Systemic arteriosclerosis is associated with left ventricular remodeling but not atherosclerosis: a TASCFORCE study

Arteriosclerosis is the stiffening of the arterial wall, which occurs with advancing age and is strongly associated with major adverse cardiovascular events [1]. It is predominantly a product of age and pulse pressure, reflecting the repetitive strain of the pulsatile cardiac output on the elastic fibres of the arterial wall. While its association with cardiovascular morbidity and mortality is well established, the exact pathophysiological mechanisms by which it exerts this effect are not entirely clear [2]. The key pathophysiological process underpinning cardiovascular disease is the formation, progression and rupture of atherosclerotic plaque. Increased arterial stiffness has been linked to reduced wall shear stress and thereby may be an antecedent event to the formation of atherosclerotic plaques [3]. Alternatively it may be that, other than the aging process, arteriosclerosis and atherosclerosis are autonomous risk variables, exerting independent adverse effects on the cardiovascular system and thus requiring individual therapeutic targetting.

Previous work has demonstrated mixed results between coronary artery calcification and carotid plaque and arterial stiffness [4‐6]. However a limitation of these techniques is their focus on a single arterial territory. Atherosclerosis is a systemic disease, thus absence of plaque in one territory does not equate to absence of plaque in another [7, 8]. Whole body cardiovascular magnetic resonance angiography (WB-CMRA) allows systemic quantification of the global atherosclerosis burden within the body, with the results of this showing strong prognostic capabilities for future adverse cardiovascular events [9‐11]. Thus the aim of the current study was to compare early atherosclerotic plaque formation and arterial stiffening in a non-high risk cohort with no prior diagnosis of cardiovascular disease, to test the hypothesis that increased arterial stiffening would be associated with an increased atherosclerotic plaque burden.

Of the 2047 participants eligible for and offered a CMR scan, 1528 (74.8% of those invited) completed or partially completed the scan protocol with 13 (1%) excluded due to missing or incomplete data, leaving 1515 in the final analysis. 373 (18.2%) did not consent for a scan and 12 (0.6%) failed to attend their CMR scan appointment. 101 participants (4.9%) were not scanned due to claustrophobia (n = 83), large body habitus (n = 3), inability to establish venous access/other technical issues (n = 15), or being unsafe to scan due to presence of metalwork (n = 34).

Of the final 1515, 574 were male (53.8 ± 8.2 years old) and 941 were female (54.3 ± 8.4 years old). The male population had a significantly higher systolic and diastolic blood pressure, a higher body mass index (BMI), a lower total cholesterol driven by lower HDL-cholesterol, higher random blood glucose, lower BNP, higher LV mass, LVMVR and compliance (p < 0.05 for all) (Table 1). There was no significant difference in SAS between males and females.

In the current study we have shown: 1) that arteriosclerosis and atherosclerosis have different risk factors; 2) that when cardiovascular risk factors are accounted for, arteriosclerosis and atherosclerosis show no significant association with each other; and 3) arteriosclerosis is associated with early LV remodelling.

Studies examining the link between atherosclerosis and arteriosclerosis have produced mixed results. The Rotterdam study showed a significant link between pulse wave velocity (PWV) – a measure of arterial stiffening - and aortic arterial calcification [20], however a twin study showed that while PWV was associated with aortic wall calcification this was mediated by genetic factors and that PWV was not linked to plaque burden [21]. Previous work in 306 seventy-year-olds in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study found a correlation between the total atherosclerotic burden as measured on whole body angiography and the carotid arterial distensibility and the stroke-volume to pulse pressure ratio [22]. However this study suffered from several limitations: it did not stratify by sex, a known confounder for stroke volume and pulse pressure; and did not index the stroke volume thus opening the study to significant confounding from body size [18]. Indeed previous work has shown compliance calculated using indexed SV but not unadjusted SV to be an independent predictor for cardiovascular events demonstrating the importance of these adjustments [23]. A study by Sawabe et al. who conducted post mortem examinations in 304 individuals with a pre mortem PWV showed a weak correlation between the PWV and atherosclerotic plaque burden (spearman rho = 0.32) which persisted after accounting for age and systolic blood pressure, but did not attempt to account for other risk factors [24]. Thus the lack of correlation in our current study compared to those of the Sawabe group may be due to a lack of correction for other confounding variables such as BMI or smoking both of which we have shown to be correlated with arteriosclerosis and atherosclerosis respectively. Further supportive evidence of our results comes from a previous study on coronary plaque volume on intravascular ultrasound showing no significant correlation with carotid femoral pulse wave velocity [25]. Similarly another Rotterdam study showed a significant correlation between carotid plaque and aortic PWV which was lost after adjusting for cardiovascular risk factors [6]. Limitations of these latter studies is their correlation of one regional measure of arterial stiffness with plaque volume measured in a separate region, however atherosclerosis in one region poorly correlates with disease in other regions [8, 26]. In addition these studies examined populations at high risk for or with known cardiovascular disease. This is the first study to look at those without established cardiovascular disease and without high risk for the development of cardiovascular disease providing key insights into early disease formation. Thus it is feasible that in advanced disease, increased arterial stiffness could interact with existing plaque to accelerate its growth or reduce its stability.

The finding of a significant correlation between systemic arterial stiffness and left ventricular remodeling is in agreement with that of MESA (MultiEthnic Study of Atherosclerosis), who also found a significant increase in the LVMVR ratio with increasing arterial stiffness [27]. Given the known importance of the LVMVR in its prediction of future cardiovascular events [28], this provides further weight to this being a significant mechanism by which arterial stiffness exerts its effects on future cardiovascular risk.

Our systemic approach to the assessment of these two separate entities and our observations are both novel and useful to our understanding of cardiovascular disease, especially as we have focused on those with low-intermediate cardiovascular risk before significant disease has developed. Age, blood pressure, BMI, cholesterol and smoking are all extremely well established risk factors and are central to cardiovascular risk stratification for primary prevention strategies [29, 30]. It is therefore interesting that out of these risk factors, one (blood pressure) strongly predicts arterial stiffening, one (smoking) predicts plaque formation and another (BMI) predicts early cardiac remodeling. Given that all are strong risk factors for future cardiovascular events this study suggests that they might all exert this risk through independent, separate mechanisms although further longitudinal studies are required to determine causation. Planned long term follow-up in the TASCFORCE study will provide a key opportunity for examining these further.

Our study suffers from several limitations. Whole body angiography is a lumenographic technique, thus potentially misses the earliest stages of atherosclerosis of fatty streaks along the vascular lumen, as well as requiring the administration of intravenous contrast [31]. However no other technique currently exists for the simultaneous acquisition of the whole body vasculature. Techniques such as 3D–black-blood imaging, which can also be performed without contrast, hold potential for this but to date have only been utilized at single vessel sites [32]. In addition it is arguable that since clinical manifestations of atherosclerosis are secondary to plaque stenosis or rupture rather than simple fatty streaks, that this is the most clinically relevant association to examine. Participants were recruited based on a previous higher threshold for the diagnosis of hypertension (145/90 mmHg) and using the ATP-III criteria for cardiovascular disease 10 year risk, both of which were the reference standards at the point of study design, but have been superseded by more contemporaneous risk criteria and thresholds. Thus our ‘healthy cohort’ included some participants with what would now be considered hypertension, potentially confounding associations between stiffness, blood pressure and left ventricular remodeling, although these persisted on multiple regression models. The pulse pressure for compliance measurement was derived from the brachial blood pressure measurement rather than use of a central measurement or pulse wave analysis which is a more accurate for the estimation of this [33]. However, estimation of TAC using blood pressure derived from a brachial sphygmomanometer has consistently proven to be an independent predictor of future cardiovascular events in multiple cohorts [23, 34, 35], and the observed associations between compliance and cardiovascular risk factors are consistent with the literature using both a peripheral pressure measurement and PWV [36]. Finally the blood pressure was not acquired contemporaneously with the stroke volume. Diurnal variation and situational variations are known to affect blood pressure thus this could confound the calculation of compliance. The effect size of this is likely to be small however as if significant variation between within scan blood pressure and without scan blood pressure existed this would be most manifest in an obviation or significant reduction of the association between the compliance and blood pressure, yet these variables demonstrated the strongest correlation with one another on univariate and multivariate analysis.

In conclusion systemic arteriosclerosis is associated with LVremodelling but not atherosclerosis. Future efforts in cardiovascular risk prevention should thus seek to address both arteriosclerosis and atherosclerosis individually.