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Abstract Percutaneous coronary intervention (PCI) has evolved significantly over the past four decades. Since its inception, in-stent restenosis (ISR)-the progressive reduction in vessel lumen diameter after PCI-has emerged as the main complication of the procedure. Although the incidence of ISR has reduced from 30% at 6 months with bare-metal stents to 7% at 4 years with drug-eluting stents (DESs), its occurrence is relevant in absolute terms because of the dimensions of the population treated with PCI. The aim of this review is to summarize the emerging understanding of the biological pathways that underlie ISR. In-stent restenosis is associated with several factors, including patient-related, genetic, anatomic, stent, lesion, and procedural characteristics. Regardless of associated factors, there are common pathophysiological pathways involving molecular phenomena triggered by the mechanical trauma caused by PCI. Such biological pathways are responses to the denudation of the intima during balloon angioplasty and involve inflammation, hypersensitivity reactions, and stem cell mobilization particularly of endothelial progenitor cells (EPCs). The results of these processes are either vessel wall healing or neointimal hyperplasia and/or neo-atherosclerosis. Unravelling the key molecular and signal pathways involved in ISR is crucial to identify appropriate therapeutic strategies aimed at abolishing the 'Achille's heel' of PCI. In this regard, we discuss novel approaches to prevent DES restenosis. Indeed, available evidence suggests that EPC-capturing stents promote rapid stent re-endothelization, which, in turn, has the potential to decrease the risk of stent thrombosis and allow the use of a shorter-duration dual antiplatelet therapy. Graphical Abstract Graphical Abstract

Statins are extensively used to treat dyslipidemia, but, because of their low tolerability profile, they are discontinued in a significant proportion of patients. Ezetimibe and nutraceuticals have been introduced as alternative therapies and have proved to be effective and well tolerated. A single-blind, single-center, randomized, prospective, and parallel group trial comparing a combination of nutraceuticals (red yeast rice, policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin), called Armolipid Plus, and ezetimibe for 3 months in terms of efficacy and tolerability. Patients who did not achieve their therapeutic target (low-density lipoprotein cholesterol <100 mg/dl) could add the alternative treatment on top of randomized treatment for another 12 months: 100 patients who are dyslipidemic with ischemic heart disease treated with percutaneous coronary intervention were enrolled (ezetimibe n = 50, nutraceutical n = 50). Efficacy (lipid profile) and tolerability (adverse events, transaminases, and creatine kinase) were assessed after 3 and 12 months. After 3 months, 14 patients in the nutraceutical group achieved their therapeutic target, whereas none of the patients in the ezetimibe group did. At 1-year follow-up, 58 patients (72.5%) of the combined therapy group (n = 86) and 14 (100%) of the nutraceutical group reached the therapeutic goal. No patients experienced important undesirable effects. In conclusion, nutraceuticals alone or in combination with ezetimibe are well tolerated and improve the lipid profile in statin-intolerant patients with coronary heart disease. Further studies are needed to assess long-term effects of nutraceuticals on mortality.

Aortic stenosis (AS) remains the most prevalent valvular heart disease worldwide and is increasingly managed through transcatheter aortic valve implantation (TAVI). With the 2025 ESC/EACTS Guidelines lowering the age threshold for TAVI to 70 years, the focus has shifted from short-term survival to lifetime management, necessitating rigorous evaluation of device durability, coronary access, and biological valve degeneration. This review synthesizes the latest evidence-based strategies for TAVI, contrasting randomized trial data with long-term registry findings. We critically analyze the hemodynamic trade-offs between self-expandable valves and balloon-expandable valves, particularly in patients with small aortic annuli, where SEVs demonstrate superior indexed effective orifice areas and reduced rates of patient-prosthesis mismatch (SMALL-TAVI registry). We further examine the expansion of indications into complex anatomical subsets, including bicuspid aortic valves (BIVOLUTX, STABILITY) and pure aortic regurgitation, where dedicated anchoring mechanisms are required to mitigate the risk of valve migration. Procedural optimization is addressed through the \"minimalist\" TAVI pathway (BENCHMARK registry), which emphasizes conscious sedation and ultrasound-guided vascular access to reduce length of stay without compromising safety. Finally, we discuss emerging biomarkers (MMP-3, osteopontin) and the role of epicardial adipose tissue as novel predictors of structural valve deterioration, signaling a potential shift toward biological modulation of valvular disease.

We pooled available data on follow-up events in patients with patent foramen ovale and cryptogenic stroke to evaluate the net clinical benefit of different therapeutic strategies (percutaneous closure vs antiplatelet vs anticoagulant therapy). MEDLINE/PubMed and Cochrane databases and reviewed cited references to identify relevant studies were used; 3,311 patients from 21 clinical studies, both observational and randomized, with follow-up ≥12 months were overall included. Net clinical benefit was evaluated considering the cumulative incidence of both stroke and/or transient ischemic attack and major bleeding events. Anticoagulant therapy was more effective than antiplatelet therapy in preventing recurrent stroke and/or transient ischemic attack (event rates: 7.7% vs 9.8%, respectively, p = 0.03), but at the price of more than sixfold greater risk of major bleeding (7.1% vs 1.3%; odds ratio 6.49, 95% confidence interval 3.25 to 12.99, p <0.00001). Patent foramen ovale closure was associated over the long term with significant net clinical benefit versus both antiplatelet and anticoagulant therapy; such benefit was driven by 50% relative reduction of stroke and/or transient ischemic attack versus antiplatelet therapy and by 82% relative reduction of major bleeding versus anticoagulant therapy. In conclusion, results of this large study-level meta-analysis may influence practice patterns in patients with patent foramen ovale and cryptogenic stroke; an individualized approach tailored on both the risk of recurrent cerebral events and the bleeding risk should be used to identify the best therapeutic option (percutaneous closure vs antiplatelet therapy vs anticoagulant therapy).

Acute coronary syndrome, cardiac surgery, and cardiac structural interventions are among the most common situations leading to allogeneic red blood cell consumption due to the prevalence of bleeding and anemia. The wide variability in the use of transfusions derives from the current lack of data, and the absence of strong evidence and clear guideline recommendations. The current approach is to avoid unnecessary blood transfusions and limit their use to life-saving conditions; this conservative strategy derives from often controversial and inconclusive results of observational and randomized studies where liberal and restricted red blood transfusion strategies seemed to have similar outcomes. The pivotal question for future research lies in elucidating whether blood transfusions function as an active participant or merely a catalyst in amplifying adverse events. The present review aims to summarize the current literature data and critically analyze the available evidence for red blood transfusions in cardiac interventions.

Although the entire vascular bed is constantly exposed to the same risk factors, atherosclerosis manifests a distinct intra-individual pattern in localization and progression within the arterial vascular bed. Despite shared risk factors, the development of atherosclerotic plaques is influenced by physical principles, anatomic variations, metabolic functions, and genetic pathways. Biomechanical factors, particularly wall shear stress (WSS), play a crucial role in atherosclerosis and both low and high WSS are associated with plaque progression and heightened vulnerability. Low and oscillatory WSS contribute to plaque growth and arterial remodeling, while high WSS promotes vulnerable changes in obstructive coronary plaques. Axial plaque stress and plaque structural stress are proposed as biomechanical indicators of plaque vulnerability, representing hemodynamic stress on stenotic lesions and localized stress within growing plaques, respectively. Advancements in imaging and computational fluid dynamics techniques enable a comprehensive analysis of morphological and hemodynamic properties of atherosclerotic lesions and their role in plaque localization, evolution, and vulnerability. Understanding the impact of mechanical forces on blood vessels holds the potential for developing shear-regulated drugs, improving diagnostics, and informing clinical decision-making in coronary atherosclerosis management. Additionally, Computation Fluid Dynamic (CFD) finds clinical applications in comprehending stent-vessel dynamics, complexities of coronary bifurcations, and guiding assessments of coronary lesion severity. This review underscores the clinical significance of an integrated approach, concentrating on systemic, hemodynamic, and biomechanical factors in atherosclerosis and plaque vulnerability among patients with coronary artery disease.

Primary percutaneous coronary intervention (PCI) is the current class I therapeutic approach to treat acute ST-elevation myocardial infarction (STEMI). While primary PCI can restore adequate flow in the infarcted artery in the majority of cases, some patients experience the 'no-reflow' phenomenon, i.e., an abnormal myocardial reperfusion occurring even after the occluded coronary artery has been opened. No-reflow occurs when microvascular obstruction arises from embolization of thrombus or components of the atheromatous plaques. These embolic materials travel downstream within the infarct-related artery at time of primary PCI, leading to compromised blood flow. Currently, no expert consensus documents exist to outline an optimal strategy to prevent or treat no-reflow. Interventional cardiologists frequently employ intracoronary adenosine, calcium channel blockers, nicorandil, nitroprusside or glycoprotein IIb/IIIa inhibitors. However, evidence suggests that these interventions consistently enhance myocardial blood flow in only a specific subset of patients experiencing no-reflow. A recent and innovative therapeutic approach gaining attention is low-dose fibrinolysis during primary PCI, which offers the potential to augment coronary flow post-myocardial revascularization.

Ranolazine is a new antianginal drug that reduces intracellular sodium and calcium accumulation during ischemia, thus potentially limiting myocardial ischemia. It remains unknown, however, if the drug can play a role in the pathophysiology of periprocedural myocardial infarction. The aim of this study was to verify in a randomized study if pretreatment with ranolazine before percutaneous coronary intervention (PCI) has any protective effect on periprocedural myocardial damage. Seventy patients with stable angina (age 62 ± 18 years, 42 men) scheduled for elective coronary intervention entered a randomized, double-blind, placebo-controlled pilot trial. For 7 days before the procedure, 35 patients were assigned to receive ranolazine (1,000 mg twice daily) and 35 patients had placebo. Creatine kinase-MB and troponin I levels were measured at baseline and at 8 and 24 hours postprocedure. Comparison between the 2 groups did not show any difference in clinical features, extent of coronary artery disease, and technical aspects of PCI. Periprocedural myocardial infarction (ie, postprocedural increase of creatine kinase-MB ≥3 times above the upper limit of normal) was less commonly seen after PCI in the ranolazine than in the placebo group (6% vs 22%, P = .041). Detection of markers of myocardial injury above the upper limit of normal tended to be lower in the ranolazine vs placebo group: 23% vs 40% for creatine kinase-MB (P = .192) and 31% vs 48% for troponin I (P = .223). Postprocedural peak markers levels were also significantly lower in the ranolazine vs placebo group (creatine kinase-MB: 3.1 ± 15.0 and 7.7 ± 19.1 ng/mL, P < .05; troponin I: 0.15 ± 0.35 and 0.47 ± 0.49 ng/mL, P < .05). No significant adverse effect was reported by the 2 groups of patients. Pretreatment with ranolazine 1,000 mg twice daily for 7 days significantly reduced procedural myocardial injury in elective PCI.

Thrombus aspiration during percutaneous coronary intervention can result in improved rates of normal epicardial flow and myocardial perfusion, but several unmet needs remain. The purpose of the Delivery of thrombolytIcs before thrombectomy in patientS with ST-segment elevatiOn myocardiaL infarction Undergoing primary percuTaneous coronary interventION (DISSOLUTION) trial was to evaluate the hypothesis that local delivery of thrombolytics can enhance the efficacy of thrombus aspiration in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. A total of 102 patients with ST-segment elevation myocardial infarction and angiographic evidence of massive thrombosis in the culprit artery were randomly assigned to receive a local, intrathrombus bolus of 200,000 U of urokinase (n = 51) or saline solution (n = 51) by way of an infusion microcatheter, followed by manual aspiration thrombectomy. The end points included the final Thrombolysis In Myocardial Infarction flow grade and frame count, myocardial blush grade, 60-minute ST-segment resolution >70%, and major adverse cardiac and cerebrovascular events, defined as the death, reinfarction, stroke, or clinically driven target vessel revascularization at 6 months. The use of intrathrombus urokinase was associated with a significantly higher incidence of Thrombolysis In Myocardial Infarction flow grade 3 (90% vs 66%, p = 0.008) and lower postpercutaneous coronary intervention Thrombolysis In Myocardial Infarction frame count (19 ± 15 vs 25 ± 17, p = 0.033). The postprocedural myocardial perfusion was significantly increased with the use of urokinase (myocardial blush grade 2 or 3, 68% vs 45%, p = 0.028), with more patients showing ST-segment resolution >70% (82% vs 55%, p = 0.006). At 6 months of follow-up, the patients treated with intrathrombus urokinase showed a better major adverse cardiac event-free survival (6% vs 21%; log-rank p = 0.044). In conclusion, local, intrathrombus delivery of thrombolytics before manual thrombectomy improved the postprocedural coronary flow and myocardial perfusion and the 6-month clinical outcomes.