Cross-sectional associations with arterial stiffness
The cross-sectional associations are presented in Table 3. c-fPWV was associated with 2-h glucose (β = 0.13, P < 0.001), MAP (β = 0.29, P < 0.001), and HR (β = 0.20, P < 0.001) in model 2. The same variables that were predictive of c-fPWV were also associated with c-fPWV in the cross-sectional analysis except for in model 1, in which a negative association was found for LDL (β = −0.10, P < 0.001) and no association was found for eGFR. When excluding individuals with ongoing lipid-lowering drug therapy at follow-up, there were no significant associations between c-fPWV and LDL cholesterol. The associations between HDL cholesterol and triglycerides, however, remained after this exclusion in model 1 (β = −0.14, P < 0.001; and β = 0.11, P < 0.001, respectively) and in model 2 (β = −0.08, P < 0.001; and β = 0.09, P < 0.001, respectively). Median c-fPWV for individuals without diabetes was 10.0 m/s, with undiagnosed diabetes was 11.7 m/s, and with diagnosed diabetes was 11.1 m/s. These differences were statistically significant when comparing individuals without diabetes with known or newly detected diabetes, but not between the two diabetes groups (Fig. 4).
Characteristics of individuals with high or low arterial stiffness
Table 4 shows a comparison of follow-up characteristics between individuals aged below 75 years with high (c-fPWV ≥12 m/s) or low (<8 m/s) arterial stiffness, respectively. After adjustment for age, sex, HR, and MAP, the group with high arterial stiffness (EVA) was characterized by significantly more prevalent diabetes and hypertension compared to the group with low arterial stiffness, whereas there was no difference in smoking habits or level of physical activity.
This observational study shows that waist circumference, fasting glucose, HOMA-IR, HbA1c, triglycerides, and HDL cholesterol are all predictors of arterial stiffness after a follow-up period of 17 years in a middle-aged population at baseline. The results also indicated higher c-fPWV values in men than in women, which correspond to previous findings .
Lipids and obesity
Our findings further show that both triglycerides and HDL cholesterol at both baseline and follow-up were associated with arterial stiffness after adjusting for cardiovascular risk factors including BMI, whereas LDL cholesterol was not. The negative cross-sectional association between LDL cholesterol and arterial stiffness seen before full adjustment was not seen in the sub-analysis of individuals without lipid-lowering treatment and is most likely caused by an over-representation of individuals with cardiovascular disease receiving treatment.
In a systematic review from 2009, low HDL cholesterol and increased triglycerides (dyslipidemia) were significantly associated with arterial stiffness in only four out of 37, and one out of 38 studies, respectively, although many of these studies were small or carried out in specific populations . In general, our findings on lipids are similar to results from a study presenting longitudinal associations between arterial stiffness and waist circumference, HDL cholesterol, and triglycerides . Measures of obesity both at baseline and follow-up are associated with arterial stiffness, where the association to waist circumference tends to be stronger than that to BMI, a previously reported pattern . This indicates that abdominal obesity is the underlying factor behind these results, which in itself is a marker of metabolic changes and chronic inflammation based on other studies .
Diabetes and hyperglycemia
Our results show independent associations between baseline fasting glucose, HOMA-IR, and HbA1c in relation to c-fPWV. Fasting glucose and 2-h glucose at follow-up (cross-sectional) were also associated with arterial stiffness. Diabetes is well known to be associated with increased arterial stiffness, and some studies indicate that the impact of diabetes on the elastic arteries takes place early, already during a prediabetic state of insulin resistance [8,9]. This is supported by our results among individuals with no history of diabetes, showing that individuals with undiagnosed diabetes have stiffer arteries than individuals with fasting and 2-h glucose below the reference values for diabetes.
It has been debated how much hyperglycemia increases arterial stiffness directly via, for example, advanced glycosylated end (AGE) products causing cross-linking of collagen in the arterial intima-media and reduction of the elastin content, and how much can be attributed to more complex metabolic changes associated with hyperglycemia and insulin resistance [9,23]. Our data support the hypothesis that hyperglycemia, dyslipidemia, and abdominal obesity accelerates the vascular stiffening seen with increasing chronological age. The mechanisms behind this process are not clear, but insulin resistance might be involved in the pathogenesis. However, baseline HOMA-IR did not show a stronger association to arterial stiffness than fasting glucose. This does not support the hypothesis of insulin resistance as a driving force behind the arterial stiffening process, although HOMA-IR might be regarded as too crude a measure of insulin sensitivity.
Some studies have demonstrated that diabetes should have a higher impact on arterial stiffness in women than in men [9,24,25] – results that could not be confirmed in this study. Longitudinal studies with more precise measurements of glucose metabolism and insulin sensitivity (clamp) are thus needed to shed more light on the pathophysiological mechanisms behind these associations.
Glomerular filtration rate
There were no associations between baseline or follow-up eGFR levels and arterial stiffness after adjustment for other cardiovascular risk factors. Several studies have shown that CKD patients have an increased arterial stiffness, but results regarding the relationship between arterial stiffness and CKD severity have been conflicting [11,26]. In our community-based population, the eGFR is higher than in CKD patients and can, to a greater extent, be explained by age and other cardiovascular risk factors. Thus, there should be fewer individuals exhibiting the phenotype of arterial remodeling with calcifications associated with more severe CKD, which could explain the absence of association between eGFR and c-fPWV.
Smoking is known to be an important contributor to atherosclerosis, but the possible role of smoking in arterial stiffening remains much more uncertain. Although some previous studies show an association between smoking and arterial stiffness [27,28], many studies do not . Since nicotine increases HR, adjusting for HR and MAP at the time of the PWV measurement is essential for any analysis investigating this relationship. In this study, there was no association between current or ever-smoking and arterial stiffness. Even in the comparison between individuals with high or low arterial stiffness, the results show no tendency towards smoking being more prevalent among individuals with high arterial stiffness, which is a marker of EVA. This absence of association between smoking and arterial stiffness is, in our opinion, in line with the majority of studies on this subject.
Our interpretation of the findings in general is that the well known cluster of risk factors associated with ‘atherosclerosis’ (smoking, hypertension, LDL cholesterol, diabetes) is only partly associated with ‘arteriosclerosis’ (hypertension, dyslipidemia, hyperglycemia) . As the development of arteriosclerosis is believed to precede the development of atherosclerosis, or at least run in parallel during early stages, our findings also point to the importance of nonhemodynamic metabolic factors for this development.
Strengths and limitations of the study
Strengths of this study include its large sample from a community-based population and the adjustment for hemodynamic factors (MAP, HR, ongoing drug pressure-lowering drug treatment). Its observational design with measurement of arterial stiffness at follow-up only prevents us from drawing firm conclusions regarding causality. Previous studies from MDC have shown that the cohort was fairly representative at the baseline examination, even though mortality rates were higher in nonparticipants . The participant rates at the re-examination was high – about 70% of those who were alive and invited to the re-examination participated. However, as many of the participants from baseline investigation were not alive for the follow-up investigation, because of missing blood samples, and since measurement of c-fPWV cannot be performed in individuals with atrial fibrillation or other cardiac arrhythmias, the total drop-out from MDC baseline is 56% and it can be assumed that the final population was healthier than the general population. Even so, the associations between the risk markers and arterial stiffness (c-fPWV) found in this study should be valid also in the general population in a wider age span. Our risk markers do not, regretfully, include any marker of inflammation, which is unfortunate, as several inflammatory conditions are known to be associated with arterial stiffness . However, inflammatory markers such as CRP are affected to a large degree by different pro-inflammatory conditions such as (abdominal) obesity, a phenotypic variable used in our analyses. Future studies will expand on the influence of chronic inflammation as well as genetic markers on arterial stiffness in our population.
In conclusion, results from this observational study show that hyperglycemia, dyslipidemia (high triglycerides, low HDL cholesterol), and waist circumference are all independent nonhemodynamic long-term predictors of arterial stiffness, following full adjustment, in both sexes. Smoking, LDL cholesterol, and eGFR were not associated with arterial stiffness.
The study was supported by the Medical Research Council of Sweden (grant K2011–65X-20752–04–6), the Region Skåne County Council, the Ernhold Lundstrom Foundation, and so on.
Conflicts of interest
There are no conflicts of interest.
Reviewers’ summary evaluations Reviewer 1
The nonhemodynamic cluster of risk factors and predictors of arterial stiffness in a middle-aged population included abdominal obesity, hyperglycemia and dyslipidemia but not smoking and LDL cholesterol. This pattern existed in both sexes. The strength of the article is that it is a large study from a community-based population. The experimental design is observational with measurement of arterial stiffness at follow-up only which prevents firm conclusions regarding causality. The weakness of the study is the high-drop out rate.
A strength of this study is the recruitment of a large sample from a community-based population. In addition, the follow-up period is long. A limitation is the fact that complete data were obtained from only 44% of the baseline population. From the data presented in the paper, one may conclude that the subjects not included in the regression analyses had more risk factors than the general population. Therefore, the absence of correlations between risk markers and arterial stiffness should be interpreted with caution.
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Keywords:Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ageing; arterial stiffness; diabetes mellitus; epidemiology; follow-up; glucose; hypertension; pulse wave velocity