Gunnar Engström

Association of Cardiometabolic Multimorbidity With Mortality.

IMPORTANCEnThe prevalence of cardiometabolic multimorbidity is increasing.nnnOBJECTIVEnTo estimate reductions in life expectancy associated with cardiometabolic multimorbidity.nnnDESIGN, SETTING, AND PARTICIPANTSnAge- 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.nnnEXPOSURESnA history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).nnnMAIN OUTCOMES AND MEASURESnAll-cause mortality and estimated reductions in life expectancy.nnnRESULTSnIn 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.nnnCONCLUSIONS AND RELEVANCEnMortality 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.

Risk Profiles for Aortic Dissection and Ruptured or Surgically Treated Aneurysms: A Prospective Cohort Study

Background Community screening to guide preventive interventions for acute aortic disease has been recommended in high‐risk individuals. We sought to prospectively assess risk factors in the general population for aortic dissection (AD) and severe aneurysmal disease in the thoracic and abdominal aorta. Methods and Results We studied the incidence of AD and ruptured or surgically treated aneurysms in the abdominal (AAA) or thoracic aorta (TAA) in 30 412 individuals without diagnosis of aortic disease at baseline from a contemporary, prospective cohort of middle‐aged individuals, the Malmö Diet and Cancer study. During up to 20 years of follow‐up (median 16 years), the incidence rate per 100 000 patient‐years at risk was 15 (95% CI 11.7 to 18.9) for AD, 27 (95% CI 22.5 to 32.1) for AAA, and 9 (95% CI 6.8 to 12.6) for TAA. The acute and in‐hospital mortality was 39% for AD, 34% for ruptured AAA, and 41% for ruptured TAA. Hypertension was present in 86% of individuals who subsequently developed AD, was strongly associated with incident AD (hazard ratio [HR] 2.64, 95% CI 1.33 to 5.25), and conferred a population‐attributable risk of 54%. Hypertension was also a risk factor for AAA with a smaller effect. Smoking (HR 5.07, 95% CI 3.52 to 7.29) and high apolipoprotein B/A1 ratio (HR 2.48, 95% CI 1.73 to 3.54) were strongly associated with AAA and conferred a population‐attributable risk of 47% and 25%, respectively. Smoking was also a risk factor for AD and TAA with smaller effects. Conclusions This large prospective study identified distinct risk factor profiles for different aortic diseases in the general population. Hypertension accounted for more than half of the population risk for AD, and smoking for half of the population risk of AAA.

Risk factors for the progression of carotid intima-media thickness over a 16-year follow-up period: The Malmö Diet and Cancer Study

OBJECTIVEnTo evaluate the progression of carotid intima-media thickness (IMT) in the common carotid artery (CCA) and the bifurcation over a mean follow-up of 16 years in relation to cardiovascular risk factors.nnnMETHODSnThe study population included 3426 middle-aged Swedish men and women participating in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the cardiovascular cohort of the Malmö Diet and Cancer Study (MDCS).nnnRESULTSnThere were differences in risk factor patterns in arterial segments in that diabetes and male sex were associated with the progression of IMT in the bifurcation, but not in the CCA, and high-density lipoprotein cholesterol (HDL) was associated with the progression of IMT in the CCA, but not in the bifurcation. Favourable changes in systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL) and HDL during follow-up decreased the IMT progression rate in the CCA. There was a cumulative relationship between traditional cardiovascular risk factors (i.e., regular smoking, LDL/HDL-ratioxa0≥xa03, hypertension) and IMT progression rates. The odds ratio (OR) of high IMT CCA progression rate (>75th percentile) was 1.0 (reference), 1.4 (95% CI: 1.1, 1.7), 1.7 (95% CI: 1.3, 2.2) and 2.1 (95% CI: 1.4, 3.1), respectively, for individuals with none, one, two, and three risk factors.nnnCONCLUSIONnThere were differences in the associations between risk factors and progression rate in different arterial segments. Favourable changes in SBP and lipids during the follow-up period were associated with reduced IMT progression rates in the CCA.

Prevalence of knee pain and knee OA in southern Sweden and the proportion that seeks medical care

OBJECTIVEnThe aim of this study was to estimate the prevalence of frequent knee pain in radiographic, symptomatic and clinically defined knee OA in middle-aged and elderly patients and the proportion that seeks medical care.nnnMETHODSnIn 2007 a random sample of 10 000 56- to 84-year-old residents of Malmö, Sweden, were questioned about knee pain. We classified subjects reporting knee pain with a duration of at least 4 weeks as having frequent knee pain. A random sample of 1300 individuals with frequent knee pain and 650 without were invited for assessment by the ACR clinical knee OA criteria and for bilateral weight-bearing knee radiography. We considered a Kellgren-Lawrence grade ≥2 as radiographic knee OA and that in combination with frequent knee pain as symptomatic knee OA. By linkage with the Skåne Healthcare Register, we determined the proportion of subjects that had consulted for knee OA or pain.nnnRESULTSnThe 10 000 subjects had a mean age of 70 years (s.d. 7.6), a mean BMI of 27.1 kg/m(2) and 62% were women. The prevalence of frequent knee pain was 25.1% (95% CI 24.1, 26.1), higher in women and similar across age groups. The prevalence of radiographic knee OA was 25.4% while 15.4% had either symptomatic or clinically defined knee OA. Of these, 68.9% consulted a physician for knee OA or pain during 2004-11.nnnCONCLUSIONnFifteen per cent of middle-aged or elderly individuals have knee OA and symptoms. About one in three of those do not consult a physician. Inefficient care of OA and self-coping may be an explanation.

Cadmium exposure and atherosclerotic carotid plaques -Results from the Malmö diet and Cancer study.

BACKGROUNDnEpidemiological studies indicate that cadmium exposure through diet and smoking is associated with increased risk of cardiovascular disease. There are few data on the relationship between cadmium and plaques, the hallmark of underlying atherosclerotic disease.nnnOBJECTIVESnTo examine the association between exposure to cadmium and the prevalence and size of atherosclerotic plaques in the carotid artery.nnnMETHODSnA population sample of 4639 Swedish middle-aged women and men was examined in 1991-1994. Carotid plaque was determined by B-mode ultrasound. Cadmium in blood was analyzed by inductively coupled plasma mass spectrometry.nnnRESULTSnComparing quartile 4 with quartile 1 of blood cadmium, the odds ratio (OR) for prevalence of any plaque was 1.9 (95% confidence interval 1.6-2.2) after adjustment for sex and, age; 1.4 (1.1-1.8) after additional adjustment for smoking status; 1.4 (1.1-1.7) after the addition of education level and life style factors; 1.3 (1.03-1.8) after additional adjustment for risk factors and predictors of cardiovascular disease. No effect modification by sex was found in the cadmium-related prevalence of plaques. Similarly, ORs for the prevalence of small and large plaques were after full adjustment 1.4 (1.0-2.1) and 1.4 (0.9-2.0), respectively. The subgroup of never smokers showed no association between cadmium and atherosclerotic plaques.nnnCONCLUSIONSnThese results extend previous studies on cadmium exposure and clinical cardiovascular events by adding data on the association between cadmium and underlying atherosclerosis in humans. The role of smoking remains unclear. It may both cause residual confounding and be a source of pro-atherogenic cadmium exposure.

Copeptin is an independent predictor of diabetic heart disease and death.

Background We previously discovered that high copeptin is associated with incidence of diabetes mellitus (diabetes), abdominal obesity, and albuminuria. Furthermore, copeptin predicts cardiovascular events after myocardial infarction in diabetic patients, but whether it is associated with heart disease and death in individuals without diabetes and prevalent cardiovascular disease is unknown. In this study, we aim to test whether plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin prohormone, predicts heart disease and death differentially in diabetic and nondiabetic individuals. Methods We related plasma copeptin to a combined end point composed of coronary artery disease (CAD), heart failure (HF), and death in diabetes (n = 895) and nondiabetes (n = 4187) individuals of the Malmö Diet and Cancer Study–Cardiovascular cohort. Results Copeptin significantly interacted with diabetes regarding the combined end point (P = .006). In diabetic individuals, copeptin predicted the combined end point (hazard ratio [HR] 1.32 per SD, 95% CI 1.10-1.58, P = .003) after adjustment for conventional risk factors, prevalent HF and CAD, and remained significant after additional adjustment for either fasting glucose (P = .02) or hemoglobin A1c (P = .02). Furthermore, in diabetic individuals, copeptin predicted CAD (HR 1.33 per SD, 95% CI 1.04-1.69, P = .02), HF (HR 1.62 per SD, 95% CI 1.09-2.41, P = .02), and death (HR 1.32 per SD, 95% CI 1.04-1.68, P = .02). Interestingly, among nondiabetic individuals, copeptin was not associated with any of the end points. Conclusions Copeptin predicted heart disease and death, specifically in diabetes patients, suggesting copeptin and the vasopressin system as a prognostic marker and therapeutic target for diabetic heart disease and death.

Red cell distribution width in relation to incidence of stroke and carotid atherosclerosis: a population-based cohort study.

Background Increased red cell distribution width (RDW) has been related to poor prognosis in patients with cardiovascular disease, and is a predictor of cardiovascular mortality in the general population. The purpose of the present study was to investigate if RDW is associated with increased incidence of stroke and its subtypes in individuals from the general population. Methods Red cell distribution width was measured in 26,879 participants (16,561 women and 10,318 men aged 45–73 years) without history of coronary events or stroke, from the population-based Malmö Diet and Cancer Study. Incidences of total stroke and stroke subtypes over a mean follow-up of 15.2 years were calculated in relation to sex-specific quartiles of RDW. The presence of carotid plaque and intima–media thickness, as assessed by ultrasound, was studied in relation to RDW in a randomly selected subcohort (n = 5,309). Results Incidences of total stroke (n = 1,869) and cerebral infarction (n = 1,544) were both increased in individuals with high RDW. Hazard ratios (HRs) in the highest compared to the lowest quartile were 1.31 for total stroke (95% confidence interval [CI]: 1.11–1.54, p for trend = 0.004) and 1.32 for cerebral infarction (95% CI: 1.10–1.58, p for trend = 0.004) after adjustment for stroke risk factors and hematological parameters. The adjusted HR for intracerebral hemorrhage (n = 230) was 1.44 (95% CI: 0.90–2.30) and the HR for subarachnoid hemorrhage (n = 75) was 0.94 (95% CI: 0.43–2.07), in the highest compared to the lowest quartile of RDW. Red cell distribution width was positively associated with intima–media thickness of the common carotid artery (p for trend = 0.011). Conclusions Red cell distribution width in the highest quartile was associated with increased incidence of total stroke and cerebral infarction. There was no significant association between RDW and incidence of intracerebral or subarachnoid hemorrhage.

Blood cadmium levels and incident cardiovascular events during follow-up in a population-based cohort of swedish adults : The malmö diet and cancer study

Background: Cadmium exposure may increase the risk of cardiovascular disease. The only published longitudinal study on cadmium and incident cardiovascular disease was performed in American Indians with relatively high cadmium exposure. Objectives: Our aim was to examine the association between blood cadmium at baseline and incident cardiovascular events in a population-based study of Swedish men and women with cadmium levels similar to those of most European and U.S. populations. Methods: A Swedish population-based cohort (n = 6,103, age 46–67 years) was recruited between 1991 and 1994. After we excluded those with missing data on smoking, 4,819 participants remained. Acute coronary events, other major cardiac events, stroke, and cardiovascular mortality were followed until 2010. Associations with blood cadmium (estimated from cadmium in erythrocytes) were analyzed using Cox proportional hazards regression including potential confounders and important cardiovascular risk factors. Results: Hazard ratios for all cardiovascular end points were consistently increased for participants in the 4th blood cadmium quartile (median, 0.99 μg/L). In models that also included sex, smoking, waist circumference, education, physical activity, alcohol intake, serum triglycerides, HbA1c, and C-reactive protein, the hazard ratios comparing the highest and lowest quartiles of exposure were 1.8 (95% CI: 1.2, 2.7) for acute coronary events, and 1.9 (1.3, 2.9) for stroke. Hazard ratios in never-smokers were consistent with these estimates. Conclusions: Blood cadmium in the highest quartile was associated with incident cardiovascular disease and mortality in our population-based samples of Swedish adults. The consistent results among never-smokers are important because smoking is a strong confounder. Our findings suggest that measures to reduce cadmium exposures are warranted, even in populations without unusual sources of exposure. Citation: Barregard L, Sallsten G, Fagerberg B, Borné Y, Persson M, Hedblad B, Engström G. 2016. Blood cadmium levels and incident cardiovascular events during follow-up in a population-based cohort of Swedish adults: the Malmö Diet and Cancer Study. Environ Health Perspect 124:594–600;u2002http://dx.doi.org/10.1289/ehp.1509735

Non-hemodynamic predictors of arterial stiffness after 17 years of follow-up: the Malmö Diet and Cancer study

Background: Arterial stiffness plays a fundamental role in the development of hypertension and is a risk factor for both cardiovascular disease and mortality. The stiffening that occurs with increasing age has, in numerous cross-sectional studies, been shown to be associated with several cardiovascular risk factors. This observational study aims to characterize the predictive and cross-sectional markers focusing on the non-hemodynamic component of arterial stiffness. Method: In all, 2679 men and women from Malmö, Sweden, were examined at baseline during 1991–1994, and again at follow-up during 2007–2012 (mean age 72 years, 38% men). Follow-up examination included measurement of arterial stiffness by carotid–femoral pulse wave velocity (c-fPWV), after a mean period of 17 years. The associations between c-fPWV and risk markers were calculated with multiple linear regression. Results: The results indicated that for both sexes, waist circumference (&bgr;u200a=u200a0.17, Pu200a<u200a0.001), fasting glucose (&bgr;u200a=u200a0.13, Pu200a<u200a0.001), Homeostatic Model Assessment – Insulin Resistance (&bgr;u200a=u200a0.10, Pu200a<u200a0.001), triglycerides (&bgr;u200a=u200a0.10, Pu200a<u200a0.001), and high-density lipoprotein cholesterol (&bgr;u200a=u200a−0.08, Pu200a<u200a0.001) were all predictors of cfPWV adjusted for mean arterial pressure and heart rate, as well as for classical cardiovascular risk factors and drug treatment. There were no associations between baseline or follow-up low-density lipoprotein cholesterol, smoking, or eGFR and c-fPWV. Conclusion: The non-hemodynamic cluster of risk markers and predictors of arterial stiffness in a middle-aged population includes abdominal obesity, hyperglycemia, and dyslipidemia, but not smoking and low-density lipoprotein cholesterol. This pattern existed in both sexes.

A high quality diet is associated with reduced systemic inflammation in middle-aged individuals

OBJECTIVEnTo examine if overall diet quality is associated with cellular and soluble biomarkers of systemic inflammation in middle-aged individuals.nnnMETHODSnA group of 667 individuals, aged 63-68 years, selected from the cardiovascular arm of the Malmö Diet and Cancer cohort, participated in this study. Baseline examinations consisted of an extensive socio-demographic questionnaire, anthropometric measurements, blood sampling and detailed dietary data. Mononuclear leukocytes frozen at baseline were thawed and analysed with flow cytometry to quantify monocyte subsets based on CD14 and CD16 expression. Plasma cytokines were measured using multiplexed immune assays. A diet quality index consisting of six components (saturated fatty acids, polyunsaturated fatty acids, fish and shellfish, dietary fibre, fruit and vegetables, and sucrose) was constructed to measure adherence to the Swedish Nutrition Recommendations/Dietary Guidelines. General linear models were used to investigate associations between index scores and several biomarkers of inflammation.nnnRESULTSnA higher percentage of women reported adherence to the nutritional recommendations and had better overall diet quality than men. Participants with higher diet quality were more likely to have a healthier lifestyle. The levels of high-sensitive CRP, S100A8/A9, TNF-α, white blood cells, neutrophils, lymphocytes and CD14(+)CD16(++) were lower in participants with higher index scores. The associations remained significant after adjustment for potential confounders.nnnCONCLUSIONnIn this cross-sectional study, we found that a high diet quality is associated with lower systemic inflammation. As the incidence of cardiovascular disease and cancer is directly correlated with the levels of inflammation, our findings might indicate a protective role of high-quality diet.