Carotid intima‐media thickness as a target‐organ damage and treatment‐target: Need for a major revision?

wileyonlinelibrary.com/journal/jch | 255 ©2018 Wiley Periodicals, Inc. Arterial hypertension emerged as a predominant health care aspect over the last few decades and the management of patients with high blood pressure (BP) has been presented as a crucial challenge in everyday clinical practice.1 Hypertensive individuals are at increased risk of cardiovascular morbidity and mortality. Allcause mortality and elevated BP levels detrimentally affect several targetorgans.2,3 Specifically, hypertension leads to functional and structural abnormalities in the myocardium, brain, kidneys, vasculature, and retina. The assessment of several indexes for hypertension-related targetorgan damage, such as left ventricular hypertrophy and left ventricular mass, urinary albumin excretion and estimated glomerular filtration rate, pulse wave velocity, pulse pressure, ambulatory arterial stiffness, carotid intimamedia thickness (CIMT) and coronary artery calcification, anklebrachial index, as well as sexual dysfunction revealed that a subclinical targetorgan damage could exist years prior to the manifestation of a major cardiovascular event (ie, myocardial infarction, stroke, cardiovascular death). 3,4 These findings suggest that the evaluation of targetorgan damage could offer a significant prognostic value among hypertensive patients. Nowadays, it is well established that the presence of subclinical targetorgan damage independently magnifies cardiovascular risk. However, even if the evaluation of targetorgans of hypertensive patients in total is recommended,3 it remains uncertain (with few exceptions) whether BPlowering therapy could improve the above mentioned deteriorations, and more importantly, whether these ameliorations result in clinically meaningful benefits (reduction in major cardiovascular events) or a wellcontrolled hypertension status.5 Thirtyyears ago, Pignoli et al.6 first described invivo measurement of arteries intimamedia thickness via ultrasound. Probably due to the anatomical position of carotid arteries, CIMT is widely used in clinical practice and cardiovascular studies as an indicator of atherosclerotic damage. For many years, changes over CIMT had been used as a surrogate cardiovascular endpoint, however, this adoption seems quite arbitrary.7 Indeed, it is well established that increased CIMT is associated with elevated BP levels, resulting in more prevalent cardiovascular events in both hypertensive and normotensive individuals.3,8–10 Nevertheless, for CIMT to be considered as a real cardiovascular risk factor and not a marker or an epiphenomenon, a change in CIMT due to a therapeutic intervention has to be related with similar cardiovascular benefit.11 In the 2year Cholesterol Lowering Atherosclerosis Study (CLAS), the treatment with colestipolniacin led to attenuation of CIMT increase rate.12 The study cohort (146 males who previously underwent coronary artery bypass grafting) was assessed after an average of 8.8 years of followup following the integration of CLAS. Interestingly, it was found that a lower rate of CIMT increase resulted in a reduction in coronary events. In contrast, the European Lacidipine Study on Atherosclerosis (ELSA) reported that baseline CIMT level is related with cardiovascular events, but no predictive value of CIMT (on any major cardiovascular endpoint) was observed when the analysis included baseline and ontreatment CIMT values.13 The effects of treatmentinduced CIMT changes on cardiovascular risk have been further evaluated in a few metaanalyses, providing conflicting outcomes. In a metaregression analysis of 15 598 patients, it was documented that regression in CIMT progress between activetreatment (antihypertensive, antidiabetic, or lipidlowering) and placebo groups was associated with a greater risk of myocardial infarction in the placeboarm.14 Specifically, every 0.01 mm/y regression in CIMT features a lower risk of myocardial infarction (odds ratio [OR]: 0.82; 95% CI: 0.69 to 0.96). Of note, this finding was not confirmed among randomized controlled trials assessing statin treatment; an observation that could suggest a potential strong role of antihypertensive treatment in such benefits. Costanzo et al.15 conducted a metaregression analysis to evaluate the effect of treatmentinduced change in CIMT on cardiovascular events, by pooling data from 41 studies (n = 18 307). It was found that CIMT regression was not assessed DOI: 10.1111/jch.13184