Adiponectin and insulin resistance are related to restenosis and overall new PCI in subjects with normal glucose tolerance: the prospective AIRE Study.

BACKGROUND: In patients with Normal Glucose Tolerance (NGT) some causes of ischemic heart disease (IHD) were not completely investigated. The role both of metabolic milieu and adipokines in IHD progression was not fully investigated. Our aim was to assess the link between adipokines plasma levels, insulin resistance (IR) and IHD in NGT patients undergoing Percutaneous Coronary Intervention (PCI). METHODS: AIRE is a single-center prospective longitudinal observational study investigating the IHD outcome of NGT subjects who underwent coronary revascularization by PCI in a third level cardiology center at A.O. dei Colli Hospital, University of Campania "Luigi Vanvitelli". Six hundred seventy-nine subjects hospitalized in 2015 for coronary arteriography not suffering from Acute Coronary Syndrome (ACS) in the previous 4 weeks, as well as from all conditions could affect glycemic plasma levels and IR status, were assessed for eligibility. Fifty-four patients with neither history of diabetes nor Altered Fasting Glucose (AFG)/Impaired Fasting Glucose (IGT) after Oral Glucose Tolerance Test (OGTT) were finally enrolled. Primary endpoint was the assessment of the relationship of adipokines and HOMA-IR with the occurrence of restenosis in NGT subjects. As secondary endpoint we assessed the association of the same adipokines and IR with overall ACS events after PCI in NGT subjects. RESULTS: The 54 NGT patients enrolled were mainly males (85%), with a median age of 60 years [IQR 58-63 years]. Only 4 patients (7.4%) experimented restenosis. Median follow-up was equal to 29.5 months [IQR 14.7-34 months]. Adiponectin levels were independently associated to restenosis (OR 0.206; 95% CI 0.053-0.796; p = 0.000). Instead HOMA-IR and adiponectin appeared independently associated both to de novo IHD (OR 9.6*1013; 95% CI 3.026-3.08*1027; p = 0.042 and OR 0.206; 95% CI 0.053-0.796; p = 0.000, respectively) and overall new PCI (OR 1.5*1011; 95% CI 2.593-8.68*1021; p = 0.042 and OR 0.206; 95% CI 0.053-0.796; p = 0.000, respectively). Moreover, we fixed a potential cut-off for adiponectin for risk of restenosis (≤ 8.5 µg/mL) and overall new PCI (≤ 9.5 µg/mL). CONCLUSION: IR and cytokines play a role in progression of any stage of IHD also in NGT subjects. Our results in this setting of patients, though the relatively small sample size, represent a novelty. Future studies on larger populations are needed to analyze more in depth adipokines and insulin resistance role on IHD progression in non-diabetic people.

Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque.

BACKGROUND AND AIMS: Preclinical evidence suggests that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors hold anti-inflammatory properties independently of their ability to lower LDL-cholesterol (C). However, whether PCSK9 inhibitors exert anti-inflammatory effects within the atherosclerotic plaque in humans is unknown. We explored the impact of PCSK9 inhibitors, used as monotherapy, compared with other lipid-lowering drugs (oLLD) on the expression of inflammatory markers within the plaque, assessing also the subsequent incidence of cardiovascular events. METHODS: In an observational study, we recruited 645 patients on stable therapy for at least six months and undergoing carotid endarterectomy, categorizing patients according to the use of PCSK9 inhibitors only (n = 159) or oLLD (n = 486). We evaluated the expression of NLRP3, caspase-1, IL-1ß, TNFα, NF-kB, PCSK9, SIRT3, CD68, MMP-9, and collagen within the plaques in the two groups through immunohistochemistry, ELISA, or immunoblot. A composite outcome including non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality was assessed during a 678 ± 120 days follow-up after the procedure. RESULTS: Patients treated with PCSK9 inhibitors had a lower expression of pro-inflammatory proteins and a higher abundance of SIRT3 and collagen within the plaque, a result obtained despite comparable levels of circulating hs-CRP and observed also in LDL-C-matched subgroups with LDL-C levels <100 mg/dL. Patients treated with PCSK9 inhibitors showed a decreased risk of developing the outcome compared with patients on oLLD, also after adjustment for multiple variables including LDL-C (adjusted hazard ratio 0.262; 95% CI 0.131-0.524; p < 0.001). The expression of PCSK9 correlated positively with that of pro-inflammatory proteins, which burden was associated with a higher risk of developing the outcome, independently of the therapeutic regimen. CONCLUSIONS: The use of PCSK9 inhibitors is accompanied by a beneficial remodelling of the inflammatory burden within the human atheroma, an effect possibly or partly independent of their LDL-C lowering ability. This phenomenon might provide an additional cardiovascular benefit.

Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment.

OBJECTIVE: We evaluated sodium-glucose co-transporter2 (SGLT2) expression and the effect of SGLT2 inhibitor (SGLT2i) therapies on carotid plaques of asymptomatic diabetic and non-diabetic patients. METHODS: Plaques were obtained from 296 non-diabetic patients and 227 patients with type 2 diabetes undergoing carotid endarterectomy. 97 patients with type 2 diabetes were treated with SGLT2 inhibitors for 16 ± 4 months before endarterectomy. After propensity score matching analysis, patients with type 2 diabetes were categorized without (n = 87) and with SGLT2i therapy (n = 87). To investigate SGLT2 expression levels' effects on major adverse endpoints (MACE = stroke, transient ischemic attack, myocardial infarction, and death), we evaluated MACE outcomes at a 2-year follow-up. RESULTS: Compared to plaques from patients without diabetes, plaques from patients with diabetes had higher SGLT2 expression, inflammation, and oxidative stress, along with lower SIRT6 expression and collagen content. Compared with plaques from patients with diabetes, SGLT2i-treated patients with type 2 diabetes presented increased SIRT6 expression and collagen content and lowered inflammation and ion and oxidative stress, thus indicating a more stable plaque phenotype. These results supported in vitro observations on human aorta endothelial cells (EC) (TeloHAEC-cells). Indeed, EC treated with high glucose (25 mM) in the presence of SGLT2i (100 nM canagliflozin) presented higher SIRT6 expression and decreased mRNA and protein SGLT2 levels, nuclear factor-kappa B (NF-B(NF-κB), and matrix metallopeptidase 9 (MMP-9) expression compared to cells treated only with high glucose. After two years following endarterectomy, a multivariable Cox regression analysis showed significantly higher 2-year overall survival from MACE in patients without diabetes (P < 0.01). Among patient with diabetes, the current SGLT2i users presented a significantly lower rate of MACE through 2 years compared to non-SGLT2i users (P < 0.05). CONCLUSIONS: These findings unveil a critical involvement of the SGLT2/SIRT6 pathway in the inflammatory process of diabetic atherosclerotic lesions and suggest its possible favorable modulation by SGLT2i.

Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway.

AIMS: Glucagon like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPP-4) inhibitors reduce atherosclerosis progression in type 2 diabetes mellitus (T2DM) patients and are associated with morphological and compositional characteristics of stable plaque phenotype. GLP-1 promotes the secretion of adiponectin which exerts anti-inflammatory effects through the adaptor protein PH domain and leucine zipper containing 1 (APPL1). The potential role of APPL1 expression in the evolution of atherosclerotic plaque in TDM2 patients has not previously evaluated. METHODS: The effect of incretin therapy in the regulation of adiponectin/APPL1 signaling was evaluated both on carotid plaques of asymptomatic diabetic (n=71) and non-diabetic patients (n=52), and through in vitro experiments on endothelial cell (EC). RESULTS: Atherosclerotic plaques of T2DM patients showed lower adiponectin and APPL1 levels compared with non-diabetic patients, along with higher oxidative stress, tumor necrosis factor-α (TNF-α), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-users. Similarly, in vitro observations on endothelial cells co-treated with high-glucose (25mM) and GLP-1 (100nM) showed a greater APPL1 protein expression compared with high-glucose treatment alone. CONCLUSIONS: Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM.

Coronary angioplasty with stenting for acute coronary syndrome in patients with isolated single coronary artery: a report of two cases.

In the largest reported series of patients, the overall angiographical incidence of congenital coronary anomalies was 1.3%. Among these anomalies, an isolated single coronary artery is a rare, congenital coronary anomaly with an incidence of 0.044-0.23%. In this kind of anomaly, the coronary arteries arise by a single coronary ostium in the right or left sinus of Valsalva. Percutaneous coronary revascularization plays an important role in the management of acute coronary syndrome, and coronary anomalies may determine a lower success rate of this intervention. We report two cases of isolated single coronary arteries who underwent successful coronary angioplasty and stenting for acute coronary syndrome.

Acute aortic syndromes at high surgical risk: the endovascular approach.

AIMS: Acute aortic syndromes (AAS) still represent life-threatening conditions. The aim of this study was to describe our experience in the management of patients (pts) with AAS and to evaluate the safety and feasibility of endovascular treatment (EVT) in high surgical risk patients. METHODS AND RESULTS: One hundred and four patients underwent EVT. We selected 56 pts with AAS: 17 complicated type B aortic dissections, five traumatic aortic ruptures at the isthmus, 11 thoracic aneurysms and 23 pts with large AAA with impending rupture. All these pts were at high surgical risk because of their comorbidities and/or their emergency situation. They were clinically followed during hospitalisation and they underwent a 2 mm-interval CT-scan two weeks, six and 12 months after discharge and every year after. Death, paraplegia, open surgical conversion did not occur. Two pts underwent a successful secondary EVT for type I endoleak. One patient with thoracic aortic aneurysm died of septic shock from pneumonia 78 days after discharge and two pts with AAA suffering from a severe three-vessel coronary disease experienced sudden death at one year follow-up. CONCLUSIONS: EVT seems to be a safe and effective therapeutic option with good short- and midterm results in patients with AAS at high surgical risk. Thus, it can be considered as a less-invasive alternative in patients considered otherwise unsuitable for conventional surgery, even though a careful, continued follow-up is still necessary to confirm the long-term safety and effectiveness of EVT in AAS.

Abciximab in elderly with acute coronary syndrome invasively treated: effect on outcome.

Older age is an independent predictor of mortality after percutaneous coronary intervention (PCI) in patients with Non-ST elevation Acute Coronary Syndrome (ACS). GPIIb/IIIa inhibitors are proved to improve outcome in high risk patients, but conflicting data are available about the effects of these inhibitors in elderly. Accordingly, we studied a consecutive population of elderly patients undergoing PCI for Non-ST elevation ACS. A total of 500 patients were divided in: GPI group (247 pts; mean age 77+/-1.9 years) treated by stenting plus abciximab and, no GPI group (253 pts; mean age 77+/-2.4 years) treated by stenting alone. Propensity analysis was used to account for the nonrandomized use of GPIIb/IIIa inhibitors. During hospitalization, incidence of death was similar among groups (3.2% vs 4.6%) without difference regarding incidence of major (1.6% vs 1.1%) and minor bleedings (4% vs 3%). At long-term follow-up the rate of death was significantly lower in GPI group (4.5% vs 12.3%; p=0.002) as well as the rate of acute myocardial infarction (2.8% vs 11.1%; p=0.0001), and pre-PCI (5.7% vs 13.4%; p=0.003). Cox regression analysis identified abciximab use as an independent predictor of lower long-term major adverse cardiac event (MACE) after adjustment for propensity score (Exp (B) 0.620, 95%CI 0.394-0.976, p=0.039). Our results suggest that addition of abciximab to stenting improves outcome in elderly patients with Non-ST elevation ACS, leading to an absolute benefit for reduction of death and MACE, with an acceptable rate of major and minor bleedings.