GLP-1 receptor agonists-SGLT-2 inhibitors combination therapy and cardiovascular events after acute myocardial infarction: an observational study in patients with type 2 diabetes.

BACKGROUND: Few studies explored the effect of the combination of glucose sodium-cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on the incidence of cardiovascular events in patients with type 2 diabetes (T2D) and acute myocardial infarction (AMI). METHODS: We recruited patients with T2D and AMI undergoing percutaneous coronary intervention, treated with either SGLT-2i or GLP-1RA for at least 3 months before hospitalization. Subjects with HbA1c < 7% at admission were considered in good glycemic control and maintained the same glucose-lowering regimen, while those with poor glycemic control (HbA1c ≥ 7%), at admission or during follow-up, were prescribed either a SGLT-2i or a GLP-1RA to obtain a SGLT-2i/GLP-1RA combination therapy. The primary outcome was the incidence of major adverse cardiovascular events (MACE) defined as cardiovascular death, re-acute coronary syndrome, and heart failure related to AMI during a 2-year follow-up. After 3 months, the myocardial salvage index (MSI) was assessed by single-photon emission computed tomography. FINDINGS: Of the 537 subjects screened, 443 completed the follow-up. Of these, 99 were treated with SGLT-2i, 130 with GLP-1RA, and 214 with their combination. The incidence of MACE was lower in the combination therapy group compared with both SGLT-2i and GLP-1RA treated patients, as assessed by multivariable Cox regression analysis adjusted for cardiovascular risk factors (HR = 0.154, 95% CI 0.038-0.622, P = 0.009 vs GLP-1RA and HR = 0.170, 95% CI 0.046-0.633, P = 0.008 vs SGLT-2i). The MSI and the proportion of patients with MSI > 50% was higher in the SGLT-2i/GLP-1RA group compared with both SGLT-2i and GLP-1RA groups. INTERPRETATION: The combination of SGLT-2i and GLP-1RA is associated with a reduced incidence of cardiovascular events in patients with T2D and AMI compared with either drug used alone, with a significant effect also on peri-infarcted myocardial rescue in patients without a second event. Trial registraition ClinicalTrials.gov ID: NCT06017544.

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.

SGLT-2 inhibitors and in-stent restenosis-related events after acute myocardial infarction: an observational study in patients with type 2 diabetes.

BACKGROUND: No study evaluated the incidence of intra-stent restenosis (ISR)-related events in patients with type 2 diabetes (T2DM) and acute myocardial infarction (AMI) treated or not with sodium/glucose cotransporter 2 inhibitors (SGLT2i). METHODS: We recruited 377 patients with T2DM and AMI undergoing percutaneous coronary intervention (PCI). Among them, 177 T2DM were treated with SGLT2 inhibitors before PCI. The primary outcome was major adverse cardiovascular events (MACE) defined as cardiac death, re-infarction, and heart failure related to ISR. In patients without ISR, minimal lumen area and minimal lumen diameter were assessed by coronary CT-angiography at 1-year follow-up. RESULTS: Glycemic control was similar in SGLT2i-treated patients and never SGLT2i-users. The incidence of ISR-related MACE was higher in never SGLT2i-users compared with SGLT2i-treated patients, an effect independent of glycemic status (HR = 0.418, 95% CI = 0.241-0.725, P = 0.002) and observed also in the subgroup of patients with HbA1c < 7% (HR = 0.393, 95% CI = 0.157-0.984, P = 0.027). In patients without the event, the stent patency was greater in SGLT2i-treated patients compared with never SGLT2i-users at 1-year follow-up. CONCLUSIONS: SGLT2i treatment in T2DM is associated with a reduced incidence of ISR-related events, independently of glycemic control.

Thrombus aspiration in hyperglycemic ST-elevation myocardial infarction (STEMI) patients: clinical outcomes at 1-year follow-up.

OBJECTIVES: We evaluate whether the thrombus aspiration (TA) before primary percutaneous coronary intervention (PPCI) may improve STEMI outcomes in hyperglycemic patients. BACKGROUND: The management of hyperglycemic patients during STEMI is unclear. METHODS: We undertook an observational cohort study of 3166 first STEMI. Patients were grouped on the basis of whether they received TA or not. Moreover, among these patients we selected a subgroup of STEMI patients with hyperglycemia during the event (glycaemia > 140 mg/dl). The endpoint at 1 year included all-cause mortality, cardiac mortality and re-hospitalization for coronary disease, heart failure and stroke. RESULTS: One-thousand STEMI patients undergoing PPCI to plus TA (TA-group) and 1504 STEMI patients treated with PPCI alone (no-TA group) completed the study. In overall study-population, Kaplan-Meier-analysis demonstrated no significant difference in mortality rates between patients with and without TA (P = 0.065). After multivariate Cox-analysis (HR: 0.94, 95% CI 0.641-1.383) and the addition of propensity matching (HR: 0.86 95% CI 0.412-1.798) TA was still not associated with decreased mortality. By contrast, in hyperglycemic subgroup STEMI patients (TA-group, n = 331; no-TA group, n = 566), Kaplan-Meier-analysis demonstrated a significantly lower mortality (P = 0.019) in TA-group than the no-TA group. After multivariate Cox-analysis (HR: 0.64, 95% CI 0.379-0.963) and the addition of propensity matching (HR: 0.54, 95% CI 0.294-0.984) TA was still associated with decreased mortality. CONCLUSIONS: TA was not associated with lower mortality in PPCI for STEMI when used in our large all-comer cohort. Conversely, TA during PPCI for STEMI reduces clinical outcomes in hyperglycemic patients. Trial registration NCT02817542. 25th, June 2016.

Correction to: Thrombus aspiration in hyperglycemic ST-elevation myocardial infarction (STEMI) patients: clinical outcomes at 1-year follow-up.

Following publication of the original article [1], the authors reported an error in Acknowledgment section. The last sentence should read as "All authors have read and approval the submission to Cardiovascular Diabetology.

[Treatment of acute myocardial infarction in 2017]. / Il trattamento dell'infarto miocardico acuto nel 2017.

Acute myocardial infarction is a clinical cardiac emergency associated with potential and substantial morbidity and mortality. This disorder is triggered by an acute coronary syndrome caused by episodes of plaque ulceration, fissuration, or rupture with subsequent production of thrombogenic material and intravascular thrombus formation. The presence or absence of ST-segment elevation on the ECG defines the two main clinical spectrum of ST-segment elevation or non-ST-segment elevation myocardial infarction. In the last three decades, pharmacological and interventional management as well as in-hospital care have dramatically improved. Recent advances in antithrombotic strategies, percutaneous access (radial versus femoral), timing of revascularization, new generation coronary stents, lipid profile management, and cardiac rehabilitation programs at discharge have lead the European Task Force on ST-Elevation Myocardial Infarction to revise the 2012 guidelines and to release, in the current year, an updated version.

Effects of α-lipoic acid therapy on sympathetic heart innervation in patients with previous experience of transient takotsubo cardiomyopathy.

BACKGROUND: Takotsubo syndrome is a stress cardiomyopathy, characterized by reversible left ventricle (LV) apical ballooning in the absence of significant angiographic coronary artery stenosis. The frequent association with emotional stress suggests in this disease an autonomic nervous system involvement. We could think that a therapeutic treatment targeting heart sympathetic dysfunction could be of crucial importance. METHODS: From January 2010 to June 2012, 886 patients were consecutively evaluated at Cardarelli Hospital, Naples, Italy. Among these, 48 patients met takotsubo cardiomyopathy (TCM) criteria. Each patient was assessed with history and physical examination, 12-lead electrocardiogram, serum troponin, coronary arteriography, and left ventricular angiogram, perfusion myocardial scintigraphy with technetium 99m, with echocardiography and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. At discharge, the surviving patients were randomly assigned to α-lipoic acid (ALA) treatment (600mg once daily) or placebo. Following discharge, after the initial TCM event, patients returned to our outpatient clinic at Internal Medicine of the Second University Naples for the follow-up evaluation quarterly until 12 months. Routine analysis, myocardial damage serum markers, oxidative stress serum markers, pro-inflammatory cytokines, and sympathetic tone activity were evaluated in all patients. RESULTS: ALA administration improved MIBG defect size at 12 months compared to placebo. CONCLUSIONS: Adrenergic cardiac innervation dysfunction in TCM patients persists after previous experience of transient stress-induced cardiac dysfunction. ALA treatment improves the adrenergic cardiac innervation. This study evaluates whether sympatho-vagal alterations are TCM event-related.

Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment.

The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic patients is unknown. We evaluated SIRT6 expression and the effect of incretin-based therapies in carotid plaques of asymptomatic diabetic and nondiabetic patients. Plaques were obtained from 52 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Twenty-two diabetic patients were treated with drugs that work on the incretin system, GLP-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors for 26 ± 8 months before undergoing the endarterectomy. Compared with nondiabetic plaques, diabetic plaques had more inflammation and oxidative stress, along with a lesser SIRT6 expression and collagen content. Compared with non-GLP-1 therapy-treated plaques, GLP-1 therapy-treated plaques presented greater SIRT6 expression and collagen content, and less inflammation and oxidative stress, indicating a more stable plaque phenotype. These results were supported by in vitro observations on endothelial progenitor cells (EPCs) and endothelial cells (ECs). Indeed, both EPCs and ECs treated with high glucose (25 mmol/L) in the presence of GLP-1 (100 nmol/L liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression compared with cells treated only with high glucose. These findings establish the involvement of SIRT6 in the inflammatory pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin, the effect of which is associated with morphological and compositional characteristics of a potential stable plaque phenotype.

Peri-procedural tight glycemic control during early percutaneous coronary intervention is associated with a lower rate of in-stent restenosis in patients with acute ST-elevation myocardial infarction.

OBJECTIVE: We examined the effects of peri-procedural intensive glycemic control (IGC) during early percutaneous coronary intervention (PCI) on restenosis rate in hyperglycemic patients with ST-segment elevation myocardial infarction (STEMI). RESEARCH DESIGN AND METHODS: A total of 165 hyperglycemic patients (glucose ≥ 140 mg/dl) with first STEMI undergoing PCI were studied. Patients were randomized to IGC for almost 24 h after PCI (n = 82; glucose, 80-140 mg/dl) followed by multidose sc insulin during the hospital stay or conventional glycemic control (CGC; n = 83; glucose, 180-200 mg/dl) followed by conventional therapy. Coronary angiography was performed at study entry and at 6-month follow-up. Blood samples for glycemia, hemoglobin A1c, inflammatory markers (C-reactive protein and TNF-α), monocyte chemoattractant-protein-1, and oxidative stress (nitrotyrosine) were collected immediately before and 24 h, 30 and 180 d after PCI. RESULTS: After insulin infusion, mean plasma glucose during the peri-procedural period was greater in the CGC group than in the IGC group (CGC, 191 ± 15 mg/dl; IGC, 145 ± 35 mg/dl; P < 0.001). After the insulin infusion period, the levels of markers of oxidative stress (nitrotyrosine), inflammation (C-reactive protein, TNF-α), and monocyte chemoattractant-protein-1 were significantly higher in CGC patients compared with IGC patients. Moreover, ICG during PCI reduces restenosis by half (48 and 24%) at 6 months. During follow-up, there was no difference in mortality rates, glucose, inflammatory and oxidative stress markers among the groups. In-stent restenosis was positively associated with mean plasma glucose levels as well as oxidative stress and inflammatory markers during the insulin infusion period. CONCLUSIONS: In hyperglycemic patients with STEMI, optimal peri-procedural glycemic control by reducing oxidative stress and inflammation may improve the outcome after PCI.

Correlations between progression of coronary artery disease and circulating endothelial progenitor cells.

The pathophysiology of coronary artery disease (CAD) progression is not well understood. Endothelial progenitor cells (EPCs) may have an important role. In the present observational cohort study we assessed the number of circulating EPCs in 136 patients undergoing elective percutaneous coronary intervention and who had at least one major epicardial vessel with a nonsignificant stenosis [<50% diameter stenosis (DS)], and the relationship between plasma EPC levels and the 24-mo progression of the nonsignificant coronary artery lesion. The following cell populations were analyzed: CD34(+), CD133(+), CD34(+)/KDR(+), CD34(+)/VE cadherin(+), and endothelial cell colony-forming units (CFU-ECs). Progression was defined as a >15% DS increase of the objective vessel at follow-up. At 24 mo, 57 patients (42%) experienced significant progression. Independent predictors of disease progression were LDL cholesterol > 100 mg/dl (OR=1.03; 95% CI 1.01-1.04; P=0.001), low plasma levels of CFU-ECs (OR=3.99; 95% CI 1.54-10.37; P=0.005), and male sex (OR=3.42; 95% CI 1.15-10.22; P=0.027). Circulating levels of EPCs are significantly lower in patients with angiographic CAD progression.

Comparison of bivalirudin monotherapy versus unfractionated heparin plus tirofiban in patients with diabetes mellitus undergoing elective percutaneous coronary intervention.

Bivalirudin demonstrated similar efficacy but resulted in a lower rate of bleeding compared to unfractionated heparin (UFH) plus platelet glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention. It has not been clearly evaluated whether this can also be applied to patients with diabetes mellitus. A total of 335 consecutive patients with diabetes mellitus referred for elective percutaneous coronary intervention were randomized in the Novel Approaches for Preventing or Limiting EventS (NAPLES) trial to receive bivalirudin monotherapy or UFH plus routine tirofiban. The primary composite end point (30-day composite incidence of death, urgent repeat revascularization, myocardial infarction, and all bleeding) was lower in the bivalirudin group than in the UFH plus tirofiban group (18.0% vs 31.5%, odds ratio 0.47, 95% confidence interval 0.28 to 0.79, p = 0.004). No death, urgent revascularization, or Q-wave myocardial infarction occurred. The rate of non-Q-wave myocardial infarction was similar in the 2 groups (10.2% in the bivalirudin group vs 12.5% in the UFH plus tirofiban group, p = 0.606). In contrast, fewer patients in the bivalirudin group experienced bleeding (8.4% vs 20.8%, odds ratio 0.34, 95% confidence interval 0.18 to 0.67, p = 0.002). This difference was mainly ascribed to the lower rate of minor bleeding (7.8% in the bivalirudin group vs 18.5% in the UFH plus tirofiban group, odds ratio 0.37, 95% confidence interval 0.19 to 0.74, p = 0.005), although the rate of major bleeding in the 2 groups was comparable (0.6% vs 2.4%, respectively; p = 0.371). In conclusion, in patients with diabetes mellitus undergoing elective percutaneous coronary intervention, the strategy of bivalirudin monotherapy compared to UFH plus routine tirofiban is safe and feasible and associated with a significant reduction of in-hospital bleeding.

Comparison of coronary drug-eluting stents versus coronary artery bypass grafting in patients with diabetes mellitus.

We compared 1-year outcome after drug-eluting stent (DES) implantation with off-pump bypass grafing (OPCABG) in patients with type 2 diabetes mellitus and multivessel coronary artery disease involving the proximal segment of the left anterior descending coronary artery. All consecutive diabetic patients treated by DES (DES group) or OPCABG (CABG group) in our institution from April 2002 to December 2004 because of de novo coronary lesions were included. Patients in the CABG group (n = 149) were older and had a higher rate of 3-vessel disease than those in the DES group (n = 69). At 12 months, major adverse cardiac and cerebrovascular events occurred in 29% of the DES group and 20.5% of the CABG group (unadjusted analysis, odds ratio 1.20, 95% confidence interval [CI] 0.93 to 1.54, p = 0.17). After propensity score analysis, adjusting for baseline differences between the 2 cohorts, DESs increased the risk of 12-month major adverse cardiac and cerebrovascular events (hazard ratio 1.88, 95% CI 1.09 to 3.02, p = 0.020). This was due to the higher rate for repeat revascularization in the DES group (19% vs 5%, odds ratio 2.05, 95% CI 1.12 to 3.75, p = 0.001). In contrast, there was no difference in the rate of the composite end points of death, myocardial infarction, and stroke (DES group 13%, CABG group 12%; adjusted analysis, hazard ratio 0.80, 95% CI 0.80 to 1.35, p = 0.40). In conclusion, at 1 year in diabetic patients with multivessel coronary artery disease involving the proximal left anterior descending coronary artery, the advantage of OPCABG over DES implantation seems to be limited at a lower rate of repeat revascularization. No difference seems to exist in the rate of death, stroke, and myocardial infarction.

Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies.

BACKGROUND: Volume supplementation by saline infusion combined with N-acetylcysteine (NAC) represents an effective strategy to prevent contrast agent-induced nephrotoxicity (CIN). Preliminary data support the concept that sodium bicarbonate and ascorbic acid also may be effective in preventing CIN. METHODS AND RESULTS: Three hundred twenty-six consecutive patients with chronic kidney disease, referred to our institutions for coronary and/or peripheral procedures, were randomly assigned to prophylactic administration of 0.9% saline infusion plus NAC (n=111), sodium bicarbonate infusion plus NAC (n=108), and 0.9% saline plus ascorbic acid plus NAC (n=107). All enrolled patients had serum creatinine > or = 2.0 mg/dL and/or estimated glomerular filtration rate < 40 mL x min(-1) x 1.73 m(-2). Contrast nephropathy risk score was calculated in each patient. In all cases, iodixanol (an iso-osmolar, nonionic contrast agent) was administered. The primary end point was an increase of > or = 25% in the creatinine concentration 48 hours after the procedure (CIN). The amount of contrast media administered (179+/-102, 169+/-92, and 169+/-94 mL, respectively; P=0.69) and risk scores (9.1+/-3.4, 9.5+/-3.6, and 9.3+/-3.6; P=0.21) were similar in the 3 groups. CIN occurred in 11 of 111 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P=0.019 by Fisher exact test versus saline plus NAC group), and in 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P=1.00 versus saline plus NAC group). CONCLUSIONS: The strategy of volume supplementation by sodium bicarbonate plus NAC seems to be superior to the combination of normal saline with NAC alone or with the addition of ascorbic acid in preventing CIN in patients at medium to high risk.

Induction of tissue factor in the arterial wall during recurrent thrombus formation.

OBJECTIVE: Tissue factor (TF) is normally expressed at low levels in the media of blood vessels, but it is readily induced after vessel injury. It is not known whether vascular damage per se or thrombus formation is responsible for this phenomenon. METHODS AND RESULTS: Cyclic flow variations (CFVs), attributable to recurrent thrombus formation, were induced in stenotic rabbit carotid arteries with endothelial injury. CFVs were observed for 30 minutes and 2, 4, and 8 hours in different groups of animals. Another group of rabbits pretreated with hirudin before inducing arterial damage to inhibit thrombus formation was observed for 8 hours. Arterial sections were immunostained for TF. Undamaged arteries served as controls. In additional rabbits, in situ hybridization experiments were performed. No TF expression was observed in the media of control vessels, whereas a progressive increase in TF mRNA and protein expression was observed in carotid arteries as CFVs progressed. No increase in TF expression was observed in animals pretreated with hirudin. In vitro experiments demonstrated that TF mRNA is induced in smooth muscle cells stimulated with activated platelets as well as with some platelet-derived mediators. CONCLUSIONS: This phenomenon may contribute to sustain intravascular thrombus formation after the initial thrombogenic stimulus.

Percutaneous treatment of early occlusion of a complex arterial coronary graft: a case report.

The internal mammary arteries are now widely used for surgical myocardial revascularization. Because of its excellent long-term patency rates, re-do surgery is rarely requested and transluminal percutaneous angioplasty of these arterial grafts is still relatively infrequent. This procedure is performed mainly at the distal anastomotic site but also at the origin of the vessel from the subclavian artery, frequently just to treat a local traumatic dissection due to the catheter. We here report the case of a successful angioplasty and stenting of the body of the graft for an early total occlusion of a complex, bifurcated arterial bypass to the left coronary system.