Carotid siphon calcifications are associated with all-cause mortality: Results from the Atahualpa Project

The carotid siphon is the intracranial arterial segment most susceptible to develop atherosclerotic lesions. ¹ These lesions typically present as calcium deposits in the tunica media and represent a reliable biomarker of intracranial atherosclerotic disease. ² Therefore, carotid siphon calcifications (CSC) may be related to premature mortality. However, studies assessing CSC-related mortality are limited. This cohort study, embedded within the population-based Atahualpa Project, ³ aimed to assess differences in mortality risk according to CSC severity.

The Atahualpa Project is a population-based prospective cohort study designed to determine risk factors associated with the increasing burden of noncommunicable neurological and cardiovascular diseases in individuals of Amerindian ancestry living in rural Ecuador. ⁴ For the purposes of the present study, community-dwellers aged ⩾ 40 years (mean age 54.9 ± 12.6 years; 55% women) who received baseline head computed tomography (CT) and clinical interviews were prospectively followed. According to Woodcock et al., ⁵ CSC Grade 1 were defined as the absence or near-absence of calcification, Grade 2 as tiny, scattered calcifications, Grade 3 as thick interrupted or thin confluent calcifications, and Grade 4 as thick contiguous calcifications. For simplicity in analyses and based on our previous work, ⁶ individuals were further classified into those with low (Grades 1 and 2) and high (Grades 3 and 4) calcium content in carotid siphons. Cox-proportional hazards models were adjusted for demographics, cardiovascular risk factors (smoking status, body mass index, physical activity, diet, blood pressure, fasting glucose, and total cholesterol blood levels), the presence of strokes at baseline and follow-up, and the regular use of statins over the study years. Cardiovascular risk factors were stratified according to the American Heart Association’s proposed criteria. ⁷ This model was fitted to estimate the mortality hazard ratio (HR) according to CSC severity. All participants signed a comprehensive informed consent at enrolment, and the study was approved by the Ethics Committee of our institution.

Medical students continuously visited households where participants live to identify cases with a suspected overt stroke, which was confirmed by a neurologist with the aid of a magnetic resonance image (MRI). In the event of death, certificates were reviewed and verbal autopsies were obtained to ascertain the date and probable cause of death. The last administrative censoring date was set as March 1, 2022. Participants who declined consent and those who emigrated were censored at the last annual survey when the individuals were interviewed, and those who died were censored at the time of death. All these individuals contributed to the total time of follow-up.

Of 933 individuals identified during door-to-door surveys, 778 (83%) received a head CT and baseline clinical interviews, and were eligible for this study. The total follow-up of study participants was 4691 (95% CI: 4577–4806) person-years and the mean follow-up was 6.03 (± 2.09) years. High calcium content in the carotid siphons were determined in 171/778 (22%) individuals. There were several differences in clinical characteristics across individuals with low and high calcium content in the carotid siphons (online Supplemental Table 1).

One hundred and eight participants (14%) died during the follow-up, resulting in an overall unadjusted crude mortality rate of 2.3 (95% CI: 1.9–2.8) per 100 person-years. Mortality occurred in 54/607 (9%) individuals with low calcium content and in 54/171 (32%) of those with high calcium content in the carotid siphons (p < 0.001). An adjusted Cox-proportional hazard model showed that individuals with high calcium content maintained an almost twofold mortality risk (HR: 1.82; 95% CI: 1.20–2.77; p = 0.005) compared to those with low calcium content in the carotid siphons (Figure 1). Increased age at baseline, poor physical activity, and higher levels of fasting glucose remained significant in this multivariate model (online Supplemental Table 2). The association between CSC severity and strokes at baseline and during follow-up was significant in unadjusted analysis but lost significance in the multivariate model. It is possible that high calcium content in the carotid siphons may be a stroke risk factor but not necessarily related to atherosclerosis. ⁸

Figure 1.

Kaplan–Meier survival curves and hazards ratios with 95% CI for all-cause mortality according to calcium content in the carotid siphons, adjusted for demographics, cardiovascular risk factors, statins use, and overt strokes (prevalent and incident).

As mentioned, information on mortality risk in subjects with CSC is limited. In ischemic stroke patients undergoing thrombolysis, mortality risk at 6 months was significantly higher among those with CSC. ⁹ The same increased risk of mortality was noticed in another series of acute ischemic stroke patients followed-up for about 9 years. ¹⁰ The Rotterdam study investigated the association between arterial calcifications in six different vascular beds and mortality risk. Study results showed significant associations between all-cause, vascular, and nonvascular mortality, and intracranial calcifications in men, although the association was only significant for vascular mortality in women. ¹¹

Our study has limitations. Suspected inaccuracies in death certificates and verbal autopsy reports limited correct classification of the cause of death. This was particularly true in subjects who died during an acute episode of COVID-19 (17 study participants) in whom it was not possible to ascertain whether the fatal outcome was related to a vascular event. CSC were visually rated, but the Woodcock scale has been validated against semiautomated scores and volumetric measurements of calcium content in the carotid siphons. ¹² Less than 15% of the population with vascular risk factors received proper therapy during the study years, precluding assessment of the impact of medications on the association between CSC and mortality. In addition, generalization of our findings to other populations or ethnic groups should be undertaken with caution in view of the homogeneity of study participants. These limitations are counterbalanced by the major strengths of our study, including its prospective design, the population-based design, the systematic assessment of covariates by means of uniform and standardized protocols, and the practice of high-resolution CT using the same equipment and protocol in all cases.

In conclusion, study results show a significant association between high calcium content in the carotid siphons and all-cause mortality. These results open avenues of research for the implementation of therapeutic strategies aimed at the control of risk factors associated with intracranial arterial calcifications that, in turn, may reduce premature mortality.

Supplemental Material

sj-pdf-1-vmj-10.1177_1358863X221111821 – Supplemental material for Carotid siphon calcifications are associated with all-cause mortality: Results from the Atahualpa Project

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X221111821 for Carotid siphon calcifications are associated with all-cause mortality: Results from the Atahualpa Project by Oscar H Del Brutto and Robertino M Mera in Vascular Medicine