We have found that IMT rate-of-change is associated with incident stroke in this multi-ethnic cohort. Other risk factors positively associated with incident stroke include age, systolic blood pressure and lower HDL cholesterol levels whereas common carotid artery IMT, smoking and diabetes were not.
We conservatively set time zero for the Cox proportional hazards models at the second carotid IMT examination when IMT rate-of-change is measured and current risk factors evaluated. While this approach decreases the number of events, it reduces bias introduced by interventions instituted in response to incident events occurring during the time interval between IMT measurements.
We have found that IMT is associated with incident stroke in our unadjusted analyses but this association became non-significant after adjustment for risk factors. We believe that some of the differences between our observations and previous studies might be due to the low number of events in our population and the location where we performed IMT measurements:
- The number of incident strokes in studies showing an association between CCA IMT and incident stroke is larger than ours. The Cardiovascular Health Study (CHS) study reported 284 incident strokes in a group of 4466 individuals over 4.7 years. The Atherosclerosis Risk in Communities (ARIC) study reported on 199 ischemic strokes over 7.2 years2. The Rotterdam Study reported on 160 strokes in 5479 individual over 5.2 years9. However, the Tromso study with 397 events over 10 years of follow-up in 6584 participants did not find CCA IMT to be a consistent predictor of stroke10. We report on only 42 events over 3.2 years for 5028 individuals.
- Most studies perform IMT measurements close to the carotid artery bulb11-13. In ARIC, common carotid artery IMT measurements included plaque formation in at least 7% of individuals13. By design, the MESA IMT Progression study places the site of IMT measurements lower in the common carotid artery in an area free of plaque (). We are likely focusing on associations between stroke and a pathologic process distinct from plaque formation14.
Stroke risk factors include prevalent cardiovascular disease, atrial fibrillation, left ventricular hypertrophy by electrocardiographic criteria, age, systolic blood pressure, diabetes, cigarette smoking15
. Prevalent cardiovascular disease and atrial fibrillation are absent in our cohort. Left ventricular hypertrophy was present in 56 individuals (data not shown) and only one individual had an incident stroke. We observe a positive association of incident stroke with age and systolic blood pressure as reported in the Framingham Heart Study15
. Lack of significance for diabetes and smoking is likely due to a lack of statistical power secondary to the small number of stroke events. The positive association between stroke and lower HDL cholesterol levels is consistent with high HDL-Cholesterol levels having a protective effect for cardiovascular disease.
A limitation of our study is the inherent variability of IMT measurements since we perform IMT progression measurements at six separate centers without the rigid enrollment criteria used in drug intervention trials where change in IMT serves as outcome16-18
. This might have increased the variability of the measurements in a global fashion but did not affect our findings since clinic site did not predict events.
Change in plaque area might be a better predictor of stroke since it has better reproducibility19, 20
than CCA IMT and given that plaque area itself is associated with stroke10
. Published data from one study has shown an association between change in plaque area and stroke20
Because of low event rate (n =1) for Chinese participants () we adjusted our models for ethnicity but did not investigate ethnic specific hazards ratios.
In a literature review, we found one study that addressed IMT rate-of-change as a risk factor for stroke: The European Lacipidine Study on Atherosclerosis (ELSA). The ELSA study investigated the associations of anti-hypertensive therapy on IMT progression and cardiovascular outcomes5
. ELSA reported a positive association between baseline IMT and stroke but not for change in IMT5
We conclude that common carotid artery IMT rate-of-change is associated with stroke in a cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline. Given the inherent variability of IMT and IMT rate-of-change measurements, these results require confirmation in other cohort studies.