[Hypercholesterolemia and laboratory reports: joint document from the Italian Society of Cardiology (SIC) and the Italian Society of Clinical Biochemistry and Clinical Molecular Biology - Lab Medicine (SIBioC)]. / Ipercolesterolemia e referti di laboratorio: documento congiunto della Società Italiana di Cardiologia (SIC) e Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica - Medicina di Laboratorio (SIBioC).

Dyslipidemia is one of the most important risk factors for the development of atherosclerotic disease and its control, through well-proven therapies, allows an optimal risk management over time. LDL-cholesterol targets are well defined by international guidelines and based on individual cardiovascular risk. As guidelines evolve, also laboratory reports need to do the same, including lipid reference values by cardiovascular risk classes, to avoid misunderstandings and inappropriate lipid-lowering therapy withdrawal. The aim of the present joint document from the Italian Society of Cardiology (SIC) and the Italian Society of Clinical Biochemistry and Clinical Molecular Biology - Lab Medicine (SIBioC) is to analyze the importance of cardiovascular risk estimation, therapeutical targets, and crucial elements about dyslipidemia in laboratory tests, as well as to suggest a shared proposal for the report of lipid profile parameters to be applied to all clinical scenarios of our daily practice.

ICARUS score for predicting peri-procedural bleeding in patients undergoing percutaneous coronary intervention with cangrelor.

BACKGROUND: Tools for precise prediction of bleeding risk in patients undergoing percutaneous coronary intervention (PCI) with cangrelor are lacking. METHODS: Consecutive patients undergoing PCI and treated with cangrelor in 7 centers were retrospectively enrolled. The primary endpoint was Bleeding Academic Research Consortium (BARC) BARC 2, 3, or 5 bleeding 48 h after PCI. Predictors of BARC 2-5 bleeding were identified in a derivation cohort and combined into a numerical risk score. Discrimination and calibration were assessed in the derivation and validation cohorts. A threshold to define high bleeding risk (HBR) was identified and its diagnostic accuracy was compared with that of currently recommended bleeding risk scores. RESULTS: 1071 patients undergoing PCI with cangrelor were included. Fifty-four patients (5 %) experienced a BARC 2-5 bleeding, of whom 24 (44 %) from the access site. Age ≥ 75 years (odds ratio [OR] 2.58, 95 % confidence interval [CI] 1.21-5.48, p = 0.01), acute coronary syndrome at presentation (OR 8.14, 95 % CI 2.28-52, p = 0.01), and femoral access (OR 6.21, 95 % CI 2.71-14, p < 0.001) independently predicted BARC 2-5 bleeding at 48 h after PCI. The three items were combined to form a new risk score, the ICARUS score, showing good discrimination in both the derivation (area under the curve [AUC] 0.78) and internal validation (AUC 0.77) cohorts, and excellent calibration. An ICARUS score > 9 points accurately identified patients at HBR, showing better discrimination than other risk scores. CONCLUSIONS: A risk score based on age, clinical presentation and access site, predicts the risk of periprocedural bleeding in patients receiving cangrelor (ClinicalTrials.gov ID: NCT05505591).

Secondary prevention and extreme cardiovascular risk evaluation (SEVERE-0): Prevalence of extreme cardiovascular risk in cardiological rehabilitation patients and its impact on functional improvement.

BACKGROUND AND AIMS: Patients with recent Acute Coronary Syndrome (ACS) or Chronic Coronary Syndrome (CCS) are all at very high CardioVascular (CV) risk. However, some of them are more likely to experience recurrent cardiovascular events (i.e extreme CV risk). A definition of which patients should be included in this category has been recently proposed by the European Society of Cardiology but data on its prevalence are still lacking, especially in the context of Cardiac Rehabilitation (CR). Furthermore, if this condition had an impact on the CR related functional improvement is not known. Our study has been designed to answer to both these questions. METHODS AND RESULTS: The study included 938 ACS/CCS patients who attended the CR program at the Niguarda Hospital (Milan). Extreme CV patients were defined as the presence of a previous CV events within 2 years or the presence of peripheral arteriopathy or the presence of a multivessel coronary involvement. Functional improvement was evaluated through 6-Minute Walking Test (6-MWT). As many as 26.9% of the patients had an extreme CV risk. They were older (67.8 ± 10.4 vs 64.1 ± 11.1 years; p ≤ 0.001), had a higher prevalence of CV risk factors and comorbidities and had a lower functional improvement during CR (102.9 ± 68.6 vs 138.1 ± 86.5 m; p ≤ 0.001). Extreme CV risk present a significant association with the 6-MWT results at multivariate analysis. CONCLUSION: Extreme CV risk is a very frequent condition among patients with ACS/CCS reaching the prevalence of 26.9%. Furthermore, being at extreme CV risk adversely affects the patient's functional improvement obtained during CR.

Preliminary study on the role of human defensins, interleukins and PCSK9 in early and late preeclampsia.

The lack of reliable methods for preeclampsia (PE) early diagnosis limits the opportunities for timely prevention, diagnosis and treatment. This study aims to identify the alterations of biochemical parameters and the immune system activity to build a panel of markers that can support preeclampsia diagnosis. For this study, we recruited 30 pregnant women: 10 healthy pregnant women (CTR); 10 pregnant women with early preeclampsia (EP); 10 pregnant women with late preeclampsia (LP). We evaluated lipid profile and, by gene expression, we assessed PCSK9, IL-2, IL-6, IL-8, IL-10, TNF-α and TGF-ß. Moreover, we evaluated both the serum and gene levels of the defensins HBD-1, HBD-2, HBD-4 and HNP-1. Our results showed an increase in gene expression levels of IL-6 and IL-8 in EP compared to LP (IL-6: median 11.7 vs 3.3, p = 0.005; IL-8: median 634.1 vs 214.1, p = 0.013) and to CTR (IL-6: median 11.7 vs 0.5, p < 0.001; IL-8: median 634.1 vs 225.6, p = 0.012), highlighting a massive activation of immune system in case of more severe preeclampsia. Furthermore, higher serum levels of HBD1 in LP compared to CTR (median: 278.8 vs 67.8, p = 0.005) and to EP (median: 278.8 vs 68.6, p = 0.001) might indicate that the same immune system puts in action protective actions to prevent adverse outcome in these cases. Finally, gene expression levels of PCSK9 decreased significantly in women with EP compared to controls and to LP (median: 0.2 vs 0.9, p = 0.010; median: 0.2 vs 1.2, p = 0.012), causing a decrease in circulating LDL-c necessary for the synthesis of placental hormones.

The clinical relevance of the reversal of coronary atherosclerotic plaque.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death globally despite advances in preventive therapies. Understanding of the initiation and progression of atherosclerosis, the interplay between lipoproteins, endothelial dysfunction, inflammation, and immune responses is critical to treating this disease. The development of vulnerable coronary plaques prone to thrombosis, can lead to acute coronary syndromes, for these reasons, the potential plaque stabilization and regression through pharmacological interventions, particularly lipid-lowering agents like statins and PCSK9 inhibitors is crucial. The imaging techniques such as intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT) play a key role in assessing plaque composition and guiding interventional therapeutic strategies. Clinical evidence supports the efficacy of intensive lipid-lowering therapy in inducing plaque regression, with studies demonstrating reductions in plaque volume and improvements in plaque morphology assessed by IVUS, OCT and NIRS. While pharmacological interventions show promise in promoting plaque regression and stabilization, their impact on long-term cardiovascular events requires further investigation. Multimodality imaging and comprehensive outcome trials are proposed as essential tools for elucidating the relationship between plaque modification and clinical benefit in coronary atherosclerosis. The stabilization or regression of atherosclerotic plaque might serve as the phenomenon linking the reduction in LDL-C levels to the decrease in cardiovascular events. Overall, this review emphasizes the ongoing efforts to advance our understanding of ASCVD pathophysiology and optimize therapeutic approaches for improving patient outcomes.

Insulin Resistance/Hyperinsulinemia as an Independent Risk Factor That Has Been Overlooked for Too Long.

Unfortunately, cardiovascular diseases and cancers are still the leading causes of death in developed and developing countries despite the considerable progress made in the prevention and treatment of diseases. Maybe we missed something? Insulin resistance (IR) with associated hyperinsulinemia (Hypein) is a silent pandemic whose prevalence is continually growing in developed and developing countries, now exceeding 51% of the general population. IR/Hypein, despite the vast scientific literature supporting its adverse action on the development of type 2 diabetes, cardiovascular alterations, tumors, neurological disorders, and cellular senescence, is not yet considered an independent risk factor and, therefore, is not screened in the general population and adequately treated. There are now numerous substances, drugs, and natural substances that, in association with the correction of a wrong lifestyle, can help to reduce IR/Hypein. We are convinced that the time has come to implement a prevention plan against this critical risk factor. Therefore, this manuscript aims to highlight IR/Hypein as an independent risk factor for type 2 diabetes, cardiovascular diseases, cancers, cellular senescence, and neuropsychiatric disorders, supporting our conviction with the available scientific literature on the topic.

Strike early-strike strong lipid-lowering strategy with PCSK9i in ACS patients. Real-world evidence from AT-TARGET-IT registry.

AIMS: No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in real-world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. METHODS: The lipid control outcome was the percentage of patients reaching the LDL-C target of < 55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization) during follow-up in relation to quartiles of LDL-C at first lipid control. RESULTS: We included 771 patients with ACS from AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C <55 mg/dL. CONCLUSIONS: Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk.

This study, from AT-TARGET-IT registry, investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. Intensive and early PCSK9i therapy reduce composite major cardiovascular (CV) events in patients in reaching LDL-C target values. A strike early-strike strong strategy is safe and effective.

Intravenous antiplatelet therapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention : A report from the INVEST-STEMI group.

The use of intravenous antiplatelet therapy during primary percutaneous coronary intervention (PPCI) is not fully standardized. The aim is to evaluate the effectiveness and safety of periprocedural intravenous administration of cangrelor or tirofiban in a contemporary ST-segment elevation myocardial infarction (STEMI) population undergoing PPCI. This was a multicenter prospective cohort study including consecutive STEMI patients who received cangrelor or tirofiban during PPCI at seven Italian centers. The primary effectiveness measure was the angiographic evidence of thrombolysis in myocardial infarction (TIMI) flow < 3 after PPCI. The primary safety outcome was the in-hospital occurrence of BARC (Bleeding Academic Research Consortium) 2-5 bleedings. The study included 627 patients (median age 63 years, 79% males): 312 received cangrelor, 315 tirofiban. The percentage of history of bleeding, pulmonary edema and cardiogenic shock at admission was comparable between groups. Patients receiving cangrelor had lower ischemia time compared to tirofiban. TIMI flow before PPCI and TIMI thrombus grade were comparable between groups. At propensity score-weighted regression analysis, the risk of TIMI flow < 3 was significantly lower in patients treated with cangrelor compared to tirofiban (adjusted OR: 0.40; 95% CI: 0.30-0.53). The risk of BARC 2-5 bleeding was comparable between groups (adjusted OR:1.35; 95% CI: 0.92-1.98). These results were consistent across multiple prespecified subgroups, including subjects stratified for different total ischemia time, with no statistical interaction. In this real-world multicenter STEMI population, the use of cangrelor was associated with improved myocardial perfusion assessed by coronary angiography after PPCI without increasing clinically-relevant bleedings compared to tirofiban.

[Multidistrict atherosclerotic disease: epidemiological and clinical framework]. / Malattia aterosclerotica polidistrettuale: inquadramento epidemiologico e clinico.

Atherosclerosis is a systemic disease that can involve different arterial districts. Traditionally, the focus of cardiologists has been on the diagnosis and treatment of atherosclerotic coronary artery disease (CAD). However, atherosclerosis localization in other districts is increasingly common and is associated with an increased risk of CAD and, more generally, of adverse cardiovascular events. Although the term peripheral arterial disease (PAD) commonly refers to the localization of atherosclerotic disease in the arterial districts of the lower limbs, in this document, in accordance with the European Society of Cardiology guidelines, the term PAD will be used for all the locations of atherosclerotic disease excluding coronary and aortic ones. The aim of this review is to report updated data on PAD epidemiology, with particular attention to the prevalence and its prognostic impact on patients with CAD. Furthermore, the key points for an appropriate diagnostic framework and a correct pharmacological therapeutic approach are summarized, while surgical/interventional treatment goes beyond the scope of this review.

Hyperkalaemia in Cardiological Patients: New Solutions for an Old Problem.

Hyperkalaemia is one of the most common electrolyte disorders in patients with cardiovascular disease (CVD). The true burden of hyperkalaemia in the real-world setting can be difficult to assess, but in population-based cohort studies up to 4 in 10 patients developed hyperkalaemia. In addition to drugs interfering with potassium metabolism and food intake, several conditions can cause or worsen hyperkalaemia, such as advanced age, diabetes, and chronic kidney disease. Mortality, cardiovascular morbidity, and hospitalisation are higher in patients with hyperkalaemia. Hyperkalaemia represents a major contraindication or a withholding cause for disease-modifying therapies like renin-angiotensin-aldosterone inhibitors (RAASi), mainly mineralocorticoid receptor antagonists. Hyperkalaemia can be also classified as acute and chronic, according to the onset. Acute hyperkalaemia is often a life-threatening emergency requiring immediate treatment to avoid lethal arrhythmias. Therapy goal is cell membrane stabilisation by calcium administration, cellular intake, shift of extracellular potassium to the intracellular space (insulin, beta-adrenergic agents, sodium bicarbonate), and increased elimination with diuretics or dialysis. Chronic hyperkalaemia was often managed with dietary counselling to prevent potassium-rich food intake and tapering of potassium-increasing drugs, mostly RAASi. Sodium polystyrene sulphonate, a potassium binder, was the only therapeutic option. Recently, new drugs such as patiromer and sodium zirconium cyclosilicate give new opportunities for the treatment of hyperkalaemia, as they proved to be safe, well tolerated, and effective. Aim of this review is to describe the burden of hyperkalaemia in cardiovascular patients, its direct and indirect effects, and the therapeutic options now available in the acute and chronic setting.

[Lipoprotein(a): relationships with atherosclerosis and valvular heart disease, and emerging therapies]. / Lipoproteina(a): associazione con la malattia aterosclerotica e valvolare e terapie emergenti.

Lipoprotein(a) [Lp(a)] is a well-established cardiovascular risk factor, whose relationship with atherosclerotic disease has been confirmed by epidemiological, genome-wide association, Mendelian randomization, and meta-analysis studies. This association is determined by its pro-atherogenic, pro-thrombotic and pro-inflammatory properties. Lp(a) is the most common monogenic risk factor for atherosclerosis, with a prevalence of about 1 in 5 people. Recently, its etiopathogenetic relationship with calcific and degenerative valvular heart diseases, particularly with aortic and mitral stenosis, has been suspected. It has not yet been demonstrated whether its reduction translates into a lower risk of cardiovascular events. Up to now, Lp(a) has been considered a non-modifiable risk factor, as current lipid-lowering drugs have limited effects on its levels. New specific lipid-lowering therapies with high efficacy in reducing circulating Lp(a) levels are being investigated in randomized trials; however, the effects of this reduction on cardiovascular outcomes are still being studied.

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.

Secondary Prevention and Extreme Cardiovascular Risk Evaluation (SEVERE-1), Focus on Prevalence and Associated Risk Factors: The Study Protocol.

INTRODUCTION: Despite significant improvement in secondary CardioVascular (CV) preventive strategies, some acute and chronic coronary syndrome (ACS and CCS) patients will suffer recurrent events (also called "extreme CV risk"). Recently new biochemical markers, such as uric acid (UA), lipoprotein A [Lp(a)] and several markers of inflammation, have been described to be associated with CV events recurrence. The SEcondary preVention and Extreme cardiovascular Risk Evaluation (SEVERE-1) study will accurately characterize extreme CV risk patients enrolled in cardiac rehabilitation (CR) programs. AIM:  Our aims will be to describe the prevalence of extreme CV risk and its association with newly described biochemical CV risk factors. AIM: Our aims will be to describe the prevalence of extreme CV risk and its association with newly described biochemical CV risk factors. METHODS: We will prospectively enrol 730 ACS/CCS patients at the beginning of a CR program. Extreme CV risk will be retrospectively defined as the presence of a previous (within 2 years) CV events in the patients' clinical history. UA, Lp(a) and inflammatory markers (interleukin-6 and -18, tumor necrosis factor alpha, C-reactive protein, calprotectin and osteoprotegerin) will be assessed in ACS/CCS patients with extreme CV risk and compared with those without extreme CV risk but also with two control groups: 1180 hypertensives and 765 healthy subjects. The association between these biomarkers and extreme CV risk will be assessed with a multivariable model and two scoring systems will be created for an accurate identification of extreme CV risk patients. The first one will use only clinical variables while the second one will introduce the biochemical markers. Finally, by exome sequencing we will both evaluate polygenic risk score ability to predict recurrent events and perform mendellian randomization analysis on CV biomarkers. CONCLUSIONS: Our study proposal was granted by the European Union PNRR M6/C2 call. With this study we will give definitive data on extreme CV risk prevalence rising attention on this condition and leading cardiologist to do a better diagnosis and to carry out a more intensive treatment optimization that will finally leads to a reduction of future ACS recurrence. This will be even more important for cardiologists working in CR that is a very important place for CV risk definition and therapies refinement.

Immune-Checkpoint Inhibitor-Related Myocarditis: Where We Are and Where We Will Go.

Immune checkpoint inhibitors (ICIs) are specific monoclonal antibodies directed against inhibitory targets of the immune system, mainly represented by programmed death-1 (PD1) ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), thus enabling an amplified T-cell-mediated immune response against cancer cells. These drugs have significantly improved prognosis in patients with advanced metastatic cancer (e.g., melanoma, non-small cell lung cancer, renal cell carcinoma). However, uncontrolled activation of anti-tumor T-cells could trigger an excessive immune response, possibly responsible for multi-organ damage, including, among others, lymphocytic myocarditis. The incidence of ICIs-induced myocarditis is underestimated and the patients affected are poorly characterized. The diagnosis and management of this condition are mainly based on expert opinion and case reports. EKG and ultrasound are tests that can help identify patients at risk of myocarditis during treatment by red flags, such as QRS complex enlargement and narrowing of global longitudinal strain (GLS). Therapy of ICI-related myocarditis is based on immunosuppressors, monoclonal antibodies and fusion proteins. A future strategy could involve the use of microRNAs. This review considers the current state of the art of immune-related adverse cardiovascular events, focusing on histological and clinical features, diagnosis and management, including current treatments and future pharmacological targets.

Retraction of: "Differential effects of the phosphodiesterase inhibition in chronic heart failure depending on the echocardiographic phenotype (HFREF or HFpEF): a meta-analysis".

The paper entitled "Differential effects of the phosphodiesterase inhibition in chronic heart failure depending on the echocardiographic phenotype (HFREF or HFpEF): a meta-analysis" by Renato De Vecchis et al., which was published in Minerva Cardioangiologica 2018 October;66(5):659-70, has been retracted by the Publisher due to plagiarism.

Visceral adipose tissue and residual cardiovascular risk: a pathological link and new therapeutic options.

Obesity is a heterogeneous disease that affects almost one-third of the global population. A clear association has been established between obesity and cardiovascular disease (CVD). However, CVD risk is known to be related more to the local distribution of fat than to total body fat. Visceral adipose tissue (VAT) in particular has a high impact on CVD risk. This manuscript reviews the role of VAT in residual CV risk and the available therapeutic strategies for decreasing residual CV risk related to VAT accumulation. Among the many pathways involved in residual CV risk, obesity and particularly VAT accumulation play a major role by generating low-grade systemic inflammation, which in turn has a high prognostic impact on all-cause mortality and myocardial infarction. In recent years, many therapeutic approaches have been developed to reduce body weight. Orlistat was shown to reduce both weight and VAT but has low tolerability and many drug-drug interactions. Naltrexone-bupropion combination lowers body weight but has frequent side effects and is contraindicated in patients with uncontrolled hypertension. Liraglutide and semaglutide, glucagon-like peptide 1 (GLP-1) agonists, are the latest drugs approved for the treatment of obesity, and both have been shown to induce significant body weight loss. Liraglutide, semaglutide and other GLP-1 agonists also showed a positive effect on CV outcomes in diabetic patients. In addition, liraglutide showed to specifically reduce VAT and inflammatory biomarkers in obese patients without diabetes. GLP-1 agonists are promising compounds to limit inflammation in human visceral adipocytes.

Understanding the role of coronary artery revascularization in patients with left ventricular dysfunction and multivessel disease.

Coronary artery disease (CAD) is the most common cause of heart failure with reduced ejection fraction (HFrEF). Advances and innovations in medical therapy have been shown to play a crucial role in improving the prognosis of patients with CAD and HFrEF; however, mortality rate in these patients remains high, and the role of surgical and/or percutaneous revascularization strategy is still debated. The Surgical Treatment for Ischemic Heart Failure (STICH) trial and the Revascularization for Ischemic Ventricular Dysfunction (REVIVED) trial have attempted to provide an answer to this issue. Nevertheless, the results of these two trials have generated further uncertainties. Their findings do not provide a definitive answer about the ideal clinical phenotype for surgical or percutaneous coronary revascularization and dispute the historical dogma on myocardial viability and the theory of myocardial hibernation, raising new questions about the proper selection of patients who are candidates for coronary revascularization. The aim of this review is to provide an overview on the actual available evidence of coronary artery revascularization in patients with CAD and left ventricular dysfunction and to suggest new insights on the proper selection and management strategies in this high-risk clinical setting.

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.

Impact of SGLT2-inhibitors on contrast-induced acute kidney injury in diabetic patients with acute myocardial infarction with and without chronic kidney disease: Insight from SGLT2-I AMI PROTECT registry.

AIMS: To analyze the association between chronic SGLT2-I treatment and development of contrast-induced acute kidney injury (CI-AKI) in diabetic patients with acute myocardial infarction (AMI) undergoing PCI. METHODS: Multicenter international registry of consecutive patients with type 2 diabetes mellitus (T2DM) and AMI undergoing PCI between 2018 and 2021. The study population was stratified by the presence of chronic kidney disease (CKD) and anti-diabetic therapy at admission (SGLT2-I versus non-SGLT2-I users). RESULTS: The study population consisted of 646 patients: 111 SGLT2-I users [28 (25.2%) with CKD] and 535 non-SGLT2-I users [221 (41.3%) with CKD]. The median age was 70 [61-79] years. SGLT2-I users exhibited significantly lower creatinine values at 72 h after PCI, both in the non-CKD and CKD stratum. The overall rate of CI-AKI was 76 (11.8%), significantly lower in SGLT2-I users compared to non-SGLT2-I patients (5.4% vs 13.1%, p = 0.022). This finding was also confirmed in patients without CKD (p = 0.040). In the CKD cohort, SGLT2-I users maintained significantly lower creatinine values at discharge. The use of SGLT2-I was an independent predictor of reduced rate of CI-AKI (OR 0.356; 95%CI 0.134-0.943, p = 0.038). CONCLUSION: In T2DM patients with AMI, the use of SGLT2-I was associated with a lower risk of CI-AKI, mostly in patients without CKD.