MODULAZIONE DELLA RISPOSTA INFIAMMATORIA NELLA PREVENZIONE DELLA RESTENOSI POST STENT CORONARICO: IL TRIAL CLINICO MULTICENTRICO RANDOMIZZATO \u201cCEREA-DES\u201d

Obiettivo: \ue8 conosciuto che l\u2019aterosclerosi coronarica e la restenosi intra-stent sono processi in gran parte regolari da meccanismi infiammatori sistemici. Questo studio ha arruolato pazienti con coronarosclerosi significativa trattabile con angioplastica coronarica ed impianto di stent. Lo scopo dello studio \ue8 la comparazione dei risultati clinici ottenuti in un gruppo di controllo trattato con impianto di stent metallici (BMS) con due gruppi in trattamento: impianto di BMS e terapia orale con prednisone o impianto di stent a rilascio di farmaco (DES), in presenza di terapia medica ottimale per tutti i gruppi. In un sottogruppo di pazienti si \ue8 indagato il rilascio di interleuchina-6 (IL-6), tumor necrosis factor-a (TNF-a) e l\u2019attivazione di NF-kB in monociti circolanti. Si \ue8 anche studiata una possibile relazione tra il pattern di attivazione monocitaria e la crescita neointimale che segue l\u2019impianto di uno stent metallico. Metodi: in 5 centri ospedalieri italiani di alta specializzazione sono stati arruolati 375 pazienti non diabetici con patologia coronarica, senza controindicazioni ad eseguire doppia terapia antiaggregante o terapia corticosteroidea, nel contesto di uno studio clinico randomizzato, controllato ed indipendente, condotto tra il 2007 ed il 2009. I pazienti sono stati allocati in tre gruppi da 125 soggetti ciascuno: BMS (gruppo di controllo), BMS e trattamento orale con alte dosi di prednisone a scalare per 40 giorni (gruppo BMS+prednisone) oppure stent medicato (gruppo DES). L\u2019end-point primario era rappresentato dalla sopravvivenza libera da morte cardiovascolare, infarto miocardico, e ricorrenza di ischemia con necessit\ue0 di nuova rivascolarizzazione sul vaso responsabile ad un anno di follow-up. Gli eventi clinici sono stati assegnati da un comitato indipendente preposto all\u2019incarico. Inoltre, 40 pazienti sono entrati a far parte del sottostudio volto ad esaminare il pattern di attivazione monocitaria (20 pazienti dal gruppo BMS e 20 pazienti da gruppo BMS+Prednisone). In questo gruppo \ue8 stato dosato il rilascio di IL-6, TNF-a e l\u2019attivazione di NF-kB da monociti periferici non stimolati e stimolati con LPS o PMA, al basale e dopo 10 e 30 giorni dalla procedura. Il Late Lumen Loss (LLL) al controllo angiografico (in media 9 mesi dalla procedura indice) \ue8 stato calcolato attraverso l\u2019analisi coronarica quantitativa (QCA). Risultati: \ue8 stato raccolto il follow-up a 12 mesi per tutti i pazienti arruolati. I pazienti del gruppo di controllo (BMS) hanno mostrato una sopravvivenza libera da eventi cardiaci minore rispetto a quella dei pazienti trattati con DES o BMS+Prednisone. L\u2019end-point primario era dell\u201980.8% nel gruppo BMS, dell\u201988.0% nel gruppo BMS+Prednisone e dell\u201988.8% nel gruppo DES (rispettivamente p=0.04 e p=0.006 rispetto ai controlli). I benefici della terapia steroidea apparivano concentrati in quei pazienti con infiammazione attivata, in cui si riscontrava quindi una proteina C reattiva ad alta sensibilit\ue0 (hs-PCR) elevata. La terapia con prednisone utilizzata nello studio si \ue8 dimostrata ben tollerabile, essendo gli effetti collaterali riscontrati in genere di lieve entit\ue0 e reversibili (soprattutto edemi e ritenzione idrica). Le concentrazioni plasmatiche di prednisone correlavano inversamente con il rilascio monocitario di IL-e TNF-a (rispettivamente R2 = 0.45,p = 0.04 and R2 = 0.69, p = 0.005) e con l\u2019attivazione di NF-kB (R2 = 0.58, p = 0.01). La riduzione del rilascio di TNF-a e l\u2019attivazione di NF-kB risultavano significativamente correlate (R2 = 0.56, p = 0.01). I pazienti in terapia con prednisone mostravano una riduzione del rilascio di citochine proinfiammatorie e dell\u2019attivazione di TNF-a a 10 e 30 giorni significativamente maggiori rispetto ai soggetti non trattati. I valori di LLL al follow-up angiografico risultavano significativamente minori nel gruppo prednisone (0.44\ub10.35mm vs 0.80\ub10.53mm, p = 0.02) e correlavano con la riduzione del rilascio di TNF-a (R2 = 0.41,p = 0.01). Conclusioni: Il trattamento con DES o BMS+Prednisone, rispetto all\u2019impianto del solo BMS, si accompagna ad una maggiore sopravvivenza libera da eventi cardiaci ad un anno dalla procedura. Si confermano precedenti esperienze di ricerca che indicano i pazienti con infiammazione attivata (elevata hs-PCR) come coloro che maggiormente possono beneficiare della terapia steroidea. La terapia steoidea a dosaggio immunosoppressivo, somministrata per via orale in un limitato periodo di tempo (40 giorni) \ue8 efficace nel ridurre l\u2019attivazione monocitaria mediata dalla via del fattore trascrizionale NF-kB ed il conseguente rilascio di citochine pro-infiammatorie in pazienti trattati con stenting coronarico. La riduzione del rilascio di TNF-a correla con la riduzione di LLL al follow-up angiografico, confermando cos\uec il razionele del potenziale beneficio della terapia con prednisone nella prevenzione della restenosi intra-stent.Objective: it is known that coronary atherosclerosis and in-stent restenosis are largely ruled by inflammatory mechanisms. This study enrolled patients with coronary artery disease amenable to percutaneous coronary interventions and stent implantation. Its aim was to compare the clinical outcome obtained in a control group of patients treated with bare metal stent (BMS) versus other two study groups: BMS plus oral prednisone or drug eluting stents (DES), all assuming similar optimal adjunctive medical treatment. In a subgroup of patients the release of interleukin-6 (IL-6), tumour necrosis factor (TNF-a) and NF-kB activation in circulating monocytes were studied and also related with the neointimal growth that follows bare metal stent (BMS) implantation. Methods: five tertiary Italian hospitals enrolled 375 non-diabetic patients with coronary artery disease and no contraindications to dual anti-platelet treatment or corticosteroid therapy in a randomized, controlled, independent study performed between 2007 and 2009. Patients were allocated into three study groups of 125 patients each: BMS (controlgroup), BMS followed by a 40-day prednisone treatment (BMS and prednisone group) or DES (DES group). Primary endpoint was the event-free survival of cardiovascular death, myocardial infarction and recurrence of ischemia needing repeated target vessel revascularization at one year as adjudicated by an independent clinical events committee. Moreover, 40 patients (20 from the control group and 20 from the Prednisone group) entered the monocyte activation sub-study. The release of IL-6, TNF-a and NF-kB p50 subunit translocation at baseline, at 10 and 30 days were evaluated from peripheral non-stimulated and stimulated (LPS and PMA) monocytes. Late luminal loss (LLL) 9 months after angioplasty was calculated by quantitative coronary angiography. Results: one-year follow-up was obtained in all patients. Patients receiving BMS alone as compared to those treated with prednisone or DES had lower event-free survival; the primary endpoint was 80.8% in controls compared to 88.0% in the BMS and prednisone and 88.8% in the DES groups respectively (p=0.04 and p=0.006). The benefits of the steroids appear to be restricted to patients with an activated inflammation, identified by an elevated hs-PCR. Prednisone therapy resulted well tolerated and generally associated with mild and reversible side effects. Plasma concentrations of prednisone correlated inversely with IL-6 and TNF-a release (R2 = 0.45,p = 0.04 and R2 = 0.69, p = 0.005, respectively) and NF-kB activation from monocytes (R2 = 0.58, p = 0.01). The reduction of TNF-a release and NF-kB activation were significantly related (R2 = 0.56, p = 0.01). Prednisone patients showed a significantly larger reduction of cytokine release and NF-kB activation compared to non-treated patients, at 10 days and 30 days. LLL was lower in the prednisone group (0.44\ub10.35mm versus 0.80\ub10.53mm, p = 0.02) and correlated with reduction of TNF-a (R2 = 0.41,p = 0.01). Conclusions: as compared with BMS alone, prednisone treatment after BMS or DES implantation result in a better event-free survival at one year. Previous observations on the benefits of the steriods in patients with active inflammation (elevated hs-PCR) are confirmed. High doses of oral prednisone reduce NF-kB pathway activation and pro-inflammatory cytokine release in circulating activated monocytes of patients treated with coronary stenting. TNF-a release reduction correlates with decreased LLL, confirming a potential benefit of steroid therapy in preventing in-stent restenosis

Ten-Year Experience with Endomyocardial Biopsy after Orthotopic Heart Transplantation: Comparison between Trans-Jugular and Trans-Femoral Approach

Background: Endomyocardial biopsy (EMB) is considered the gold standard for monitoring allograft rejection after heart transplantation. EMB is an invasive procedure that may be performed via a trans-jugular or a trans-femoral approach with a complication rate reported as less than 6%. The aim of this study was to evaluate the complication rate after EMBs in heart recipients and to compare the results of EMBs performed via a trans-jugular or a trans-femoral approach. Methods: Medical records of heart recipients undergoing EMBs between January 2012 and December 2022 were retrospectively reviewed. EMB-related complications were classified as major (death, pericardial effusion, hemopericardium, cardiac tamponade requiring a pericardiocentesis or an urgent cardiac surgery, ventricular arrythmias, permanent atrio-ventricular block requiring permanent pacing, hemothorax, pneumothorax and retroperitoneal bleeding) and minor (de novo tricuspid regurgitation, arrhythmias, coronary artery fistula, vascular access site complications). Results: A total of 1698 EMBs were performed during the study period at our institution in 212 heart recipients. There were 927 (55%) EMBs performed through a trans-jugular approach (TJ group) and 771 (45%) EMBs performed through a trans-femoral approach (TF group). A total of 60 (3.5%) complications were recorded, including nine (0.5%) major complications (six cardiac tamponades, two pneumothorax and one retroperitoneal bleeding) and 51 (3%) minor complications (seven coronary fistulae, five de novo tricuspid regurgitation, four supraventricular arrythmias and thirty-five vascular access site complications). No difference was found in total (38 [4%] vs. 22 [3%]; p = 0.16) and major (6 [1%} vs. 3 [0.4%]; p = 0.65) complications (32 [3%] vs. 19 [2%]; p = 0.23) between the TJ group and the TF group. No difference was found in male sex, age at time of EMB and time from HT between complicated and not complicated EMBs. Conclusions: EMBs represent a safe procedure with a low risk of complications. In our experience, EMBs performed via a trans-jugular approach are as safe as the trans-femoral approach

devices for mechanical circulatory support and strategies for their management in cardiogenic shock

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Proof of concept study on coronary microvascular function in low flow low gradient aortic stenosis

ObjectivesWe hypothesised that low flow low gradient aortic stenosis (LFLGAS) is associated with more severe coronary microvascular dysfunction (CMD) compared with normal-flow high-gradient aortic stenosis (NFHGAS) and that CMD is related to reduced cardiac performance. MethodsInvasive CMD assessment was performed in 41 consecutive patients with isolated severe aortic stenosis with unobstructed coronary arteries undergoing transcatheter aortic valve implantation (TAVI). The index of microcirculatory resistance (IMR), resistive reserve ratio (RRR) and coronary flow reserve (CFR) were measured in the left anterior descending artery before and after TAVI. Speckle tracking echocardiography was performed to assess cardiac function at baseline and repeated at 6 months. ResultsIMR was significantly higher in patients with LFLGAS compared with patients with NFHGAS (24.1 (14.6 to 39.1) vs 12.8 (8.6 to 19.2), p=0.002), while RRR was significantly lower (1.4 (1.1 to 2.1) vs 2.6 (1.5 to 3.3), p=0.020). No significant differences were observed in CFR between the two groups. High IMR was associated with low stroke volume index, low cardiac output and reduced peak atrial longitudinal strain (PALS). TAVI determined no significant variation in microvascular function (IMR: 16.0 (10.4 to 26.1) vs 16.6 (10.2 to 25.6), p=0.403) and in PALS (15.9 (9.9 to 26.5) vs 20.1 (12.3 to 26.7), p=0.222). Conversely, left ventricular (LV) global longitudinal strain increased after TAVI (-13.2 (8.4 to 16.6) vs -15.1 (9.4 to 17.8), p=0.047). In LFLGAS, LV systolic function recovered after TAVI in patients with preserved microvascular function but not in patients with CMD. ConclusionsCMD is more severe in patients with LFLGAS compared with NFHGAS and is associated with low-flow state, left atrial dysfunction and reduced cardiac performance

Intracoronary physiology-guided percutaneous coronary intervention in patients with diabetes

Objective: The risk of vessel-oriented cardiac adverse events (VOCE) in patients with diabetes mellitus (DM) undergoing intracoronary physiology-guided coronary revascularization is poorly defined. The purpose of this work is to evaluate the risk of VOCE in patients with and without DM in whom percutaneous coronary intervention (PCI) was performed or deferred based on pressure-wire functional assessment. Methods: This is a retrospective analysis of a multicenter registry of patients evaluated with fractional flow reserve (FFR) and/or non-hyperaemic pressure ratio (NHPR). Primary endpoint was a composite of VOCE including cardiac death, vessel-related myocardial infarction (MI), and ischemia-driven target vessel revascularization (TVR). Results: A large cohort of 2828 patients with 3353 coronary lesions was analysed to assess the risk of VOCE at long-term follow-up (23 [14-36] months). Non-insulin-dependent-DM (NIDDM) was not associated with the primary endpoint in the overall cohort (adjusted Hazard Ratio [aHR] 1.18, 95% CI 0.87-1.59, P = 0.276) or in patients with coronary lesions treated with PCI (aHR = 1.30, 95% CI 0.78-2.16, P = 0.314). Conversely, insulin-dependent diabetes mellitus (IDDM) demonstrated an increased risk of VOCE in the overall cohort (aHR 1.76, 95% CI 1.07-2.91, P = 0.027), but not in coronary lesions undergoing PCI (aHR 1.26, 95% CI 0.50-3.16, P = 0.621). Importantly, in coronary lesions deferred after functional assessment IDDM (aHR 2.77, 95% CI 1.11-6.93, P = 0.029) but not NIDDM (aHR = 0.94, 95% CI 0.61-1.44, P = 0.776) was significantly associated with the risk of VOCE. IDDM caused a significant effect modification of FFR-based risk stratification (P for interaction < 0.001). Conclusion: Overall, DM was not associated with an increased risk of VOCE in patients undergoing physiology-guided coronary revascularization. However, IDDM represents a phenotype at high risk of VOCE

Clinical outcomes of transcatheter aortic valve implantation: from learning curve to proficiency

Objective: The use of transcatheter aortic valve implantation (TAVI) is growing rapidly in countries with a predominantly elderly population, posing a huge challenge to healthcare systems worldwide. The increment of human and economic resource consumption imposes a careful monitoring of clinical outcomes and cost-benefit balance, and this article is aimed at analysing clinical outcomes related to the TAVI learning curve.Methods: Outcomes of 177 consecutive transfemoral TAVI procedures performed in 5 years by a single team were analysed by the Cumulative Sum of failures method (CUSUM) according to the clinical events comprised in the Valve Academic Research Consortium (VARC-2) safety end point and the VARC-2 definition of device success. Margins for events acceptance were extrapolated from landmark trials that tested both balloon or self-expandable percutaneous valves.Results: 30-day and 1-year survival rates were 97.2% and 89.9%, respectively. Achievement of the primary end point (number of cases needed to provide the acceptable margin of the composite end point of any death, stroke, myocardial infarction, life-threatening bleeding, major vascular complications, stage 2-3 acute kidney injury and valve-related dysfunction requiring a repeat procedure) required the performance of 54 cases, while the learning curve to achieve 'device success' identified 32 cases to reach the expected proficiency. In this experience, the baseline clinical risk as assessed by the Society of Thoracic Surgeons (STS) score determined the long-term survival rather than the adverse events related to the learning curve.Conclusions: A relatively large number of cases are required to achieve clinical outcomes comparable to those reported in high-volume centres and controlled trials. According to our national workload standards, this represents more than 2 years of continuous activity

The promise of vascular reparative therapy in standby mode. How long before a final decision? Complete vessel wall regeneration and vascular scaffold resorption after left anterior descending reconstructions

The promise of vascular reparative therapy in standby mode. How long before a final decision? Complete vessel wall regeneration and vascular scaffold resorption after left anterior descending reconstructions

Current Antithrombotic Therapy in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Interventions

: Acute coronary syndromes (ACS) represent a life-threatening complication of the systemic atherosclerotic process, affecting the coronary circulation. Thrombosis, defined as an uncontrolled activation of the endogenous thrombogenetic reparative process, often follows atherosclerotic plaque damage and is mainly engaged by two main pathways: platelet aggregation and coagulation. Therefore, antithrombotic therapy to modulate either pathway plays an important role for the reduction of ischaemic adverse events in ACS patients. Since the advent of aspirin and warfarin, numerous antiaggregant and anticoagulant molecules have been developed to achieve this goal, but their anti-ischaemic efficacy is often obtained at the price of augmented bleedings, which are known to be strong predictors of adverse outcome. This article briefly reviews the physiopathological mechanisms of thrombosis and presents an overview of the available literature supporting the use of these major drugs, as well as the European Society of Cardiology recommendations for their utilisation in the setting of non-ST and ST-elevation myocardial infarction undergoing invasive treatment

Choosing transcatheter aortic valve replacement in porcelain aorta: outcomes versus surgical replacement

commentary on choosing transcatheter aortic valve replacement in porcelain aort