ABC | Volume 111, Nº3, September 2018

Original Article Marino et al Adiponectin and IVUS-VH Coronary Plaque Characteristics Arq Bras Cardiol. 2018; 111(3):345-353 concentration and MACE. Clinical variables age, gender, diabetes mellitus, hypertension, and indication for coronary angiography were considered as potential confounders and were entered into the full model. These covariates were a priori chosen based on existing literature, and taking into account the number of events available. CRP was also entered into the full model, as it is the most widely investigated inflammatory marker in CAD, and has been shown to be (inversely) associated with plasma adiponectin levels. 10 When analyzing the association of adiponectin with the secondary, composite endpoint of death and ACS, and death alone, we only adjusted for age and gender because of the limited number of endpoints. First, statistical analyses were performed in the full cohort. Then, we included interaction terms (adiponectin multiplied by indication for angiography) into the models to investigate possible effect modification by indication. Subsequently, we repeated the analyses separately in patients with SAP and patients with ACS. All data were analyzed with SPSS software (SPSS 20.0, IBM corp., Armonk, New York). All statistical tests were two-tailed and p-values < 0.05 were considered statistically significant. Results Mean age of the patients was 61.5±11.4 years, 75.4% were men, 17.4% had diabetes mellitus, and median adiponectin concentration was 2.8 (1.9-4.0) μg/mL (Table 1). Coronary angiography or PCI was performed for ACS in 309 (54.2%) patients and for SAP in the remaining 261 (45.8%). Median adiponectin concentration was 2.9 (1.8-4.1) μg/mL in ACS patients and 2.9 (1.9-3.9) μg/mL in SAP patients. A total of 239 (41.9%) patients had at least 1 VH-IVUS-derived TCFA, including 69 (12.1%) patients with at least 1 VH-IVUS-derived TCFA with a plaque burden ≥ 70%. In the full cohort, adiponectin levels were not associated with composition or burden of atherosclerosis on multivariable analysis (Tables 2 and 3). Adiponectin levels were not associated with MACE after adjustment for age, gender and indication for angiography (Table 4). After further multivariable adjustment, effect estimates remained non‑significant (data not shown). Adiponectin levels tended to be univariably associated with acute MACE, (median [IQR] 1.16[0.82-1.62] μg/mL, vs. 1.02[0.64-1.38] μg/mL; HR [95%CI]: 1.77[0.96–3.23], p = 0.069), but after further adjustment this tendency disappeared. Adiponectin levels were independently associated with occurrence of death (median[IQR]1.48(1.03-1.79) μg/mL vs. 1.02(0.64-1.36) μg/mL, HR[95%CI]: 2.52[1.02–6.23], p = 0.045). Signs of interactions between adiponectin and indication for angiography were present for associations with TCFA (p for interaction 0.050 (univariable) and 0.029 (multivariable)), with lesions with MLA ≤ 4.0 (p for interaction 0.058 (univariable) and 0.10 (multivariable)), and with fibrofatty tissue fraction (p for interaction 0.042 (univariable) and 0.082 (multivariable)). The remaining interaction terms were not significant (data not shown). In patients with SAP, adiponectin levels were associated with the presence of VH-IVUS-derived TCFA lesions (median[IQR] 1.16[0.72-1.48] μg/mL vs . 0.95[0.62-1.30] μg/mL; OR[95%CI] per 1 unit increase in ln-transformed-adiponectin: 1.78[1.06- 3.00], p = 0.030) (Table 3). Furthermore, adiponectin levels were inversely associated with presence of lesions with MLA ≤ 4.0 mm 2 (median[IQR] 0.95[0.49-1.30] μg/mL vs. 1.06[0.69-1.41] μg/mL; OR [95%CI]: 0.55[0.32‑0.93], p = 0.025) (Table 3). Finally, adiponectin levels were associated with death (median[IQR] 1.62[1.32-1.84] μg/mL vs. 1.02[0.64-1.36] μg/mL; HR [95%CI]: 8.15[1.49-44.68]). After adjustment for age and gender, the HR remained similar in magnitude, although statistical significance was lost (HR [95%CI: 8.48[0.92 – 78.03], p = 0.058). In patients with ACS, no associations were present between adiponectin and composition or burden of atherosclerosis. Although no associations were present with MACE or acute MACE, a tendency toward a univariable association with death was present (median[IQR] 1.39[0.90-1.86] μg/mL vs. 1.01[0.60-1.38] μg/mL; HR [95%CI]: 2.44[0.98-6.06], p = 0.055). After adjustment for age and gender, statistical significance was lost (HR [95%CI]: 1.87[0.67-5.19], p = 0.23). Given the positive associations we found between adiponectin and death, we performed a post-hoc analysis to explore whether a synergistic effect of adiponectin and TCFA was present on death. For this purpose, we entered interaction terms into the models that consisted of adiponectin multiplied by presence of TCFA lesions. However, no effect modification could be demonstrated (interaction terms were not significant). Discussion To our best knowledge, this is the largest study that correlates circulating adiponectin with in-vivo measurements of coronary atherosclerosis using VH-IVUS in patients with known coronary disease. We found that in the full cohort, adiponectin levels were associated with death during 1-year follow-up, but not with VH-IVUS measures of atherosclerosis. In patients with SAP, adiponectin levels were positively associated with presence of VH-IVUS-derived TCFA lesions and were inversely associated with presence of lesions with MLA ≤ 4.0 mm 2 ; while the association with death was borderline significant. In ACS patients we only found a tendency toward an association with death during follow-up. Fundamental experiments, animal models and human studies on vascular function in subjects free of symptomatic cardiovascular disease have all demonstrated associations of adiponectin with vasoprotective mechanisms, including insulin-sensitizing characteristics and anti-oxidative and anti‑inflammatory properties. 4-6,8,10 In line with this, higher levels of adiponectin have been linked to decreased prevalence of CAD in healthy individuals and have demonstrated an inverse association with risk of myocardial infarction. 20,21 However, in patients with manifested CAD, adiponectin seems to play a different role. When elevated in patients with symptomatic CAD, this adipocytokine becomes associated with an increased risk of cardiovascular events; a phenomenon that has been described under the term “reverse epidemiology”. 22-25 To explain these conflicting findings, it has been proposed that increased adiponectin levels reflect a compensatory and vasculoprotective mechanism. 25 Specifically, in conditions 347