Chiara Donfrancesco

Association of Cardiometabolic Multimorbidity With Mortality.

IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy. RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Association of Cardiometabolic Multimorbidity With Mortality The Emerging Risk Factors Collaboration

IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy. RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Favorable cardiovascular risk profile and 10-year coronary heart disease incidence in women and men: results from the Progetto CUORE

Background Cardiovascular risk factor research has recently broadened its focus based on new data indicating the benefits of low risk, i.e. favorable levels of all major risk factors. The aims of this study were to assess further the relation of low risk to coronary heart disease risk, and implications for prevention. Design We conducted a prospective population-based Italian study, of 7438 men and 13 009 women aged 35–69 years, with a mean follow-up of 10.4 years and validated first coronary events. Methods Baseline coronary heart disease risk was classified into three categories: low risk; unfavorable but not high risk; and high risk. To analyze the relation of these risk profiles to coronary heart disease incidence, age-adjusted, sex-averaged coronary heart disease incidence was calculated for persons free of coronary heart disease and stroke, stratified as baseline low risk, unfavorable but not high risk or high risk. To assess the independent relationship of individual risk factors to coronary heart disease incidence, multivariate proportional hazards models were computed for combinations of risk factors. Results Only 2.7% of participants met low risk criteria; 81.4% were high risk. Age-adjusted coronary heart disease incidence for the whole cohort was 37.1 out of 10000 person-years (men 59.0; women 15.3). No coronary heart disease events occurred in low-risk men, only two in low-risk women. For women and men who were not high risk, the age-sex standardized coronary heart disease rate was 62% lower than for high-risk participants. Blood pressure, need for antihypertensive medication, smoking, hyperglycemia, diabetes, total and high-density lipoprotein cholesterol were independently related to coronary heart disease risk. Conclusions Favorable levels of all modifiable readily measured risk factors - rare among Italian adults - assure minimal coronary heart disease risk. Population-wide prevention is needed, especially improved lifestyles, to increase the proportion of the population at low risk.

Impact of Age and Gender on the Prevalence and Prognostic Importance of the Metabolic Syndrome and Its Components in Europeans. The MORGAM Prospective Cohort Project

Objective To investigate the influence of age and gender on the prevalence and cardiovascular disease (CVD) risk in Europeans presenting with the Metabolic Syndrome (MetS). Methods Using 36 cohorts from the MORGAM-Project with baseline between 1982–1997, 69094 men and women aged 19–78 years, without known CVD, were included. During 12.2 years of follow-up, 3.7%/2.1% of men/women died due to CVD. The corresponding percentages for fatal and nonfatal coronary heart disease (CHD) and stroke were 8.3/3.8 and 3.1/2.5. Results The prevalence of MetS, according to modified definitions of the International Diabetes Federation (IDF) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), increased across age groups for both genders (P<0.0001); with a 5-fold increase in women from ages 19–39 years to 60–78 years (7.4%/7.6% to 35.4%/37.6% for IDF/NCEP-ATPIII) and a 2-fold increase in men (5.3%/10.5% to 11.5%/21.8%). Using multivariate-adjusted Cox regressions, the associations between MetS and all three CVD events were significant (P<0.0001). For IDF/NCEP-ATPIII in men and women, hazard ratio (HR) for CHD was 1.60/1.62 and 1.93/2.03, for CVD mortality 1.73/1.65 and 1.77/2.06, and for stroke 1.51/1.53 and 1.58/1.77. Whereas in men the HRs for CVD events were independent of age (MetS*age, P>0.05), in women the HRs for CHD declined with age (HRs 3.23/3.98 to 1.55/1.56; MetS*age, P = 0.01/P = 0.001 for IDF/NCEP-ATPIII) while the HRs for stroke tended to increase (HRs 1.31/1.25 to 1.55/1.83; MetS*age, P>0.05). Conclusion In Europeans, both age and gender influenced the prevalence of MetS and its prognostic significance. The present results emphasise the importance of being critical of MetS in its current form as a marker of CVD especially in women, and advocate for a redefinition of MetS taking into account age especially in women.

Seasonality of cardiovascular risk factors: an analysis including over 230 000 participants in 15 countries

Objective To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies. Methods Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed. Results In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m2 for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol. Conclusions CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.

Excess dietary sodium and inadequate potassium intake in Italy: Results of the MINISAL study

OBJECTIVE As excess sodium and inadequate potassium intake are causally related to hypertension and cardiovascular disease, the MINISAL-GIRCSI Program aimed to provide reliable estimates of dietary sodium and potassium intake in representative samples of the Italian population. DESIGN AND METHODS Random samples of adult population were collected from 12 Italian regions, including 1168 men and 1112 women aged 35-79 yrs. Electrolyte intake was estimated from 24 hour urine collections and creatinine was measured to estimate the accuracy of the collection. Anthropometric indices were measured with standardised procedures. RESULTS The average sodium excretion was 189 mmol (or 10.9 g of salt/day) among men and 147 mmol (or 8.5 g) among women (range 27-472 and 36-471 mmol, respectively). Ninety-seven % of men and 87% of women had a consumption higher than the WHO recommended target of 5g/day. The 24 h average potassium excretion was 63 and 55 mmol, respectively (range 17-171 and 20-126 mmol), 96% of men and 99% of women having an intake lower than 100 mmol/day (European and American guideline recommendation). The mean sodium/potassium ratio was 3.1 and 2.8 respectively, i.e. over threefold greater than the desirable level of 0.85. The highest sodium intake was observed in Southern regions. Sodium and potassium excretion were both progressively higher the higher the BMI (p < 0.0001). CONCLUSIONS These MINISAL preliminary results indicate that in all the Italian regions thus far surveyed dietary sodium intake was largely higher and potassium intake lower than the recommended intakes. They also highlight the critical association between overweight and excess salt intake.

Impact of Age on the Importance of Systolic and Diastolic Blood Pressures for Stroke Risk The MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project

This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP ≥71 mm Hg and DBP <71 mm Hg. Stroke risk was associated positively with SBP and DBP ≥71 mm Hg (SBP/DBP ≥71 mm Hg; hazard ratios: 1.15/1.06 [95% CI: 1.12–1.18/1.03–1.09]) and negatively with DBP <71 mm Hg (0.88[0.79–0.98]). The hazard ratio for DBP decreased with age (P<0.001) and was not influenced by other cardiovascular risk factors. Taking into account the age×DBP interaction, both SBP and DBP ≥71 mm Hg were significantly associated with stroke risk until age 62 years, but in subjects older than 46 years the superiority of SBP for stroke risk exceeded that of DBP ≥71 mm Hg and remained significant until age 78 years. DBP <71 mm Hg became significant at age 50 years with an inverse relation to stroke risk. In Europeans, stroke risk should be assessed by both SBP and DBP until age 62 years with increased focus on SBP from age 47 years. From age 62 years, emphasis should be on SBP without neglecting the potential harm of very low DBP.This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP ≥71 mm Hg and DBP <71 mm Hg. Stroke risk was associated positively with SBP and DBP ≥71 mm Hg (SBP/DBP ≥71 mm Hg; hazard ratios: 1.15/1.06 [95% CI: 1.12–1.18/1.03–1.09]) and negatively with DBP <71 mm Hg (0.88[0.79–0.98]). The hazard ratio for DBP decreased with age ( P <0.001) and was not influenced by other cardiovascular risk factors. Taking into account the age×DBP interaction, both SBP and DBP ≥71 mm Hg were significantly associated with stroke risk until age 62 years, but in subjects older than 46 years the superiority of SBP for stroke risk exceeded that of DBP ≥71 mm Hg and remained significant until age 78 years. DBP <71 mm Hg became significant at age 50 years with an inverse relation to stroke risk. In Europeans, stroke risk should be assessed by both SBP and DBP until age 62 years with increased focus on SBP from age 47 years. From age 62 years, emphasis should be on SBP without neglecting the potential harm of very low DBP. # Novelty and Significance {#article-title-29}

Prevalence and cardiovascular risk profile of chronic kidney disease in Italy: results of the 2008–12 National Health Examination Survey

BACKGROUND National surveys in countries outside Europe have reported a high prevalence (11-13%) of chronic kidney disease (CKD). Studies in Europe have provided a variable prevalence likely due to differences in study design, including age and extent of geographic areas, equation used to evaluate estimated glomerular filtration rate (eGFR) and CKD stages examined. METHODS The 2008-12 National Health Examination Survey in Italy randomly extracted samples from the general population aged 35-79 years, stratified by age and gender, from the resident list of each Italian region (440 persons/1.5 million of residents). We estimated the prevalence of CKD by means of urinary albumin : creatinine ratio and eGFR (CKD-EPI equation-enzymatic assay of serum creatinine). Cardiovascular (CV) risk profile was also evaluated. RESULTS Three thousand eight hundred and forty-eight men and 3704 women were examined. In the whole population, mean age was 57 ± 12 and 56 ± 12 years in men and women, respectively; hypertension was prevalent in men and women, respectively (56 and 43%) and the same held true for overweight (48 and 33%), obesity (26 and 27%), diabetes (14 and 9%) and smoking (21 and 18%), whereas CV disease was less frequent (9 and 6%). Overall, the prevalence of CKD (95% confidence interval) was 7.05% (6.48-7.65). Early stages constituted 59% of the CKD population [Stage G1-2 A2-3: 4.16% (3.71-4.61) and Stage G3-5: 2.89% (2.51-3.26)]. At multivariate regression analysis, age, obesity, hypertension, diabetes, CV disease and smoking were all independent correlates of CKD. CONCLUSIONS CKD has a relatively lower prevalence in Italy, in particular for advanced stages, when compared with similar national surveys outside Europe. This occurs despite older age and unfavourable CV risk profile of the whole population.

Estimated Glomerular Filtration Rate, All-Cause Mortality and Cardiovascular Diseases Incidence in a Low Risk Population: The MATISS Study

Background Chronic kidney disease (CKD) independently increases the risk of death and cardiovascular disease (CVD) in the general population. However, the relationship between estimated glomerular filtration rate (eGFR) and CVD/death risk in a general population at low risk of CVD has not been explored so far. Design Baseline and longitudinal data of 1465 men and 1459 women aged 35-74 years participating to the MATISS study, an Italian general population cohort, were used to evaluate the role of eGFR in the prediction of all-cause mortality and incident CVD. Methods Bio-bank stored sera were used to evaluate eGFR at baseline. Serum creatinine was measured on thawed samples by means of an IDMS-calibrated enzymatic method. eGFR was calculated by the CKD-EPI formula. Results At baseline, less than 2% of enrolled persons had eGFR < 60 mL/min/1.73m2 and more than 70% had a 10-year cardiovascular risk score < 10%. In people 60 or more years old, the first and the last eGFR quintiles (<90 and ≥109 mL/min/1.73m2, respectively) were associated to an increased risk for both all-cause mortality (hazard ratio 1.6, 95% confidence interval 1.2-2.1 and 4.3, 1.6-11.7, respectively) and incident CVD (1.6, 1.0-2.4 and 7.0, 2.2-22.9, respectively), even if adjusted for classical risk factors. Conclusions These findings strongly suggest that in an elderly, general population at low risk of CVD and low prevalence of reduced renal filtration, even a modest eGFR reduction is related to all-cause mortality and CVD incidence, underlying the potential benefit to this population of considering eGFR for their risk prediction.

Impact of Age on the Importance of Systolic and Diastolic Blood Pressures for Stroke RiskNovelty and Significance: The MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project

This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP ≥71 mm Hg and DBP <71 mm Hg. Stroke risk was associated positively with SBP and DBP ≥71 mm Hg (SBP/DBP ≥71 mm Hg; hazard ratios: 1.15/1.06 [95% CI: 1.12–1.18/1.03–1.09]) and negatively with DBP <71 mm Hg (0.88[0.79–0.98]). The hazard ratio for DBP decreased with age (P<0.001) and was not influenced by other cardiovascular risk factors. Taking into account the age×DBP interaction, both SBP and DBP ≥71 mm Hg were significantly associated with stroke risk until age 62 years, but in subjects older than 46 years the superiority of SBP for stroke risk exceeded that of DBP ≥71 mm Hg and remained significant until age 78 years. DBP <71 mm Hg became significant at age 50 years with an inverse relation to stroke risk. In Europeans, stroke risk should be assessed by both SBP and DBP until age 62 years with increased focus on SBP from age 47 years. From age 62 years, emphasis should be on SBP without neglecting the potential harm of very low DBP.This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP ≥71 mm Hg and DBP <71 mm Hg. Stroke risk was associated positively with SBP and DBP ≥71 mm Hg (SBP/DBP ≥71 mm Hg; hazard ratios: 1.15/1.06 [95% CI: 1.12–1.18/1.03–1.09]) and negatively with DBP <71 mm Hg (0.88[0.79–0.98]). The hazard ratio for DBP decreased with age ( P <0.001) and was not influenced by other cardiovascular risk factors. Taking into account the age×DBP interaction, both SBP and DBP ≥71 mm Hg were significantly associated with stroke risk until age 62 years, but in subjects older than 46 years the superiority of SBP for stroke risk exceeded that of DBP ≥71 mm Hg and remained significant until age 78 years. DBP <71 mm Hg became significant at age 50 years with an inverse relation to stroke risk. In Europeans, stroke risk should be assessed by both SBP and DBP until age 62 years with increased focus on SBP from age 47 years. From age 62 years, emphasis should be on SBP without neglecting the potential harm of very low DBP. # Novelty and Significance {#article-title-29}