Hemodynamic gain index and risk of ventricular arrhythmias: a prospective cohort study.

Objectives: Hemodynamic gain index (HGI), a novel hemodynamic index obtained from cardiopulmonary exercise testing (CPX), is associated with adverse cardiovascular outcomes. However, its specific relationship with ventricular arrhythmias (VAs) is unknown. We aimed to assess the association of HGI with risk of VAs in a prospective study. Design: Hemodynamic gain index was estimated using heart rate and systolic blood pressure (SBP) responses ascertained in 1945 men aged 42-61 years during CPX from rest to maximum exercise, using the formula: [(Heart ratemax x SBPmax) - (Heart raterest x SBPrest)]/(Heart raterest x SBPrest). Cardiorespiratory fitness (CRF) was measured using respiratory gas exchange analysis. Hazard ratios (HRs) (95% confidence intervals, CIs) were estimated for VAs. Results: Over a median follow-up duration of 28.2 years, 75 cases of VA were recorded. In analysis adjusted for established risk factors, a unit (bpm/mmHg) higher HGI was associated with a decreased risk of VA (HR 0.72, 95% CI: 0.55-0.95). The results remained consistent on adjustment for lifestyle factors and comorbidities (HR 0.72, 95% CI: 0.55-0.93). Comparing the top versus bottom tertiles of HGI, the corresponding adjusted HRs (95% CIs) were 0.51 (0.27-0.96) and 0.52 (0.28-0.94), respectively. The associations were attenuated on addition of CRF to the model. HGI improved risk discrimination beyond established risk factors but not CRF. Conclusions: Higher HGI is associated with a reduced risk of VAs in middle-aged and older Caucasian men, but dependent on CRF levels. Furthermore, HGI improves the prediction of the long-term risk for VAs beyond established risk factors but not CRF.

Sauna bathing and mortality risk: unraveling the interaction with systolic blood pressure in a cohort of Finnish men.

Objectives: This cohort study aimed to investigate the potential interplay between systolic blood pressure (SBP), frequency of sauna bathing (FSB), and all-cause mortality risk among Caucasian men. Design: A prospective study was conducted, involving 2575 men aged 42 to 61 years. Baseline assessments included resting blood pressure measurements and self-reported sauna bathing habits. SBP levels were categorized as normal (<140 mmHg) or high (≥140 mmHg), while FSB was classified as low (≤2 sessions/week) or high (3-7 sessions/week). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression analysis, while adjusting for lifestyle factors, lipids, inflammation, and comorbidities. Results: Over a median follow-up of 27.8 years, 1,618 deaths were recorded. In the adjusted analysis, individuals with high SBP versus low SBP showed a 29% increased all-cause mortality risk (HR 1.29, 95% CI 1.16-1.43). Similarly, those with low FSB versus high FSB exhibited a 16% elevated mortality risk (HR 1.16, 95% CI 1.02-1.31). When considering combined effects, participants with high SBP-low FSB had a 47% higher mortality risk (HR 1.47, 95% CI 1.24-1.74) compared to those with normal SBP-high FSB. However, no significant association was observed between individuals with high SBP-high FSB and mortality risk (HR 1.24, 95% CI 0.98-1.57). There were potential additive and multiplicative interactions between SBP and sauna bathing concerning mortality risk. Conclusions: This study reveals a potential interplay between SBP, sauna bathing, and mortality risk in Finnish men. Frequent sauna bathing may mitigate the increased mortality risk associated with elevated SBP.

Baseline and usual triglyceride-glucose index and the risk of chronic kidney disease: a prospective cohort study.

Triglyceride-glucose (TyG) index is an emerging marker of adverse cardiometabolic conditions such as cardiovascular disease and type 2 diabetes. The long-term relevance of TyG index to chronic kidney disease (CKD) is uncertain. We aimed to assess the association of TyG index with CKD risk and its utility in risk prediction in a prospective study. The TyG index was calculated using fasting triglycerides and fasting plasma glucose (FPG) levels measured in 2362 men aged 42-61 years with normal kidney function using the formula: Ln (fasting triglycerides [mg/dL] × FPG [mg/dL]/2). Multivariable adjusted hazard ratios (HRs) (95% confidence intervals, CIs) were estimated for CKD. Correction for within-person variability was made using data from repeat measurements of triglycerides and FPG taken 11 years after baseline. Over a median follow-up duration of 17.5 years, 223 CKD cases were recorded. The age-adjusted regression dilution ratio for the TyG index was 0.54 (95% CI, 0.48-0.60). The risk of CKD increased continuously with increasing TyG index across the range 9.3 to 11.6 (p value for nonlinearity<.001). In analysis adjusted for established risk factors, a unit higher TyG index was associated with an increased risk of CKD (HR 1.59, 95% CI 1.24-2.05). Comparing extreme tertiles of the TyG index, the corresponding adjusted HR (95% CI) for CKD was 1.61 (1.15-2.27). Addition of the TyG index to a CKD risk prediction model containing established risk factors improved risk discrimination and reclassification (p value for difference in -2 log likelihood<.001; NRI=47.66%, p=.014; IDI=0.0164, p<.001). Higher TyG index is associated with an increased risk of CKD and improves the prediction and classification of CKD beyond established risk factors. Using single baseline estimations of the TyG index to investigate its association with CKD risk could considerably under-estimate the true association.

A machine learning based approach to identify carotid subclinical atherosclerosis endotypes.

AIMS: To define endotypes of carotid subclinical atherosclerosis. METHODS AND RESULTS: We integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atherosclerosis endotypes. A measure of carotid subclinical atherosclerosis, the c-IMTmean-max, was used to extract atherosclerosis-related features and SHapley Additive exPlanations (SHAP) to reveal endotypes. The association of endotypes with carotid ultrasonographic measurements at baseline, after 30 months, and with the 3-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated by linear (ß, SE) and Cox [hazard ratio (HR), 95% confidence interval (CI)] regression models. Crude estimates were adjusted by common cardiovascular risk factors, and baseline ultrasonographic measures. Improvement in ASCVD risk prediction was evaluated by C-statistic and by net reclassification improvement with reference to SCORE2, c-IMTmean-max, and presence of carotid plaques. An ensemble stacking model was used to predict endotypes in an independent validation cohort, the PIVUS (n = 1061). We identified four endotypes able to differentiate carotid atherosclerosis risk profiles from mild (endotype 1) to severe (endotype 4). SHAP identified endotype-shared variables (age, biological sex, and systolic blood pressure) and endotype-specific biomarkers. In the IMPROVE, as compared to endotype 1, endotype 4 associated with the thickest c-IMT at baseline (ß, SE) 0.36 (0.014), the highest number of plaques 1.65 (0.075), the fastest c-IMT progression 0.06 (0.013), and the highest ASCVD risk (HR, 95% CI) (1.95, 1.18-3.23). Baseline and progression measures of carotid subclinical atherosclerosis and ASCVD risk were associated with the predicted endotypes in the PIVUS. Endotypes consistently improved measures of ASCVD risk discrimination and reclassification in both study populations. CONCLUSIONS: We report four replicable subclinical carotid atherosclerosis-endotypes associated with progression of atherosclerosis and ASCVD risk in two independent populations. Our approach based on endotypes can be applied for precision medicine in ASCVD prevention.

Interplay Between Fitness, Systolic Blood Pressure and Sudden Cardiac Death (from a Cohort Study).

Modifiable risk factors, such as blood pressure and cardiorespiratory fitness (CRF) play a role in the genesis of sudden cardiac death (SCD). However, data on their joint contributions to SCD risk are scarce. We aimed to evaluate the interplay between systolic blood pressure (SBP), CRF, and SCD risk in a cohort of men. Resting SBP was measured using a random-zero sphygmomanometer and CRF was assessed using a respiratory gas exchange analyzer during clinical exercise testing at baseline in 2,291 men aged 42 to 61 years. SBP was classified as normal and high (<140 and ≥140 mm Hg, respectively) and CRF as low, medium, and high. Cox regression analysis was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for SCD. A total of 262 SCDs occurred during a median follow-up of 28.2 years. Comparing high versus normal SBP, the multivariable-adjusted HR (95% CI) for SCD was 1.35 (1.03 to 1.76). Comparing low versus high CRF levels, the corresponding adjusted HR (95% CI) for SCD was 1.81 (1.23 to 2.65). The HRs remained similar when SBP was further adjusted for CRF and CRF was further adjusted for SBP. Men with high SBP and low CRF compared with normal SBP and medium-high CRF, had an increased risk of SCD (HR 2.67, 95% CI 1.76 to 4.05), with no significant evidence of an association between men with high SBP and medium-high CRF and SCD risk (HR 1.38, 95% CI 0.84 to 2.26). There was modest evidence of an additive interaction between SBP and CRF in relation to SCD. In conclusion, there exists an interplay between SBP, CRF, and SCD risk in middle-aged and older men. Medium to high CRF levels may mitigate the increased risk of SCD in subjects with high SBP.

Cardiorespiratory Fitness and Risk of Aortic Stenosis (from a Prospective Cohort Analysis).

Cardiorespiratory fitness (CRF) is a major risk factor and predictor of atherosclerotic cardiovascular disease. However, the relationship between CRF and risk of aortic stenosis (AS) has not been previously investigated. Thus, we aimed to assess the prospective association between CRF and risk of AS. CRF, as measured by maximal oxygen uptake, was assessed using a respiratory gas exchange analyzer during cardiopulmonary exercise testing in 2,308 men aged 42 to 61 years recruited into the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for AS. During a median follow-up of 27 years, 101 cases of AS occurred. Dose-response analysis suggested there might be a nonlinear relation between CRF levels and AS risk. In an analysis adjusted for age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, history of type 2 diabetes mellitus, and coronary heart disease, the HRs 95% (CIs) of AS were 0.57 (0.34 to 0.96) and 0.91 (0.53 to 1.57) for participants in the middle and upper third of CRF levels, respectively, compared with participants in the bottom third. After further adjustment for alcohol consumption, the corresponding HRs (95% CIs) were 0.58 (0.34 to 0.97) and 0.91 (0.53 to 1.56), respectively. In conclusion, higher CRF levels may be associated with a lower incidence of AS in middle-aged and older Finnish men. Given the likely limitations of low statistical power, further research is needed to provide insights into the dose-response nature of any relationship between CRF and AS.

Cross-Sectional Gene-Smoking Interaction Analysis in Relation to Subclinical Atherosclerosis-Results From the IMPROVE Study.

BACKGROUND: Smoking is associated with carotid intima-media thickness (C-IMT). However, knowledge about how genetics may influence this association is limited. We aimed to perform nonhypothesis driven gene-smoking interaction analyses to identify potential genetic variants, among those included in immune and metabolic platforms, that may modify the effect of smoking on carotid intima-media thickness. METHODS: We used baseline data from 1551 men and 1700 women, aged 55 to 79, included in a European multi-center study. Carotid intima-media thickness maximum, the maximum of values measured at different locations of the carotid tree, was dichotomized with cut point values ≥75, respectively. Genetic data were retrieved through use of the Illumina Cardio-Metabo- and Immuno- Chips. Gene-smoking interactions were evaluated through calculations of Synergy index (S). After adjustments for multiple testing, P values of <2.4×10-7 for S were considered significant. The models were adjusted for age, sex, education, physical activity, type of diet, and population stratification. RESULTS: Our screening of 207 586 SNPs available for analysis, resulted in the identification of 47 significant gene-smoking synergistic interactions in relation to carotid intima-media thickness maximum. Among the significant SNPs, 28 were in protein coding genes, 2 in noncoding RNA and the remaining 17 in intergenic regions. CONCLUSIONS: Through nonhypothesis-driven analyses of gene-smoking interactions, several significant results were observed. These may stimulate further research on the role of specific genes in the process that determines the effect of smoking habits on the development of carotid atherosclerosis.

Serum C-reactive protein-to-albumin ratio may be a potential risk indicator for venous thromboembolism: Findings from a prospective cohort study.

BACKGROUND AND AIMS: Circulating C-reactive protein (CRP) and albumin are commonly used inflammatory biomarkers. C-reactive protein-to-albumin ratio (CAR), a novel inflammatory biomarker, has been suggested to be a more reliable risk indicator compared to CRP or albumin alone. An inflammatory hypothesis has been postulated in VTE aetiology, but the association between CAR and VTE has not been investigated. We aimed to assess the prospective association of CAR with VTE risk. METHODS AND RESULTS: C-reactive protein and albumin were measured in serum samples at baseline from 2479 men aged 42-61 years. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. During a median follow-up of 27.0 years, 168 VTE cases were recorded. In analysis adjusted for potential confounders, the HR (95% CI) for VTE comparing extreme tertiles of CAR was 1.49 (1.01-2.21), which was minimally attenuated on further adjustment for prevalent cancer, a potential mediator 1.48 (1.00-2.19). Serum CRP and albumin were each modestly associated with VTE risk in the same set of participants. CONCLUSION: In middle-aged and older men, elevated serum CAR may be associated with an increased risk of VTE. Further research is needed to replicate or refute these findings in other populations and assess if CAR may be of potential value in VTE management.

Associations of Cardiorespiratory Fitness With Estimated Remnant Cholesterol and Non-High-Density Lipoprotein Cholesterol in Healthy Men.

Remnant cholesterol (RC) and non-high-density lipoprotein cholesterol (non-HDL-C) may contribute to the residual risk for atherosclerotic cardiovascular disease. High cardiorespiratory fitness (CRF) is associated with favorable traditional lipid profiles, but its relation with RC and non-HDL-C remains unclear. We analyzed cross-sectional data on 4,613 healthy men (mean age 49 years). CRF was measured using peak oxygen uptake during incremental exercise testing and categorized into quartiles. RC was estimated as total cholesterol minus HDL-C and low-density lipoprotein cholesterol, and elevated RC was defined as ≥38 mg/100 ml (90 percentile). Non-HDL-C was calculated as total cholesterol minus HDL-C, and high non-HLD-C was defined as ≥190 mg/100 ml. CRF was inversely associated with RC (ß -0.31, 95% confidence interval [CI] -0.39 to -0.24) and non-HDL-C (ß -0.34, 95% CI -0.57 to -0.11) after adjustment for several risk factors. Each metabolic equivalent increment in CRF was associated with lower odds of having elevated RC (odds ratio [OR] 0.85, 95% CI 0.77 to 0.93) and non-HDL-C (OR 0.93, 95% CI 0.85 to 1.00) in multivariable analysis. Compared with the bottom quartile, the top quartile of CRF had significantly lower odds of elevated RC (OR 0.63, 95% CI 0.45 to 0.88) and non-HDL-C (OR 0.68, 95% CI 0.51 to 0.91). In conclusion, higher CRF was independently associated with lower levels of RC and non-HDL-C and lower odds of the prevalence of elevated RC and non-HDL-C in healthy men.

Causal analysis of plasma IL-8 on carotid intima media thickness, a measure of subclinical atherosclerosis.

BACKGROUND: We investigated the causality of IL-8 on carotid intima-media thickness (c-IMT), a measure of sub-clinical atherosclerosis. METHODS: The IMPROVE is a multicenter European study (n = 3,711). The association of plasma IL-8 with c-IMT (mm) was estimated by quantile regression. Genotyping was performed using the Illumina CardioMetabo and Immuno chips. Replication was attempted in three independent studies and a meta-analysis was performed using a random model. RESULTS: In IMPROVE, each unit increase in plasma IL-8 was associated with an increase in median c-IMT measures (all p<0·03) in multivariable analyses. Linear regression identified rs117518778 and rs8057084 as associated with IL-8 levels and with measures of c-IMT. The two SNPs were combined in an IL-8-increasing genetic risk that showed causality of IL-8 on c-IMT in IMPROVE and in the UK Biobank (n = 22,179). The effect of IL-8 on c-IMT measures was confirmed in PIVUS (n = 1,016) and MDCCC (n = 6,103). The association of rs8057084 with c-IMT was confirmed in PIVUS and UK Biobank with a pooled estimate effect (ß) of -0·006 with 95%CI (-0·008- -0·003). CONCLUSION: Our results indicate that genetic variants associated with plasma IL-8 also associate with c-IMT. However, we cannot infer causality of this association, as these variants lie outside of the IL8 locus.

Independent and Joint Associations of Exercise Blood Pressure and Cardiorespiratory Fitness With the Risk of Cardiovascular Mortality.

BACKGROUND: We tested the hypothesis that an exaggerated systolic blood pressure (ESBP) at maximal exercise workload would be associated with an increased risk of cardiovascular disease (CVD) mortality, and that high cardiorespiratory fitness (CRF) attenuates this risk. METHODS: This prospective study was based on the general population sample of 1,481 men (aged 42-61 years) who did not have a history of CVD at baseline and were followed up in the Kuopio Ischemic Heart Disease cohort study. Exercise blood pressure and CRF were measured during cardiopulmonary exercise testing, and an ESBP was defined by a peak systolic blood pressure ≥210 mm Hg and CRF categorized as tertiles and unfit and fit groups. RESULTS: During a 26-year median follow-up, 231 CVD deaths occurred. After adjusting for potential confounding factors, an ESBP was associated with an increased risk of CVD mortality (hazard ratio [HR] 1.43, 95% confidence interval: 1.06-1.94), while the highest tertile of CRF was associated with a lower risk of CVD mortality (HR 0.64, 0.43-0.95). In the joint association analyses of ESBP and CRF, ≥210 mm Hg-unfit group had a higher risk of CVD mortality (HR 1.70, 1.02-2.83), but also ≥210 mm Hg-fit group had an increased risk of CVD death (HR 1.95, 1.20-3.18) compared with their <210 mm Hg-fit counterparts. CONCLUSIONS: These results indicate that an ESBP is independently associated with an increased risk of CVD death, but moderate-to-high levels of CRF does not attenuate CVD mortality risk in those with ESBP.

Inflammation, sauna bathing, and all-cause mortality in middle-aged and older Finnish men: a cohort study.

Inflammation and sauna bathing are each related to the risk of all-cause mortality. The interplay between inflammation, sauna bathing and all-cause mortality is not well understood. We aimed to evaluate the separate and joint associations of inflammation (high sensitivity C-reactive protein, hsCRP) and frequency of sauna bathing (FSB) with all-cause mortality in a cohort of Caucasian men. We used the Kuopio Ischaemic Heart Disease Study cohort comprising 2575 men aged 42-61 years at baseline. Serum hsCRP was measured using an immunometric assay and sauna bathing habits were assessed by a self-administered questionnaire. High sensitivity CRP was categorized as normal and high (≤ 3 and > 3 mg/L, respectively) and FSB as low and high (defined as ≤ 2 and 3-7 sessions/week respectively). A total of 1618 deaths occurred during a median follow-up of 27.8 years. Comparing high vs normal hsCRP levels, the multivariable-adjusted HR (95% CI) for all-cause mortality was 1.27 (1.13-1.44). Comparing high vs low FSB, the multivariable-adjusted HR (95% CI) for all-cause mortality was 0.86 (0.76-0.97). Compared with normal hsCRP-low FSB, high hsCRP-low FSB was associated with an increased risk of all-cause mortality 1.28 (1.12-1.47), with no evidence of an association for high hsCRP-high FSB and all-cause mortality risk 1.06 (0.81-1.40). Positive additive and multiplicative interactions were found between hsCRP and FSB in relation to mortality. In a general Finnish male population, both hsCRP and FSB are each independently associated with all-cause mortality. However, frequent sauna baths appear to offset the increased all-cause mortality risk related to high hsCRP levels.

Associations of the serum n-6 PUFA with exercise cardiac power in men.

Low intake or tissue concentrations of the n-6 PUFA, especially to the major n-6 PUFA linoleic acid (LA), and low exercise cardiac power (ECP) are both associated with CVD risk. However, associations of the n-6 PUFA with ECP are unknown. The aim of the present study was to explore cross-sectional associations of the serum total n-6 PUFA, LA, arachidonic acid (AA), γ-linolenic acid (GLA) and dihomo-γ-linolenic acid (DGLA) concentrations with ECP and its components. In total, 1685 men aged 42-60 years from the Kuopio Ischaemic Heart Disease Risk Factor Study and free of CVD were included. ANCOVA was used to examine the mean values of ECP (maximal oxygen uptake (VO2max)/maximal systolic blood pressure (SBP)) and its components in quartiles of the serum total and individual n-6 PUFA concentrations. After multivariable adjustments, higher serum total n-6 PUFA concentration was associated with higher ECP and VO2max (for ECP, the extreme-quartile difference was 0·77 ml/mmHg (95 % CI 0·38, 1·16, Pfor trend across quartiles < 0·001) and for VO2max 157 ml/min (95 % CI 85, 230, Pfor trend < 0·001), but not with maximal SBP. Similar associations were observed with serum LA concentration. Higher serum AA concentration was associated with higher ECP but not with VO2max or maximal SBP. The minor serum n-6 PUFA GLA and DGLA were associated with higher maximal SBP during exercise test and DGLA also with higher VO2max but neither with ECP. In conclusion, especially LA concentration was associated with higher ECP. This may provide one mechanism for the cardioprotective properties of, especially, LA.

Serum copper-to-zinc ratio is associated with heart failure and improves risk prediction in middle-aged and older Caucasian men: A prospective study.

BACKGROUND AND AIMS: Serum copper (Cu) and zinc (Zn) may play a role in the development of adverse cardiovascular outcomes including heart failure (HF). Serum Cu/Zn-ratio has been shown to be a risk indicator for cardiovascular disease, but its relationship with HF has not been previously investigated. We aimed to assess the association between Cu/Zn-ratio and incident HF risk using a prospective cohort study. METHODS AND RESULTS: Study participants were recruited in eastern Finland with baseline examinations carried out between March 1998 and December 2001. Serum levels of Cu and Zn were measured using atomic absorption spectrometry in 1866 men aged 42-61 years without a history of HF at baseline. Multivariable-adjusted hazard ratios (HRs) with confidence intervals (CIs) were calculated for incident HF. During 26.5 years median follow-up, 365 HF cases occurred. Restricted cubic splines suggested linear relationships of serum Cu/Zn-ratio, Cu and Zn with HF risk. A unit increase in Cu/Zn-ratio was associated with an increased HF risk in analysis adjusted for several potential confounders including nutritional factors such as total energy intake, intake of fruits, berries and vegetables, and red meat (HR 1.63; 95% CI 1.06-2.51). The corresponding multivariable-adjusted HRs (95% CIs) for serum Cu and Zn were 2.42 (1.32-4.44) and 1.34 (0.50-3.63), respectively. Addition of Cu/Zn-ratio to a HF risk prediction model was associated with improved risk prediction. CONCLUSION: In middle-aged and older Finnish men, increased serum Cu/Zn-ratio is associated with an increased risk of HF in a linear dose-response fashion and might improve HF risk assessment.

Exercise cardiac power and the risk of heart failure in men: A population-based follow-up study.

BACKGROUND: Little is known about exercise cardiac power (ECP), defined as the ratio of directly measured maximal oxygen uptake with peak systolic blood pressure during exercise, on heart failure (HF) risk. We examined the association of ECP and the risk of HF. METHODS: This was a population-based cohort study of 2351 men from eastern Finland. The average time to follow-up was 25 years. Participants participated at baseline in an exercise stress test. A total of 313 cases of HF occurred. RESULTS: Men with low ECP (<9.84 mL/mmHg, the lowest quartile) had a 2.37-fold (95% confidence interval (95%CI): 1.68-3.35, p < 0.0001) hazards ratio of HF as compared with men with high ECP (>13.92 mL/mmHg, the highest quartile), after adjusting for age. Low ECP was associated with a 1.96-fold risk (95%CI: 1.38-2.78, p < 0.001) of HF after additional adjustment for conventional risk factors. After further adjustment for left ventricular hypertrophy, the results hardly changed (hazards ratio = 1.87, 95%CI: 1.31-2.66, p < 0.001). One SD increase in ECP (3.16 mL/mmHg) was associated with a decreased risk of HF by 28% (95%CI: 17%-37%). CONCLUSION: ECP provides a noninvasive and easily available measure from cardiopulmonary exercise tests in predicting HF. However, ECP did not provide additional value over maximal oxygen uptake.

Cardiorespiratory Fitness, Inflammation, and Risk of Sudden Cardiac Death in Middle-Aged Men.

Inflammation and cardiorespiratory fitness (CRF) are each independently related to the risk of sudden cardiac death (SCD). The interplay between CRF, inflammation and SCD is not well understood. We aimed to study the separate and joint associations of inflammation (high-sensitivity C-reactive protein [hsCRP]) and CRF with SCD risk in a cohort of Caucasian men. In 1,749 men aged 42 to 61 years without a history of coronary heart disease at baseline, serum hsCRP was measured using an immunometric assay, and CRF was assessed using a respiratory gas exchange analyzer during exercise testing. hsCRP was categorized as normal and high (≤3 and >3 mg/L, respectively) and CRF as low and high (median cutoff). A total of 148 SCD events occurred during a median follow-up of 28.9 years. Comparing high versus normal hsCRP, the multivariable-adjusted hazard ratio (95% confidence interval) for SCD was 1.65 (1.11 to 2.45), which remained similar on further adjustment for CRF 1.62 (1.09 to 2.40). Comparing high versus low CRF, the multivariable-adjusted hazard ratio for SCD was 0.61 (0.42 to 0.89), which remained persistent after adjustment for hsCRP 0.64 (0.44 to 0.93). Compared with normal hsCRP-low CRF, normal hsCRP-high CRF was associated with a decreased SCD risk of 0.65 (0.43 to 0.99), high hsCRP-low CRF was associated with an increased SCD risk of 1.72 (1.10 to 2.69), with no evidence of a relationship between high hsCRP-high CRF and SCD risk 0.86 (0.39 to 1.88). Positive additive and multiplicative interactions were found between hsCRP and CRF. In a middle-aged Finnish male population, both hsCRP and CRF are independently associated with SCD risk. However, high CRF levels appear to offset the increased SCD risk related to high hsCRP levels.