Subclinical Atherosclerosis, Hyperlipidemia and New-Onset Diabetes Should Not Be Ignored Despite Initial Angiographic Exclusion of Significant Atherosclerotic Occlusive Arterial Disease.

Background and Objectives: Despite the presence of atherosclerosis risk factors and symptoms associated with occlusive atherosclerotic cardiovascular disease (ASCVD), up to 30% of individuals do not present significant atherosclerotic lesions at the point of diagnostic evaluation. Those in whom ASCVD was ruled out once might be believed to be at low risk of future major cerebral and cardiac events (MACCEs). Despite this, they might still have some residual risk for MACCEs. Therefore, in the present study we aimed to evaluate risk factors for atherosclerosis progression to the stage of occlusive arterial disease in patients with cardiovascular risk factors but initially free from significant ASCVD. Materials and Methods: Between March 2012 and February 2014, a total of 686 consecutive patients presenting with clinical suspicion of significant coronary artery disease were evaluated. The actual status of atherosclerosis burden was verified in four major arterial territories (coronary, carotid, renal, lower limb arteries) with the use of angiography, computed tomography and ultrasonography. For the present study purpose, 188 (27.4%) patients were enrolled, in whom significant ASCVD (in any of the examined territories) was ruled out. In all patients, the incidence and severity of atherosclerotic risk factors, carotid intima-media complex thickness (CIMT) and carotid plaque presence were evaluated during first hospital admission. A ten-year follow-up period for a composite endpoint of MACCEs was included. Univariate and multivariate Cox proportional hazard analyses with the Simon-Makuch method for new-onset type 2 diabetes mellitus (T2DM) were performed for MACCEs. Results: MACCEs occurred in 30 (16%) of 188 patients, including 5 cardiovascular deaths, 19 non-fatal myocardial infarctions, and 6 non-fatal ischemic strokes, in a median of 48 (Q1; Q3: 25; 86) months. Univariate Cox proportional hazard analysis revealed that individuals who presented with baseline LDL cholesterol > 3.2 mmol/L, CIMT > 1 mm, carotid plaque, or experienced new-onset T2DM were predisposed to MACCE with hazard ratios (HRs) of 3.21 (p = 0.003), 3.82 (p = 0.001), 5.41 (p < 0.001), and 36.89 (p < 0.001), respectively. In multivariate Cox analysis, its associations with MACCEs were retained (HRs between 2.19 and 21.47), respectively. Conclusions: Our findings support the need for continued risk factor optimization despite the initial exclusion of obstructive ASCVD. In this study, we identified new-onset T2DM, initial LDL cholesterol, and the presence of subclinical atherosclerosis as risk factors for MACCEs.