Mikael Gottsäter

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; = 0.17, P < 0.001), fasting glucose (&bgr; = 0.13, P < 0.001), Homeostatic Model Assessment – Insulin Resistance (&bgr; = 0.10, P < 0.001), triglycerides (&bgr; = 0.10, P < 0.001), and high-density lipoprotein cholesterol (&bgr; = −0.08, P < 0.001) 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.

Acute phase proteins as prospective risk markers for arterial stiffness : The Malmö Diet and Cancer cohort

Background and objectives Arterial stiffness plays a significant role in the development and progression of adverse cardiovascular events and all-cause mortality. This observational study aims to explore the relationship between six acute phase proteins namely, ceruloplasmin, alpha-1-antitrypsin, orosomucoid, haptoglobin, complement C3 and C-reactive protein (CRP), and carotid-femoral pulse wave velocity (c-f PWV) in a population-based cohort, and to also explore the effect of low-grade inflammation on the relationship between diabetes and c-f PWV. Method The study consisted of participants from the Malmö Diet and Cancer study with data from baseline examinations (1991–1994) and follow-up examinations (2007–2012). Arterial stiffness was measured at follow-up by determining c-f PWV. After excluding participants with missing data, the total study population included 2338 subjects. General linear models were used to assess the relationship between baseline acute phase proteins and c-f PWV. Results After adjusting for traditional risk factors the participants in the 4th quartile vs 1st quartile of alpha-1-antitrypsin (geometric mean: 10.32 m/s vs 10.04 m/s) (p<0.05), C3 (10.35 m/s vs 10.06 m/s) (p<0.05) and CRP (10.37 m/s vs 9.96 m/s) (p<0.001) showed significant association with c-f PWV. Diabetes at follow-up was also associated with high c-f PWV, however, this relationship was independent of low grade inflammation. Conclusion Alpha-1-antitrypsin, C3 and CRP are associated with arterial stiffness. The results indicate that low grade inflammation is associated with arterial stiffness in addition to established cardiovascular risk factors.

Predictive markers of abdominal aortic stiffness measured by echo-tracking in subjects with varying insulin sensitivity

Arterial stiffness is influenced by advancing age and vascular disease and is an independent risk factor for cardiovascular events and death. Using ultrasound measurements, arterial stiffness in a specific arterial segment can be assessed. The aim of this observational study was to explore the prospective and cross-sectional associations between arterial stiffness measured by ultrasound locally in the abdominal aorta and cardiovascular risk factors/markers including insulin resistance measured by the homeostatic model assessment-insulin resistance (HOMA-IR), lipids and abdominal obesity. This study includes 335 subjects from Malmö, Sweden, examined in 1991–1994 and again at follow-up in 1998–2000 (mean age 64 years, 42% men). Ultrasound measurement of the abdominal aorta was performed at follow-up investigation. In the female subgroup, there was a positive association between HOMA-IR at baseline and abdominal aortic stiffness at follow-up (β=0.18, P=0.03) and a negative association between high-density lipoprotein and aortic stiffness (β=−0.23, P=0.005), independently of classical cardiovascular risk factors. These associations were not found among men. The results suggest a greater or different role of impaired glucose metabolism in the pathophysiology of arterial stiffness in women than in men.

Adrenomedullin is a marker of carotid plaques and intima-media thickness as well as brachial pulse pressure.

Background: Adrenomodulin (ADM) is a peptide hormone secreted in response to cellular strain such as ischemia and is believed to have a beneficial effect on the cardiovascular system. However, the epidemiological relationships between ADM and measurements of haemodynamics, arteriosclerosis and atherosclerosis are not well established. The aim of this study was to investigate the association between the mid-regional part of pro-ADM (MR-proADM) and brachial pulse pressure (PP), carotid intima–media thickness (cIMT) and carotid atherosclerosis. Method: This study has a cross-sectional design and includes 4924 individuals (mean age 58 years, 40% men) from Malmö, Sweden, examined between 1991 and 1994. Participants underwent physical examination, measurement of MR-proADM and ultrasound of the carotid arteries. Results: There was a positive association between MR-proADM and brachial PP, cIMT as well as a carotid plaque score. The associations were significant after adjustment for age, sex, BMI, hypertension, diabetes, low-density lipoprotein cholesterol and smoking. Conclusion: ADM is positively associated with brachial PP and both carotid IMT and plaques, suggesting a role for ADM in early haemodynamic pathophysiology related to arteriosclerosis and the atherosclerotic plaque development.

Insulin resistance and β‐cell function in smokers: results from the EGIR‐RISC European multicentre study

Tobacco smoking is known to increase the long‐term risk of developing Type 2 diabetes mellitus, but the mechanisms involved are poorly understood. This observational, cross‐sectional study aims to compare measures of insulin sensitivity and β‐cell function in current, ex‐ and never‐smokers.

Family history of cardiometabolic diseases and its association with arterial stiffness in the Malmö Diet Cancer cohort

Objective: Arterial stiffening increases with age and is associated with increased cardiovascular risk. Several risk factors have been shown to predict the development of arterial stiffening; however, a positive family history (FH+) of cardiometabolic disease (CMD) and hypertension has not been extensively studied. We hypothesize that FH+ of CMD plays a significant role in the development of arterial stiffening in offspring. Methods: We used data from the population-based Malmö Diet Cancer study (n = 3056) examined in 1992–1996 and again in 2007–2012. Several variables were analysed, including anthropometrics, carotid–femoral pulse wave velocity and FH+. The association between FH+ of CMD and arterial stiffening in the offspring was analysed with analysis of covariance in SPSS. FH+ was subdivided into three categories: family history for cardiovascular events (FH-CVEs), family history for diabetes mellitus type 2 (FH-DM2) and family history for hypertension (FH-HT). The first analysis of covariance-model was adjusted for age, sex, mean arterial pressure and heart rate; the second model additionally adjusted for self-reported medical history in the offspring. Results: Data indicated that FH-CVE (F = 14.64, P < 0.001), FH-DM2 (F = 18.57, P < 0.001) and FH-HT (F = 13.92, P < 0.001) all significantly increased carotid–femoral pulse wave velocity levels. The results remained when additional adjustment was made for confounders and for self-reported CMD in the index participants, respectively, for FH-CVE (F = 12.47, P < 0.001), FH-DM2 (F = 7.62, P = 0.006) as well as for FH-HT (F = 7.30, P = 0.007). Conclusion: These findings indicate that a FH+ of cardiometabolic conditions and hypertension affects arterial stiffness in offspring independently of haemodynamic factors and self-reported CMD in the offspring without sex differences.

4D.12: AORTIC STIFFNESS IS MODESTLY BUT EQUALLY ASSOCIATED WITH BOTH CENTRAL AND BRACHIAL PULSE PRESSURE IN ELDERLY SUBJECTS. THE MALMÖ DIET CANCER STUDY.

Objective: Arterial stiffness (AS) in the aorta is a well-documented and independent risk marker of cardiovascular disease risk and total mortality according to meta-analyses. Aortic AS can be measured by carotid-femoral pulse wave velocity (c-f PWV) as the “golden standard” method. A surrogate marker is pulse pressure (PP) during resting conditions, reflecting isolated systolic hypertension. During ageing the amplification of central blood pressure (cBP) in relation to brachial BP (bBP) is reduced. Our aim was to investigate cross-sectional associations between c-f PWV and cPP as well as bPP in an elderly population. Design and method: We examined a total of 3001 subjects (mean age 72 years, 38% men) from MDCS by use of Sphygmocor® for determination of c-f PWV and pulse wave analysis (PWA) in arteria radialis after an additional mean 30 minutes (range: 15-40 min) of supine rest in a quiet room and well standardized procedures. PWA derived data were used for estimation of central hemodynamics by a transfer function in the device after addition of data on resting brachial BP. Finally, the difference (delta) in bBP during 30 minutes of rest between PWV and PWA measurements was calculated. Adjustment was made for age and sex. Results: Mean values (SD) were for bBP: 131.0/73.4 (17.1/8.8) mmHg and for cBP: 122.3/74.4 (16.8/9.0) mmHg, with corresponding bPP: 57.5 (12.9) mmHg and cPP: 48.0 (12.3) mmHg, respectively. The pulse pressure amplification (bPP/cPP) was 21.2 (10.5) percentage. The mean c-f PWV was 10.5 (2.5) m/s. In multiple regression analysis after adjustment for age and sex, c-f PWV correlated significantly (p<0.001) and separately with both bPP (r= 0.37) and cPP (r= 0.29).: Mean c-f PWV levels in cPP quartiles ranged from 9.4 to 11.7 m/s, and in bPP quartiles from 9.2 to 12.1 m/s. c-f PWV was inversely correlated with delta bBP (r= -0.09; p<0.001) after full adjustment. Conclusions: In elderly subjects c-f PWV (as a marker of AS) is modestly associated with both central and brachial PP, but not more closely with central PP as was expected. Selective survival bias may have influenced the findings.

PREDICTION OF TOTAL AND CAUSE-SPECIFIC MORTALITY, AS WELL AS CARDIOVASCULAR MORBIDITY, IN THE ELDERLY BY CAROTID-FEMORAL PULSE WAVE VELOCITY: THE MALMO DIET CANCER STUDY

Objective: Arterial stiffness (AS) increases with age and predicts total mortality and total cardiovascular (CV) events. It has also been shown that a positive family history (FH+) of cardiometabolic disease influences AS. We aimed to: (a) examine if AS predicts total-, CV- and non-CV mortality among elderly subjects, as well as total and non-fatal CV events; and (b) to assess if FH+ influences the prediction of AS for events. Design and method: Participants from the Malmö Diet Cancer CV cohort (MDC-CV; n = 3,056, mean age 71 years, 40% men) in Sweden were examined during 2007–2012. AS was measured by carotid-femoral pulse wave velocity (c-f PWV; Sphygmocor®). Follow-up started from date of measurement and ended at death, emigration, or on 31/DEC/2014 (to be updated until 31/DEC/2016 during spring 2018). Endpoints for mortality and morbidity were assessed by linkage to National and regional registers, based on personal identification.Hazard ratios (HRs) with 95% confidence intervals (CI) were computed using multivariable Cox and competing risks regression (sub-hazard ratio, SHR) adjusting for age, sex, cardiovascular risk factors, prevalent cardiometabolic diseases, and FH+. Results: c-f PWV (per log-unit) significantly predicted total mortality, HR 2.57 (95%CI: 1.28–5.16, p = 0.008), after full adjustment for risk factors, and HR 3.01 (95%CI: 1.41–6.42) after adjusting for FH. The prediction of total CV events was of borderline significance, HR 1.85 (95%CI: 0.91–3.78, p = 0.09). After adjustment for FH+, c-f PWV had a borderline significant relationship with non-CV mortality, SHR 2.30 (95%CI: 0.89–5.95, p = 0.085). Conclusions: Arterial stiffness (c-f PWV) predicts total mortality in the elderly, even adjusted for family history of cardiometabolic disease. Thus c-f PWV is a promising risk marker for total mortality, reflecting vascular ageing (arterial stiffness), beyond the prediction offered by conventional risk factors. Updated endpoints will be included during spring 2018.

Arterial stiffness and incidence of diabetes: A population-based cohort study

OBJECTIVE Diabetes is known to be associated with increased arterial stiffness. However, the temporal association between increased carotid-femoral pulse wave velocity (c-f PWV) and diabetes is unclear. The aim of this study is to explore the relationship between arterial stiffness, as determined by c-f PWV, and incidence of diabetes. RESEARCH DESIGN AND METHODS The study population included participants from the Malmö Diet and Cancer cardiovascular cohort, using measurements from the 2007–2012 reexamination as baseline. Arterial stiffness was evaluated by measuring c-f PWV (SphygmoCor). After excluding participants with prevalent diabetes (according to measurements of fasting glucose, oral glucose tolerance tests, and physician’s diagnoses), the final study population consisted of 2,450 individuals (mean age = 71.9 ± 5.6 years). Incidence of diabetes was followed by linkage to local and national diabetes registers. Cox proportional hazards regression was used to assess the incidence of diabetes in relation to the tertiles of c-f PWV, adjusted for potential confounders. RESULTS During a mean follow-up of 4.43 ± 1.40 years, 68 (2.8%) participants developed diabetes. Crude incidence of diabetes (per 1,000 person-years) was 3.5, 5.7, and 9.5, respectively, for subjects in the first, second, and third tertiles of c-f PWV. After adjustment for potential confounders, the hazard ratio of diabetes was 1.00 (reference), 1.83 (95% CI 0.88–3.8), and 3.24 (95% CI 1.51–6.97), respectively, for the tertiles of c-f PWV (P for trend = 0.002). CONCLUSIONS Increased c-f PWV is associated with increased incidence of diabetes, independent of other risk factors. These results suggest that increased arterial stiffness is an early risk marker for developing diabetes.

PS 05-68 NO CROSS-SECTIONAL ASSOCIATION FOUND BETWEEN SKIN ADVANCED GLYCATION END PRODUCTS (AGE) AND ARTERIAL STIFFNESS IN A NON-HOSPITALIZED ELDERLY POPULATION

Objective: Evaluation of transdermal Advanced Glycation End (AGE) products autofluorescence (skin-AF) is a new method for estimation of exposure to hyperglycaemia and oxidative stress. Previous studies have shown that skin-AF is elevated in patients with some chronic disease conditions (End-stage renal disease, ESRD; type-1 diabetes) and atherosclerosis, but population-based data on the association with arteriosclerosis (arterial stiffness) are sparse. Design and Method: We examined a total of 498 elderly subjects (mean age 72 years, 39% men) from the Malmö Diet Cancer–Cardiovascular cohort during 2007–2012. Methods included measurement of skin-AF (AgeReader®, Diagnoptics) and assessment by carotid-femoral pulse wave velocity, (c-f PWV) (SphygmoCor®, AtCor Medical), in addition to a number of lab-analyses and data on medical history. Subjects with arrhythmias were excluded for technical reasons. Results: Skin-AF correlated significantly with c-f PWV (r = 0.13, p = 0.005), but after adjustment for chronological age, mean arterial pressure (MAP), and heart rate (HR), this became a non-significant trend (&bgr; = 0.07, p = 0.08). Further adjustment also for sex, diabetes, renal function and antihypertensive drug treatment resulted in non-significant findings (&bgr; = 0.02, p > 0.5). The adjusted associations between skin-AF and c-f PWV were non-significant in subjects with and without diabetes and in both sexes. In older subjects (>72 years, median) a positive correlation was seen (r = 0.164, p = 0.009), but became non-significant following adjustments. In subjects with normoglycaemia, a positive correlation was found (r = 0.225, p = 0.023), but was lost following full adjustment. Conclusions: Skin-AF for AGE is not significantly associated with measures of arterial stiffness (c-f PWV) in a non-hospitalized elderly population following adjustments. This could indicate that such associations could be different from that seen in patients with chronic disease or atherosclerosis, or that skin-AF mirrors oxidative stress exposure of greater relevance for atherosclerosis (intima) than arteriosclerosis (media).