Plaque characteristics and biomarkers predicting regression and progression of carotid atherosclerosis.

The factors that influence the atherosclerotic disease process in high-risk individuals remain poorly understood. Here, we used a combination of vascular imaging, risk factor assessment, and biomarkers to identify factors associated with 3-year change in carotid disease severity in a cohort of high-risk subjects treated with preventive therapy (n = 865). The results show that changes in intima-media thickness (IMT) are most pronounced in the carotid bulb. Progression of bulb IMT demonstrates independent associations with baseline bulb IMT, the plaque gray scale median (GSM), and the plasma level of platelet-derived growth factor (PDGF) (standardized ß-coefficients and 95% confidence interval [CI] -0.14 [-0.06 to -0.02] p = 0.001, 0.15 [0.02-0.07] p = 0.001, and 0.20 [0.03-0.07] p < 0.001, respectively). Plasma PDGF correlates with the plaque GSM (0.23 [0.15-0.29] p < 0.001). These observations provide insight into the atherosclerotic process in high-risk subjects by showing that progression primarily occurs in fibrotic plaques and is associated with increased levels of PDGF.

Reservoir-Excess Pressure Parameters Independently Predict Cardiovascular Events in Individuals With Type 2 Diabetes.

[Figure: see text].

The Malmö Offspring Study (MOS): design, methods and first results.

As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18-71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms.

Blood Lead Levels and Risk of Atherosclerosis in the Carotid Artery: Results from a Swedish Cohort.

BACKGROUND: Lead exposure has been associated with increased incidence of adverse clinical cardiovascular outcomes. Atherosclerosis has been suggested as one of the underlying mechanisms, and findings from experimental studies support this, but human data are scarce. OBJECTIVES: Our objective was to determine the association between environmental lead exposure based on blood lead (B-Pb) concentrations and the prevalence of atherosclerotic plaque in the carotid artery. METHODS: We used cross-sectional data from the Malmö Diet and Cancer Study cardiovascular cohort (MDCS-CC; recruitment in 1991-1994) covering 4,172 middle-aged men and women. B-Pb at baseline, measured by inductively coupled plasma mass spectrometry, was used as the exposure biomarker. The presence of atherosclerotic plaque in the carotid artery was determined by B-mode ultrasonography. We used logistic regression to estimate odds ratios (ORs) for prevalence of plaque in the carotid artery according to B-Pb quartiles. RESULTS: The median B-Pb was 25µg/L (range: 1.5-258), and 36% of the cohort had any atherosclerotic plaque. After controlling for confounders and known cardiovascular risk factors, the OR for prevalence of plaque in the highest quartile (Q4) of B-Pb compared with the lowest quartile (Q1) was 1.35 (95% CI: 1.09, 1.66) in the total group, 1.58 (95% CI: 1.20, 2.08) among women, and 1.18 (95% CI: 0.83, 1.69) among men. Among women, associations were limited to those who were postmenopausal [OR for Q4 vs. Q1=1.72 (95% CI: 1.26, 2.34) vs. OR=0.96 (95% CI: 0.49, 1.89 in premenopausal women)]. Associations were weak and nonsignificant in never-smokers [OR for Q4 vs. Q1=1.14 (95% CI: 0.81, 1.61)]. DISCUSSION: Our study shows an association between B-Pb concentrations and occurrence of atherosclerotic plaque in the carotid artery, adding evidence for an underlying pro-atherogenic role of lead in cardiovascular disease. Associations appeared to be limited to postmenopausal (vs. premenopausal) women. https://doi.org/10.1289/EHP5057.

Skin autofluorescence as a measure of advanced glycation end product levels is associated with carotid atherosclerotic plaque burden in an elderly population.

BACKGROUND: Advanced glycation end product is an established risk marker in diabetic vascular disease, but its possible associations with atherosclerosis in a general population are yet to be investigated. We studied the degree of carotid atherosclerosis and its association with skin autofluorescence in an elderly population. METHODS: Carotid ultrasound and skin autofluorescence measurements were performed in a subpopulation within the 'Malmö Diet and Cancer Cardiovascular Cohort' re-examination study (n = 523). Total plaque area including all prevalent plaques in the right carotid artery was calculated. Complete data on all variables were available for 496 subjects (mean age 72 years). RESULTS: Each 1 standard deviation increment of skin autofluorescence was associated with increased risk of prevalent large plaques (odds ratio, 1.32; 95% confidence interval, 1.05-1.66; p = 0.018) independently of diabetes and cardiovascular risk factors. The top versus bottom tertile of the skin autofluorescence was associated with an approximately twofold risk of being in the population with the highest plaque burden [top quartile with total plaque area ⩾ 35 mm2 (odds ratio, 1.88; 95% confidence interval, 1.05-3.39; p for trend = 0.027)] in fully adjusted analysis. CONCLUSION: In an elderly population, skin autofluorescence was associated with increasing degree of carotid atherosclerosis measured as total plaque area, independently of diabetes and cardiovascular risk factors.

Elevated circulating effector memory T cells but similar levels of regulatory T cells in patients with type 2 diabetes mellitus and cardiovascular disease.

Type 2 diabetes mellitus is associated with an elevated risk of cardiovascular disease, but the mechanism through which diabetes contributes to cardiovascular disease development remains incompletely understood. In this study, we compared the association of circulating regulatory T cells, naïve T cells, effector memory T cells or central memory T cells with cardiovascular disease in patients with and without type 2 diabetes mellitus. Percentage of circulating T cell subsets was analysed by flow cytometry in type 2 diabetes mellitus subjects with and without prevalent cardiovascular disease as well as in non-diabetic subjects with and without prevalent cardiovascular disease from the Malmö SUMMIT cohort. Subjects with type 2 diabetes mellitus had elevated percentages of effector memory T cells (CD4+CD45RO+CD62L-; 21.8% ± 11.2% vs 17.0% ± 9.2% in non-type 2 diabetes mellitus, p < 0.01) and central memory T cells (CD4+CD45RO+CD62L+; 38.0% ± 10.7% vs 36.0% ± 9.5% in non-type 2 diabetes mellitus, p < 0.01). In contrast, the frequency of naïve T cells was reduced (CD4+CD45RO-CD62L+, 35.0% ± 16.5% vs 42.9% ± 14.4% in non-type 2 diabetes mellitus, p < 0.001). The proportion of effector memory T cells was increased in type 2 diabetes mellitus subjects with cardiovascular disease as compared to those without (26.4% ± 11.5% vs 18.4% ± 10.2%, p < 0.05), while no difference in regulatory T cells was observed between these two patient groups. This study identifies effector memory T cells as a potential cellular biomarker for cardiovascular disease among subjects with type 2 diabetes mellitus, suggesting a state of exacerbated immune activation in type 2 diabetes mellitus patients with cardiovascular disease.

Use of Vascular Assessments and Novel Biomarkers to Predict Cardiovascular Events in Type 2 Diabetes: The SUMMIT VIP Study.

OBJECTIVE: Cardiovascular disease (CVD) risk prediction represents an increasing clinical challenge in the treatment of diabetes. We used a panel of vascular imaging, functional assessments, and biomarkers reflecting different disease mechanisms to identify clinically useful markers of risk for cardiovascular (CV) events in subjects with type 2 diabetes (T2D) with or without manifest CVD. RESEARCH DESIGN AND METHODS: The study cohort consisted of 936 subjects with T2D recruited at four European centers. Carotid intima-media thickness and plaque area, ankle-brachial pressure index, arterial stiffness, endothelial function, and circulating biomarkers were analyzed at baseline, and CV events were monitored during a 3-year follow-up period. RESULTS: The CV event rate in subjects with T2D was higher in those with (n = 440) than in those without (n = 496) manifest CVD at baseline (5.53 vs. 2.15/100 life-years, P < 0.0001). New CV events in subjects with T2D with manifest CVD were associated with higher baseline levels of inflammatory biomarkers (interleukin 6, chemokine ligand 3, pentraxin 3, and hs-CRP) and endothelial mitogens (hepatocyte growth factor and vascular endothelial growth factor A), whereas CV events in subjects with T2D without manifest CVD were associated with more severe baseline atherosclerosis (median carotid plaque area 30.4 mm2 [16.1-92.2] vs. 19.5 mm2 [9.5-40.5], P = 0.01). Conventional risk factors, as well as measurements of arterial stiffness and endothelial reactivity, were not associated with CV events. CONCLUSIONS: Our observations demonstrate that markers of inflammation and endothelial stress reflect CV risk in subjects with T2D with manifest CVD, whereas the risk for CV events in subjects with T2D without manifest CVD is primarily related to the severity of atherosclerosis.

Spotty Carotid Plaques Are Associated with Inflammation and the Occurrence of Cerebrovascular Symptoms.

BACKGROUND: Echolucent carotid plaques have been related to an increased risk of ischemic cerebrovascular events. The aim of the present study was to evaluate whether a new objective ultrasonographic parameter, the statistical geometric feature (SGF), reflecting spottiness of carotid plaques, can be associated with cerebrovascular symptoms and with a rupture-prone plaque phenotype. METHODS: The plaques of 144 patients who underwent carotid endarterectomy were included in this study. SGF and plaque area were estimated by outlining the plaque on ultrasound (US) images. The correlation coefficient for inter- and intraobserver variability was 0.69 and 0.93, respectively. The SGF values were normalized to the degree of stenosis (SGF/DS). The plaques collected at surgery 1 day after the US were analyzed histologically, and inflammatory markers and matrix metalloproteinases (MMPs) were measured. RESULTS: Patients with ipsilateral hemispheric symptoms had higher SGF/DS compared to patients without symptoms (0.82 [0.59-1.16] vs. 0.70 [0.56-0.89], p = 0.01). Analysis of plaque components revealed a positive correlation between SGF/DS and the percentage of the plaque area stained for lipids, macrophages, and hemorrhage. A correlation was also found between SGF/DS and plaque expression of interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, vascular endothelial growth factor A, C-C motif chemokine 3 and 20, and MMP-9. An inverse correlation was found with plaque levels of osteoprotegerin. CONCLUSIONS: The present study supports the concept that spottiness is a feature of the carotid plaques rich in inflammation and can be associated with the typical phenotype of high-risk plaques.

Cadmium, Carotid Atherosclerosis, and Incidence of Ischemic Stroke.

BACKGROUND: Exposure to cadmium has been associated with carotid plaques, inflammation in carotid plaques, and increased risk of ischemic stroke. This study examined the separate and interacting effects of blood cadmium levels and carotid plaques on the risk of incident ischemic stroke. METHODS AND RESULTS: Cadmium levels were measured in 4156 subjects (39.2% men; mean±SD age 57.3±5.9 years) without history of stroke, from the Malmö Diet and Cancer cohort. The right carotid artery was examined using B-mode ultrasound examination at baseline. Incidence of ischemic stroke was monitored over a mean follow-up of 16.7 years. Carotid plaque was present in 34.5% of participants. Cadmium was significantly higher in subjects with plaque (mean±SD: 0.53±0.58 µg/L versus 0.42±0.49 µg/L; P<0.001). A total of 221 subjects had ischemic stroke during the follow-up. Incidence of ischemic stroke was associated both with carotid plaque (hazard ratio 1.44, 95% confidence interval, 1.09-1.90, P=0.009) and cadmium (hazard ratio for quartile [Q] 4 versus Q1-3: 1.95, confidence interval, 1.33-2.85, P=0.001), after adjustment for risk factors. There was a significant interaction between cadmium and plaque with respect to risk of ischemic stroke (P=0.011). Adjusted for risk factors, subjects with plaque and cadmium in Q4 had a hazard ratio of 2.88 (confidence interval, 1.79-4.63) for ischemic stroke, compared with those without plaque and cadmium in Q1 to Q3. CONCLUSIONS: Cadmium was associated with incidence of ischemic stroke, both independently and in synergistic interaction with carotid plaques. This supports the hypothesis that cadmium promotes vulnerability of carotid plaques, thereby increasing the risk of rupture and ischemic stroke.

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.

Eosinophil Cationic Protein, Carotid Plaque, and Incidence of Stroke.

BACKGROUND AND PURPOSE: ECP (eosinophil cationic protein) is a marker of eosinophil activity and degranulation, which has been linked to atherosclerosis and cardiovascular disease. We examined the relationship between ECP, carotid plaque, and incidence of stroke in a prospective population-based cohort. METHODS: The subjects participated in the Malmö Diet and Cancer Study between 1991 and 1994. A total of 4706 subjects with no history of stroke were included (40% men; mean age, 57.5 years). Carotid plaque was determined by B-mode ultrasound of the right carotid artery. Incidence of stroke was followed up during a mean period of 16.5 years in relation to plasma ECP levels. RESULTS: Subjects in the third tertile (versus first tertile) of ECP tended to have higher prevalence of carotid plaque (odds ratio: 1.18; 95% confidence interval: 1.003-1.39; P=0.044 after multivariate adjustments). A total of 258 subjects were diagnosed with ischemic stroke (IS) during follow-up. ECP was associated with increased incidence of IS after risk factor adjustment (hazard ratio, 1.57; 95% confidence interval: 1.13-2.18; for third versus first tertile; P=0.007). High ECP was associated with increased risk of IS in subjects with carotid plaque. The risk factor-adjusted hazard ratio for IS was 1.86 (95% confidence interval: 1.32-2.63) in subjects with carotid plaque and ECP in the top tertile, compared with those without plaque and ECP in the first or second tertiles. CONCLUSIONS: High ECP is associated with increased incidence of IS. The association between ECP and IS was also present in the subgroup with carotid plaque.

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.

Fasting levels of growth hormone are associated with carotid intima media thickness but are not affected by fluvastatin treatment.

BACKGROUND: Growth hormone (GH) has been linked to cardiovascular disease but the exact mechanism of this association is still unclear. We here test if the fasting levels of GH are cross-sectionally associated with carotid intima media thickness (IMT) and whether treatment with fluvastatin affects the fasting level of GH. METHODS: We examined the association between GH and IMT in 4425 individuals (aged 46-68 years) included in the baseline examination (1991-1994) of the Malmö Diet and Cancer cardiovascular cohort (MDC-CC). From that cohort we then studied 472 individuals (aged 50-70 years) who also participated (1994-1999) in the ß-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS), a randomized, double blind, placebo-controlled, single-center clinical trial. Using multivariate linear regression models we related the change in GH-levels at 12 months compared with baseline to treatment with 40 mg fluvastatin once daily. RESULTS: In MDC-CC fasting values of GH exhibited a positive cross-sectional relation to the IMT at the carotid bulb independent of traditional cardiovascular risk factors (p = 0.002). In a gender-stratified analysis the correlation were significant for males (p = 0.005), but not for females (p = 0.09). Treatment with fluvastatin was associated with a minor reduction in the fasting levels of hs-GH in males (p = 0.05) and a minor rise in the same levels among females (p = 0.05). CONCLUSIONS: We here demonstrate that higher fasting levels of GH are associated with thicker IMT in the carotid bulb in males. Treatment with fluvastatin for 12 months only had a minor, and probably not clinically relevant, effect on the fasting levels of hs-GH.

Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes.

BACKGROUND: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. METHODS: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). RESULTS: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. CONCLUSIONS: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.

Orosomucoid, Carotid Plaque, and Incidence of Stroke.

BACKGROUND AND PURPOSE: Orosomucoid (α-1-acid glycoprotein) is an acute-phase protein that has been implicated in anti-inflammatory, immunomodulating, and angiogenic pathways. Orosomucoid has also been associated with coronary disease and stroke. The relationship between orosomucoid, carotid plaque, and stroke incidence were explored in this study. METHODS: Plasma levels of orosomucoid were assessed in 4285 subjects (39.8% men; mean age 57.5±5.9 years) without cardiovascular disease, who participated in the Malmö Diet and Cancer Study, between 1991 and 1994. The right carotid artery was examined for plaque using B-mode ultrasound examination. Incidence of stroke was followed up during a median follow-up time of 17.7 years. RESULTS: Carotid plaque was present in 43.5% at baseline. Orosomucoid was significantly higher in subjects with carotid plaque (mean±SD: 0.72±0.22 versus 0.69±0.20 g/L; P<0.001). A total of 234 subjects were diagnosed with ischemic stroke during follow-up. Orosomucoid was associated with ischemic stroke after adjustment for risk factors, with hazard ratio 1.48 (95% confidence interval, 1.02-2.16) comparing the third versus first tertile. In subjects with plaque and belonging to the top tertile of orosomucoid, the hazard ratio was 2.07 (95% confidence interval, 1.38-3.11) compared with those without plaque and with orosomucoid in the first and second tertiles, after adjustment for C-reactive protein and other risk factors. CONCLUSIONS: Elevated levels of orosomucoid are associated with increased occurrence of carotid plaque and increased incidence of ischemic stroke. The combination of high orosomucoid and carotid plaque substantially increase the risk of stroke.

The effect of smoking on carotid intima-media thickness progression rate and rate of lumen diameter reduction.

OBJECTIVE: The purpose of the study was to investigate the long-term associations between smoking habits, environmental tobacco smoke exposure (ETS), carotid intima-media thickness (IMT) progression rate, and rate of lumen diameter reduction in the carotid artery during a 16-year follow-up. Another objective was to investigate if an effect of smoking on progression rate could be explained by increased low grade inflammation. METHODS: The study population included 2992 middle-aged men and women in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the Malmö Diet and Cancer Study cardiovascular cohort. Associations between smoking, progression of carotid IMT and lumen diameter reduction due to plaque protrusion were assessed by linear regression. RESULTS: IMT progression rates and rate of lumen diameter reduction increased from never smokers with no ETS through former, moderate and heavy smokers, even after adjustment for traditional risk factors (e.g., differences in yearly progression rates (mm/year) of maximal IMT in the carotid bifurcation compared to never smokers; former smokers 0.0074 (95% CI: 0.0018-0.0129), moderate smokers 0.0106 (95% CI: 0.0038-0.0175), and heavy smokers 0.0146 (95% CI: 0.0061-0.0230)). Former smokers showed distinct lowering of progression rates after more than five years since smoking cessation. Smoking and former smoking was associated with increased low grade inflammation, however, the effect of smoking on atherosclerotic progression rate remained fairly unchanged after such adjustment. CONCLUSION: The effect of smoking and former smoking on carotid IMT progression rates and change in lumen reduction due to plaque protrusion could not be explained by differences in traditional risk factors or low grade inflammation.

Digital Photoplethysmography for Assessment of Arterial Stiffness: Repeatability and Comparison with Applanation Tonometry.

INTRODUCTION: Arterial stiffness is an independent risk factor for cardiovascular morbidity and can be assessed by applanation tonometry by measuring pulse wave velocity (PWV) and augmentation index (AIX) by pressure pulse wave analysis (PWA). As an inexpensive and operator independent alternative, photoelectric plethysmography (PPG) has been introduced with analysis of the digital volume pulse wave (DPA) and its second derivatives of wave reflections. OBJECTIVE: The objective was to investigate the repeatability of arterial stiffness parameters measured by digital pulse wave analysis (DPA) and the associations to applanation tonometry parameters. METHODS AND RESULTS: 112 pregnant and non-pregnant individuals of different ages and genders were examined with SphygmoCor arterial wall tonometry and Meridian DPA finger photoplethysmography. Coefficients of repeatability, Bland-Altman plots, intraclass correlation coefficients and correlations to heart rate (HR) and body height were calculated for DPA variables, and the DPA variables were compared to tonometry variables left ventricular ejection time (LVET), PWV and AIX. No DPA variable showed any systematic measurement error or excellent repeatability, but dicrotic index (DI), dicrotic dilatation index (DDI), cardiac ejection elasticity index (EEI), aging index (AI) and second derivatives of the crude pulse wave curve, b/a and e/a, showed good repeatability. Overall, the correlations to AIX were better than to PWV, with correlations coefficients >0.70 for EEI, AI and b/a. Considering the level of repeatability and the correlations to tonometry, the overall best DPA parameters were EEI, AI and b/a. The two pansystolic time parameters, ejection time compensated (ETc) by DPA and LVET by tonometry, showed a significant but weak correlation. CONCLUSION: For estimation of the LV function, ETc, EEI and b/a are suitable, for large artery stiffness EEI, and for small arteries DI and DDI. The only global parameter, AI, showed a high repeatability and the overall best correlations with AIX and PWV.

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.

OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. APPROACH AND RESULTS: Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. CONCLUSIONS: The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

GWAS-identified loci for coronary heart disease are associated with intima-media thickness and plaque presence at the carotid artery bulb.

BACKGROUND: Large-scale genome-wide association studies (GWAS) have so far identified 45 loci that are robustly associated with coronary heart disease (CHD) in data from adult men and women of European descent. OBJECTIVES: To examine whether the CHD-associated loci are associated with measures of atherosclerosis in data from up to 9582 individuals of European ancestry. METHODS: Forty-five SNPs representing the CHD-associated loci were genotyped in middle-aged to elderly individuals of European descent from four independent population-based studies (IMPROVE, MDC-CC, ULSAM and PIVUS). Intima-media thickness (IMT) was measured by external B-mode ultrasonography at the far wall of the bulb (sinus) and common carotid artery. Plaque presence was defined as a maximal IMT of the bulb >1.5 mm. We meta-analysed single-SNP associations across the four studies, and combined them in a genetic predisposition score. We subsequently examined the association of the genetic predisposition score with prevalent CHD and the three indices of atherosclerosis, adjusting for sex, age and Framingham risk factors. RESULTS: As anticipated, the genetic predisposition score was associated with prevalent CHD, with each additional risk allele increasing the odds of disease by 5.5% (p = 4.1 × 10(-6)). Moreover, each additional CHD-risk allele across the 45 loci was associated with a 0.24% increase in IMT (p = 4.0 × 10(-3)), and with a 2.8% increased odds of plaque presence (p = 7.4 × 10(-6)) at the far wall of the bulb. The genetic predisposition score was not associated with IMT of the common carotid artery (p = 0.47). CONCLUSIONS: Our results suggest that the association between the 45 previously identified loci and CHD at least partly acts through atherosclerosis.

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 (ß = 0.17, P < 0.001), fasting glucose (ß = 0.13, P < 0.001), Homeostatic Model Assessment - Insulin Resistance (ß = 0.10, P < 0.001), triglycerides (ß = 0.10, P < 0.001), and high-density lipoprotein cholesterol (ß = -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.