Progression of arterial calcifications: what, where, and in whom?

OBJECTIVES: There is a lack of information on the development of arteriosclerosis over time. This study aims to assess long-term sex-specific changes in arterial calcifications in five arteries, and the influence of cardiovascular risk factors hereon. METHODS: From a population-based cohort, 807 participants (mean baseline age, 65.8; SD, 4.2) underwent a non-contrast computed tomography (CT) examination between 2003 and 2006, and after a median follow-up of 14 years. We assessed incidences and changes in volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC) and intracranial carotid artery calcification (ICAC), and vertebrobasilar artery calcification (VBAC). We investigated the simultaneous presence of severe progression (upper quartile of percentual change volumes). Associations of cardiovascular risk factors with changes in calcification volumes were assessed using multivariate linear regression models. RESULTS: The difference in AAC was most substantial; the median volume (mm3) increased from of 129 to 916 in men and from 93 to 839 in women. For VBAC, no change in volumes was observed though more than a quarter of participants without baseline VBAC developed VBAC during follow-up. Severe progression was most often observed in only one artery at the same time. Hypertension was most consistently associated with increase in calcifications. Associations of diabetes, hypercholesterolemia, and smoking with changes in calcifications varied across arteries and sex. CONCLUSIONS: We found a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors were associated with increase of calcifications with sex-specific differential effects across arteries. CLINICAL RELEVANCE STATEMENT: There is a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors are associated with increase of calcifications with sex-specific differential effects across arteries; thus, assessing changes in only one artery may thus not provide a good reflection of the systemic development of arteriosclerosis. KEY POINTS: • Assessing change in arterial calcification in only one artery does not reflect the systemic development of arterial calcification. • Cardiovascular risk factors are associated with progression of arterial calcifications. • Progression of arterial calcification is sex and artery-specific.

Lipoprotein(a) is associated with a larger systemic burden of arterial calcification.

AIMS: Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for cardiovascular disease. However, population-based evidence on the link between Lp(a) and subclinical arteriosclerosis is lacking. We assessed associations of Lp(a) concentrations with arteriosclerosis in multiple arteries. METHODS AND RESULTS: From the population-based Rotterdam study, 2354 participants (mean age: 69.5 years, 52.3% women) underwent non-contrast computed tomography to assess arterial calcification as a hallmark of arteriosclerosis. We quantified the volume of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC), and intracranial carotid artery calcification (ICAC). All participants underwent blood sampling, from which plasma Lp(a) concentrations were derived. The association of plasma Lp(a) levels was assessed with calcification volumes and with severe calcification (upper quartile of calcification volume) using sex-stratified multivariable linear and logistic regression models. Higher Lp(a) levels were associated with larger ln-transformed volumes of CAC [fully adjusted beta 95% confidence interval (CI) per 1 standard deviation (SD) in women: 0.09, 95% CI 0.04-0.14, men: 0.09, 95% CI 0.03-0.14], AAC (women: 0.06, 95% CI 0.01-0.11, men: 0.09, 95% CI 0.03-0.14), ECAC (women: 0.07, 95% CI 0.02-0.13, men: 0.08, 95% CI 0.03-0.14), and ICAC (women: 0.09, 95% CI 0.03-0.14, men: 0.05, 95% CI -0.02 to 0.11]. In the highest Lp(a) percentile, severe ICAC was most prevalent in women [fully adjusted odds ratio (OR) 2.41, 95% CI 1.25-4.63] and severe AAC in men (fully adjusted OR 3.29, 95% CI 1.67-6.49). CONCLUSION: Higher Lp(a) was consistently associated with a larger calcification burden in all major arteries. The findings of this study indicate that Lp(a) is a systemic risk factor for arteriosclerosis and thus potentially an effective target for treatment. Lp(a)-reducing therapies may reduce the burden from arteriosclerotic events throughout the arterial system. TRANSLATIONAL PERSPECTIVE: In 2354 participants from the Rotterdam study, we assessed the link between Lp(a) concentrations and arterial calcifications, as proxy for arteriosclerosis, in major arteries. We found that higher Lp(a) levels were consistently associated with larger volumes of calcification in the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. The findings of our study indicate that Lp(a) is a systemic risk factor for arteriosclerosis, suggesting that the systemic burden of arteriosclerosis throughout the arterial system could be reduced by targeting Lp(a).

Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification.

AIM: Lipoprotein(a) [Lp(a)] is a potential causal factor in the pathogenesis of aortic valve disease. However, the relationship of Lp(a) with new onset and progression of aortic valve calcium (AVC) has not been studied. The purpose of the study was to assess whether high serum levels of Lp(a) are associated with AVC incidence and progression. METHODS AND RESULTS: A total of 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men), whose Lp(a) measurements were available, underwent non-enhanced cardiac computed tomography imaging at baseline and after a median follow-up of 14.0 [interquartile range (IQR) 13.9-14.2] years. New-onset AVC was defined as an AVC score >0 on the follow-up scan in the absence of AVC on the first scan. Progression was defined as the absolute difference in AVC score between the baseline and follow-up scan. Logistic and linear regression analyses were performed to evaluate the relationship of Lp(a) with baseline, new onset, and progression of AVC. All analyses were corrected for age, sex, body mass index, smoking, hypertension, dyslipidaemia, and creatinine. AVC progression was analysed conditional on baseline AVC score expressed as restricted cubic splines. Of the 702 individuals without AVC at baseline, 415 (59.1%) developed new-onset AVC on the follow-up scan. In those with baseline AVC, median annual progression was 13.5 (IQR = 5.2-37.8) Agatston units (AU). Lipoprotein(a) concentration was independently associated with baseline AVC [odds ratio (OR) 1.43 for each 50 mg/dL higher Lp(a); 95% confidence interval (CI) 1.15-1.79] and new-onset AVC (OR 1.30 for each 50 mg/dL higher Lp(a); 95% CI 1.02-1.65), but not with AVC progression (ß: -71 AU for each 50 mg/dL higher Lp(a); 95% CI -117; 35). Only baseline AVC score was significantly associated with AVC progression (P < 0.001). CONCLUSION: In the population-based Rotterdam Study, Lp(a) is robustly associated with baseline and new-onset AVC but not with AVC progression, suggesting that Lp(a)-lowering interventions may be most effective in pre-calcific stages of aortic valve disease.

Longitudinal changes of thoracic aortic diameters in the general population aged 55 years or older.

OBJECTIVE: Longitudinal data on age-related changes in the diameters of the thoracic aorta are scarce. To better understand normal variation and to identify factors influencing this process, we aimed to report male-female-specific and age-specific aortic growth rate in the ageing general population and identify factors associated with growth rate. METHODS: From the prospective population-based Rotterdam Study, 943 participants (52.0% females, median age at baseline 65 years (62-68)) underwent serial non-enhanced cardiac CT. We measured the diameters of the ascending (AA) and descending aorta (DA) at two time points and expressed absolute and relative differences. Linear mixed effects analysis was performed to identify determinants associated with change in aortic diameters. RESULTS: Mean AA diameter at baseline was 37.3±3.6 mm in male population and 34.7±3.2 mm in female population, mean DA diameter was 29.6±2.3 in male population and 26.9±2.2 mm in female population. The median absolute change in diameters during follow-up (mean scan interval 14.1±0.3 years) was 1 mm (0-2) for both the AA and DA. Absolute change per decade in AA diameter was significantly larger in males than in females (0.72 mm/decade (0.00-1.43) vs 0.70 mm/decade (0.00-1.41), p=0.006), as well as absolute change in AD diameter (0.71 mm/decade (0.00-1.42) vs 0.69 mm/decade (0.00-1.36), p=0.008). There was no significant difference between male and female population in relative change of their aortic diameters during follow-up. Age, male sex, higher body mass index (BMI) and higher diastolic blood pressure (DBP) showed a statistically significant independent association with increase in AA and DA diameters over time. CONCLUSIONS: Some degree of increase in thoracic aortic diameters is typical in both men and women of an aging population. Factors associated with this change in thoracic aortic diameters were sex, age, BMI and DBP.

Carotid Plaque Composition and Prediction of Incident Atherosclerotic Cardiovascular Disease.

BACKGROUND: Whether information on carotid plaque composition contributes to prediction of incident atherosclerotic cardiovascular disease (ASCVD) remains to be investigated. We determined the sex-specific added value of carotid plaque components for predicting incident ASCVD events, beyond traditional cardiovascular risk factors. METHODS: Between 2007 and 2012, participants from the population-based Rotterdam Study with asymptomatic carotid wall thickening >2.5 mm on ultrasonography were invited for carotid magnetic resonance imaging. Among 1349 participants (mean age: 72 years [SD±9.3], 49.5% women) without cardiovascular disease, we assessed plaque thickness, luminal stenosis (>30%), presence of intraplaque hemorrhage, lipid-rich necrotic core, and calcification. Follow-up for ASCVD was complete until January 1, 2015. Using Cox proportional hazards models, we fitted sex-specific prediction models including traditional cardiovascular risk factors (base model). We extended the base model by single and simultaneous additions of plaque characteristics and calculated improvement of model performance by the C statistics. RESULTS: During a median follow-up of 4.8 years, 60 men and 48 women developed ASCVD. In women, presence of intraplaque hemorrhage was associated with incident ASCVD (adjusted hazard ratio, 3.37 [95% CI, 1.81-6.25]). The C statistic (95% CI) improved from 0.73 (0.66-0.79) to 0.76 (0.70-0.83) after single addition of intraplaque hemorrhage to the base model. Simultaneous addition of plaque components, plaque thickness, and stenosis did not change the results. In men, only carotid stenosis was statistically significantly associated with incident ASCVD (adjusted hazard ratio, 1.75 [95% CI, 1.00-3.08]); yet, the association diminished after the addition of other plaque characteristics, and no improvements were observed in C statistics. CONCLUSIONS: Presence of intraplaque hemorrhage contributes to the prediction of incident ASCVD in women, beyond traditional cardiovascular risk factors, other plaque components, plaque size, and stenosis.

Morphological Subtypes of Intracranial Internal Carotid Artery Arteriosclerosis and the Risk of Stroke.

BACKGROUND: Accumulating evidence highlights the existence of distinct morphological subtypes of intracranial carotid arteriosclerosis. So far, little is known on the prevalence of these subtypes and subsequent stroke risk in the general population. We determined the prevalence of morphological subtypes of intracranial arteriosclerosis and assessed the risk of stroke associated with these subtypes. METHODS: Between 2003 and 2006, 2391 stroke-free participants (mean age 69.6, 51.7% women) from the population-based Rotterdam Study underwent noncontrast computed tomography to visualize calcification in the intracranial carotid arteries as a proxy for intracranial arteriosclerosis. Calcification morphology was evaluated according to a validated grading scale and categorized into intimal, internal elastic lamina (IEL), or mixed subtype. Follow-up for stroke was complete until January 1, 2016. We used multivariable Cox regression to assess associations of each subtype with incident stroke. RESULTS: The prevalence of calcification was 82% of which 39% had the intimal subtype, 48% IEL subtype, and 13% a mixed subtype. During a median follow-up of 10.4 years, 155 participants had a stroke. All 3 subtypes were associated with a higher risk of stroke (adjusted hazard ratio [95% CI] for intimal: 2.11 [1.07-4.13], IEL: 2.66 [1.39-5.11], and mixed subtype 2.57 [1.18-5.61]). The association of the IEL subtype with stroke was strongest among older participants. The association of the intimal subtype with stroke was noticeably stronger in women than in men. CONCLUSIONS: Calcification of the IEL was the most prevalent subtype of intracranial arteriosclerosis. All 3 subtypes were associated with an increased risk of stroke, with noticeable age and sex-specific differences.

Arterial calcification at different sites and prediction of atherosclerotic cardiovascular disease among women and men.

BACKGROUND AND AIMS: The sex-specific contributions of arterial calcification to atherosclerotic cardiovascular disease (ASCVD) risk prediction and stratification in the light of recent modifications by cardiovascular prevention guidelines remain unclear. We assessed the sex-specific value of calcification in different arteries, beyond the Pooled Cohort Equations (PCE) risk factors, for 10-year ASCVD risk prediction. METHODS: From 2003 to 2006, participants from the population-based Rotterdam Study (n = 2167) underwent CT to quantify coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC) and intracranial carotid artery calcification (ICAC). Follow-up for ASCVD was complete on January 1, 2015. We refitted the PCE (base model), and categorized participants into low (<5%), borderline (5%-7.5%), intermediate (7.5%-20%), and high (≥20%) ASCVD risk. We extended the models with calcifications and calculated c-statistics and net reclassification improvements for events (NRIe) and non-events (NRIne). RESULTS: CAC predicted ASCVD in women [hazard-ratio (95%-CI) per 1-SD: 1.40 (1.14-1.73)] and men [1.62 (1.27-1.93)]. After addition of CAC to the base model, the c-statistic improved from 0.71 to 0.72 in women; from 0.65 to 0.68 in men. Addition of CAC led to NRIe of 14.3% in women, 4.8% in men and NRIne of 1.5% in women, 15.1% in men. Only in women, ICAC predicted ASCVD [hazard-ratio (95%-CI) per 1-SD: 1.62 (1.26-2.08)], and improved the model (c-statistic from 0.71 to 0.73, NRIe: 9.8% and NRIne: 5.9%). CONCLUSIONS: Assessment of CAC improves ASCVD risk prediction and stratification. In women, the added value of ICAC for ASCVD risk prediction is comparable to that of CAC.

Intracranial arteriosclerosis is related to cerebral small vessel disease: a prospective cohort study.

Intracranial arteriosclerosis has been increasingly recognized as a risk factor for cognitive impairment and even dementia. A possible mechanism linking intracranial arteriosclerosis to cognitive impairment and dementia involves structural brain changes including cerebral small vessel disease (CSVD). To assess whether intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC), as proxies for intracranial arteriosclerosis, are related to CSVD. Within the population-based Rotterdam Study, between 2003 and 2006 a computed tomography (CT)-based measurement of ICAC and VBAC and at least one magnetic resonance imaging (MRI) measurement of structural brain changes were performed from 2005 onwards in 1,489 participants. To estimate the burden of calcification independent of age, we computed age-adjusted percentile curves for ICAC and VBAC separately, based on the calcification volumes. Using the longitudinal MRI data, we assessed whether a larger calcification burden accelerates structural brain changes using appropriate statistical models for repeated outcome measures. A larger burden of ICAC and VBAC was associated with an increase of CSVD markers accelerating over time. A larger burden of ICAC and VBAC was not significantly (p > 0.05) associated with accelerated brain atrophy. Arteriosclerosis is related to accelerating structural brain changes over time.

Aortic Arch Calcification and the Risk of Cancer: A Population-Based Cohort Study.

Background: Atherosclerosis and cancer share multiple disease pathways. Yet, it is unclear if atherosclerosis is associated with a subsequent higher cancer risk. We determined the association of atherosclerotic calcification in the aortic arch, as proxy for systemic atherosclerosis, with the risk of cancer. Methods: Between 2003 and 2006, 2,404 participants (mean age: 69.5 years, 52.5% women) from the prospective population-based Rotterdam Study underwent computed tomography to quantify calcification in the aortic arch. Participants were followed for the onset of cancer, death, loss to follow-up, or January 1st, 2015, whichever came first. We computed sex-specific tertiles of aortic arch calcification volumes. Next, we examined the association between the volume and severity (i.e., tertiles) of aortic arch calcification and the risk of cancer using Cox proportional hazard models. Results: During a median (interquartile range) follow-up of 9.6 years (8.9-10.5), 348 participants were diagnosed with cancer. Participants with the greatest severity of aortic arch calcification had a higher risk of cancer [hazard ratio for the third tertile compared to the first tertile of aortic arch calcification volume in the total population is 1.39 (95% CI = 1.04-1.86)]. Conclusions: Individuals with the most severe aortic arch calcification had a higher risk of cancer. While this could reflect the impact of long-term exposure to shared risk factors, it might also point toward the co-occurrence of both conditions.

Arterial calcification at multiple sites: sex-specific cardiovascular risk profiles and mortality risk-the Rotterdam Study.

BACKGROUND: Evidence has pointed towards differences in the burden of arteriosclerosis according to its location and sex. Yet there is a scarcity of population-based data on aggregated sex-specific cardiovascular risk profiles, instead of single risk factors, and mortality risk according to the location of arteriosclerosis. We assessed sex-specific cardiovascular risk profiles and mortality risk associated with arteriosclerosis. METHODS: From the population-based Rotterdam Study, 2357 participants (mean age 69 years, 53% women) underwent non-contrast computed tomography to quantify calcification, as a proxy for arteriosclerosis, in the coronary arteries (CAC), aortic arch (AAC), extracranial (ECAC) and intracranial carotid arteries (ICAC), vertebrobasilar arteries (VBAC), and aortic valve (AVC). Principal component analysis (PCA) of eight distinct cardiovascular risk factors was performed, separately for women and men, to derive risk profiles based on the shared variance between factors. We used sex-stratified multivariable logistic regression to examine the associations between PCA-derived risk profiles and severe calcification at different locations. We investigated the associations of severe calcification with mortality risk using sex-stratified multivariable Cox regression. RESULTS: PCA identified three cardiovascular risk profiles in both sexes: (1) anthropometry, glucose, and HDL cholesterol; (2) blood pressure; and (3) smoking and total cholesterol. In women, the strongest associations were found for profile 2 with severe ECAC and ICAC (adjusted OR [95% CI] 1.32 [1.14-1.53]) and for profile 3 with severe at all locations, except AVC. In men, the strongest associations were found for profile 2 with VBAC (1.31 [1.12-1.52]) and profile 3 with severe AAC (1.28 [1.09-1.51]). ECAC and AVC in women and CAC in men showed the strongest, independent associations with cardiovascular mortality (HR [95% CI] 2.11 [1.22-3.66], 2.05 [1.21-3.49], 2.24 [1.21-3.78], respectively). CONCLUSIONS: Our findings further underline the existence of sex- and location-specific differences in the etiology and consequences of arteriosclerosis. Future research should unravel which distinct pathological processes underlie differences in risk profiles for arteriosclerosis.

Seasonal variation of diet quality in a large middle-aged and elderly Dutch population-based cohort.

PURPOSE: Several studies have reported seasonal variation in intake of food groups and certain nutrients. However, whether this could lead to a seasonal pattern of diet quality has not been addressed. We aimed to describe the seasonality of diet quality, and to examine the contribution of the food groups included in the dietary guidelines to this seasonality. METHODS: Among 9701 middle-aged and elderly participants of the Rotterdam Study, a prospective population-based cohort, diet was assessed using food-frequency questionnaires (FFQ). Diet quality was measured as adherence to the Dutch dietary guidelines, and expressed in a diet quality score ranging from 0 to 14 points. The seasonality of diet quality and of the food group intake was examined using cosinor linear mixed models. Models were adjusted for sex, age, cohort, energy intake, physical activity, body mass index, comorbidities, and education. RESULTS: Diet quality had a seasonal pattern with a winter-peak (seasonal variation = 0.10 points, December-peak) especially among participants who were men, obese and of high socio-economic level. This pattern was mostly explained by the seasonal variation in the intake of legumes (seasonal variation = 3.52 g/day, December-peak), nuts (seasonal variation = 0.78 g/day, January-peak), sugar-containing beverages (seasonal variation = 12.96 milliliters/day, June-peak), and dairy (seasonal variation = 17.52 g/day, June-peak). CONCLUSIONS: Diet quality varies seasonally with heterogeneous seasonality of food groups counteractively contributing to the seasonal pattern in diet quality. This seasonality should be considered in future research on dietary behavior. Also, season-specific recommendations and policies are required to improve diet quality throughout the year.

Vertebrobasilar artery calcification: Prevalence and risk factors in the general population.

BACKGROUND AND AIMS: Arteriosclerosis in the vertebrobasilar arteries may play an important role in the etiology of posterior circulation strokes, but little is known on its prevalence, its correlation with arteriosclerosis in other major arteries, and its risk factors. Hence, we investigated these aspects of vertebrobasilar artery calcification (VBAC) as marker of vertebrobasilar arteriosclerosis. METHODS: To quantify VBAC, 2483 participants (mean age: 69.2 years, 52% female) from the Rotterdam Study underwent non-enhanced computed tomography. We determined the presence and volume of VBAC. Next, using Spearman's rank correlation, we examined the correlation between the volume of VBAC and the volume of coronary artery calcification (CAC), aortic arch calcification (AAC), and both extracranial- (ECAC), and intracranial carotid artery calcification (ICAC). Finally, we investigated associations of cardiovascular risk factors with the presence and volume of VBAC using logistic and linear regression models. RESULTS: The overall prevalence of VBAC was 21.0% (median volume: 7.3 mm3 [IQR: 2.0-25.6]). Correlations between VBAC and CAC, AAC, ECAC, and ICAC were weak to moderate (men: 0.33, 0.28, 0.30, 0.36; women: 0.26, 0.24, 0.24, 0.35, respectively). Hypertension, diabetes, and current smoking were associated with the presence of VBAC in both sexes (men: OR 1.67 [95%-CI, 1.14-2.46], 1.60 [95%-CI, 1.10-2.34], 1.48 [95%-CI, 1.02-2.14]; women: OR 1.51 [95%-CI, 1.01-2.26], 1.56 [95%-CI, 1.02-2.39], 1.53 [95%CI, 1.00-2.33], respectively). In men, obesity was also associated with VBAC (1.42 [95%-CI, 1.00-2.02]). CONCLUSIONS: VBAC occurs in over 20% of elderly community dwelling persons. Cardiovascular risk factors are associated with VBAC with similar patterns for men and women.