metabolic units (MET or metabolic equivalents of oxygen consumption; 1 SD in metabolic equivalents) in the mean intensity of leisure-time physical activity was related to a decrease (relative risk (RR) 0.85, 95% CI 0.72 to 0.99) in cancer mortality mainly due to lung and gastrointestinal cancers, after adjustment for age, examination year, alcohol consumption, smoking, body mass index and energy, fibre and fat intake. Men with leisure-time physical activity of more than 5.2 MET (highest quartile) had a lower (RR 0.63, 95% CI 0.40 to 0.99) cancer mortality compared with men whose mean intensity of physical activity was less than 3.7 MET (lowest quartile). The mean intensity of physical activity was related to the risk of cancer death among men who exercised at least 30 minutes per day on average. CONCLUSIONS: this prospective study indicates that the mean intensity of leisure-time physical activity is inversely associated with the risk of premature death from cancer in men.

Plasma N-terminal fragments of natriuretic peptides predict the risk of stroke and atrial fibrillation in men.

BACKGROUND: Risk stratification for cardiovascular outcomes is gaining importance in general population. Prognostic value of natriuretic peptides has been established in patients with heart failure. However, the prognostic significance of natriuretic peptides with respect to stroke is not well known in general populations. METHODS: Plasma natriuretic peptides were measured in a representative population-based sample of 958 men (age 46-65 years) from Eastern Finland. There were 46 cases of stroke, 74 of atrial fibrillation and 31 cases of ischaemic strokes during a follow-up of 9.6 years. RESULTS: The multivariable adjusted risk was 1.35-fold (95% CI 1.01 to 1.84, p = 0.049) for any stroke and 1.30-fold (95% CI 0.90 to 1.91, p = 0.0150) for ischaemic stroke for each log-transformed SD (0.240 pmol/l) increment in N-terminal fragment of proA-type natriuretic peptide. The respective risks were 1.36-fold (95% CI 1.05 to 1.76, p = 0.010) and 1.50-fold (95% CI 1.12 to 2.02, p = 0.007) for each log-transformed SD (0.237 pmol/l) increment in N-terminal fragment of proB-type natriuretic peptide. The multivariate adjusted risks for future atrial fibrillation were 1.71 (95% CI 1.32 to 2.22, p<0.001) and 1.68-fold (95% CI 1.38 to 2.07, p<0.001) for each log-transformed SD increment in N-terminal fragments of proA- and proB-type natriuretic peptides, respectively. CONCLUSIONS: N-terminal fragments of pro-atrial natriuretic peptide and pro-brain natriuretic peptide are new additional predictors of any stroke and atrial fibrillation. Natriuretic peptides provide prognostic information for stroke and atrial fibrillation and may help in identifying subjects at risk for stroke and atrial fibrillation.

Exercise workload, cardiovascular risk factor evaluation and the risk of stroke in middle-aged men.

OBJECTIVE: We investigated the prognostic significance of risk scores and exercise workload with respect to stroke. Background. There are no data on exercise workload combined with European Systematic Coronary Risk Evaluation (SCORE) in the prediction of stroke. METHODS: Exercise workload was measured by exercise test with an electrically braked cycle ergometer performed at baseline. The study is based on a random population-based sample of 1639 men (42-60 years) without history of type 2 diabetes or atherosclerotic cardiovascular disease including coronary heart disease, stroke or claudication. RESULTS: During an average follow-up of 16 years, a total of 97 strokes occurred, of which 71 were ischaemic strokes. Independent predictors for all strokes were European SCORE [for 1% increment, relative risk (RR): 1.12, 95% CI: 1.02 to 1.22, P=0.017), maximal workload (for 20 W increment, RR: 0.87, 95% CI: 0.80 to 0.95, P=0.003) and body mass index (for 5 kg m(-2) increment, RR: 1.08, 95% CI: 1.03 to 1.14, P=0.004), when adjusted for serum HDL, alcohol consumption, C-reactive protein, family history of coronary heart disease, exercise-induced ST changes and the use of medications for hypertension, dyslipidaemia or aspirin. The risk was 2.54-fold (95% CI: 1.27-5.09, P=0.008) for any strokes and 4.43-fold (95% CI 1.69-11.78, P=0.003) for ischaemic strokes amongst men with exercise capacity less than 162 W when compared with those with high exercise capacity over 230 W, after adjustment for risk factors. CONCLUSIONS: Low exercise workload predicts an especially high risk for stroke in the presence of high risk SCORE.

The predictive value of cardiorespiratory fitness combined with coronary risk evaluation and the risk of cardiovascular and all-cause death.

BACKGROUND: There are no data on directly measured cardiorespiratory fitness combined coronary risk evaluation with respect to death from cardiovascular diseases and all-causes. We investigated the prognostic significance of risk scores and cardiorespiratory fitness with respect to cardiovascular disease and all-cause mortality. METHODS: Cardiorespiratory fitness (maximal oxygen uptake, VO2peak) was measured by exercise test with an electrically braked cycle ergometer. The study is based on a random population-based sample of 1639 men (42-60 years) without history of type 2 diabetes or atherosclerotic cardiovascular diseases. RESULTS: During an average follow-up of 16 years, a total of 304 deaths occurred. Independent predictors for all-cause death were European Score (for 1% increment, RR 1.15, 95% CI 1.10-1.20), VO2peak (for 1 MET increment, RR 0.84, 95% CI 0.78-0.89), when adjusted for C-reactive protein, alcohol consumption, serum high-density lipoprotein, waist-to-hip ratio, family history of coronary heart disease, exercise-induced ST changes and the use of medications for hypertension, dyslipidaemia or aspirin. Also, Framingham risk score was related to the risk of death (RR 1.05, 95% CI 1.03-1.07, P < 0.001). Subjects with high European or Framingham score and low VO2peak represent the highest risk group. CONCLUSION: An important finding is that the risk scores can be used to identify men for whom low cardiorespiratory fitness predicts an especially high risk for death from cardiovascular and any other cause.

Low maximal oxygen uptake is associated with elevated depressive symptoms in middle-aged men.

A low level of physical activity has been associated with depression, and increased physical activity has been found to have a positive effect on mood. However, the association between maximal oxygen uptake (VO(2max)) and mood has been poorly studied. In this study VO(2max) (ml/kg per min) was measured in a sample of 1,519 men aged 46-61 years during a cycle ergometer test by using respiratory gas exchange. Men with a history of psychiatric disorder or serious physical illness were excluded. Depressive symptoms were assessed using the 18-item Human Population Laboratory Depression Scale (HPL). Those who scored 5 or more in the HPL were considered to have elevated depressive symptoms. The participants were classified into quartiles according to the VO(2max). Those in the lowest quartile had a more than 3-fold (OR: 3.42; 95% CI: 1.65-7.09; p < 0.001) higher risk of having elevated depressive symptoms compared with those in the highest quartile, even after adjusting for several confounders (OR: 3.38; 95% CI: 1.60-7.14; p < 0.001). In conclusion, low VO(2max) is associated with having elevated depressive symptoms in middle-aged men.

Peak oxygen pulse during exercise as a predictor for coronary heart disease and all cause death.

OBJECTIVE: To investigate the prognostic value of peak oxygen pulse, which is the amount of oxygen consumed per heart beat during exercise, and to compare the prognostic value of peak oxygen pulse and maximum oxygen uptake (Vo(2max)) with respect to coronary heart disease (CHD) and overall death. DESIGN: Prospective population-based study based on 1596 men without CHD or the use of beta blockers at baseline. RESULTS: The risk of CHD was 2.45 (95% CI 1.10 to 5.45) times higher in men with low peak oxygen pulse (< 13.5 ml/beat) than in those with high peak oxygen pulse (> 17.8 ml/beat) after adjustment for age, alcohol consumption, smoking, body mass index, blood pressure, serum lipids, diabetes, family history of CHD and ischaemic ST changes during exercise. During an average follow up of 14 years, 267 men died, 67 of them due to CHD. The respective risk for overall death was 1.79 (95% CI 1.21 to 2.65). The continuous variable Vo(2max) was a stronger risk predictor than peak oxygen pulse for CHD and overall death. CONCLUSIONS: Assessment of oxygen pulse provides no complementary information to Vo(2max) about cardiorespiratory fitness and prognosis for CHD. The analysis of respiratory gas exchange including the assessment of oxygen pulse during exercise does, however, provide an additional means for defining prognosis for patients with CHD.

Cardiac power during exercise and the risk of stroke in men.

BACKGROUND AND PURPOSE: Low maximal oxygen uptake (VO2max) has been shown to predict the risk of stroke. However, VO2max does not take into account the differences in cardiac afterload between subjects. The aim of this study was to examine the relationship of exercise cardiac power (ECP), defined as a ratio of VO2max with peak systolic blood pressure (SBP) during exercise, with the risk for stroke. METHODS: Population-based cohort study with an average follow-up of 12 years from eastern Finland. A total of 1761 men with no history of stroke or coronary heart disease at baseline participated. Among these men, 91 strokes occurred, of which 69 were attributable to ischemic causes. RESULTS: The relative risk of any stroke in men with low ECP (<10.3 mL/mm Hg) was 2.7 (95% CI, 1.2 to 6.0; P=0.01; P=0.02 for the trend across the quartiles), and the relative risk for ischemic stroke was 2.7 (95% CI, 1.1 to 7.0; P=0.03; P=0.04 for trend across the quartiles) compared with men having high ECP (>14.3 mL/mm Hg) during exercise after adjusting for age, examination year, cigarette smoking, alcohol consumption, body mass index, diabetes, serum total cholesterol level, energy expenditure of physical activity, exercise-induced myocardial ischemia, and the use of antihypertensive medication. After further adjustment for resting SBP, results were statistically nonsignificant. CONCLUSIONS: Low ECP provides noninvasive and easily available measure for stroke risk. One of the most potential explanations for the association between ECP and the increased risk of stroke is an elevated afterload and peripheral resistance indicated by elevated SBP.