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Abstract Background The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. Methods We tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted. Results We identified two 9p21.3-variants, rs4977574 (P < 4×10-4) and rs2383207 (P < 1.5×10-3) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82×10-2. Further investigation showed that rs10738610 (P < 1.99×10-2) was found to be significantly associated with severity of CAD in subjects with T2D. Conclusions The 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes.

The Multidrug Resistance protein ( ABCB1 , MDR1 ) is involved in the transport of xenobiotics and antiretroviral drugs. Some variants of the ABCB1 gene are of clinical importance; among them, exon 12 (c.1236C>T, rs1128503), 21 (c.2677G>T/A, rs2032582), and 26 (c.3435C>T, rs1045642) have a high incidence in Caucasians. Several protocols have been used for genotyping the exon 21 variants, such as allele-specific PCR-RFLP using adapted primer to generate a digestion site for several enzymes and automatic sequencing to detect the SNVs, TaqMan Allele Discrimination assay and High-Resolution Melter analysis (HRMA). The aim was to describe a new approach to genotype the three variants c.2677G>T/A for the exon 21 doing only one PCR with the corresponding primers and the digestion of the PCR product with two restriction enzymes: BrsI to identify A allele and BseYI to differentiate between G or T. An improvement of this methodology was also described. The proposal technique here described is demonstrated to be very efficient, easy, fast, reproducible, and cost-effective.

Aim: Randomized controlled trials comparing the use of the MitraClip device in addition to guideline directed medical therapy (GDMT) to GDMT alone in patients with secondary mitral regurgitation (MR) have shown conflicting results. However, if these differences could be due to the underlying MR aetiology is still unknown. Therefore, we aimed to evaluate if the effects of percutaneous edge-to-edge repair with MitraClip implantation could differ in patients with ischaemic (I-MR) and non-ischaemic mitral regurgitation (NI-MR)., Methods and Results: PubMed, Embase, BioMed Central, and the Cochrane Central Register of Controlled Trials were searched for all studies including patients with secondary MR treated with the MitraClip device. Data were pooled using a random-effects model. Primary endpoint was the composite of all-cause death and heart failure-related hospitalization. Secondary endpoints were the single components of the primary endpoint, New York Heart Association functional Classes III and IV, and mitral valve re-intervention. Seven studies enrolling 2501 patients were included. Patients with I-MR compared with patients with NI-MR had a similar risk of the primary endpoint (odds ratio: 1.17; 95% confidence interval: 0.93 to 1.46; I 2 : 0%). The risk of all-cause death was increased in patients with I-MR (odds ratio: 1.31; 95% confidence interval: 1.07 to 1.62; I 2 : 0%), while no differences were observed between the two groups in terms of the other secondary endpoints., Conclusions: The risk of mortality after MitraClip implantation is lower in patients with NI-MR than in those with I-MR. No absolute differences in the risk of heart failure related hospitalization were observed between groups., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In Argentina, porphyria cutanea tarda (PCT) is strongly associated with infection with human immunodeficiency virus (HIV); however, whether the onset of this disease is associated with HIV infection and/or the antiretroviral therapy has not been determined. The ABCB1 gene variants c.1236C>T, c.2677G>T/A and c.3435C>T affect drug efflux. The GSTT1 null, GSTM1 null and GSTP1 (c.313A>G) gene variants alter Glutathione S-transferase (GST) activity, modifying the levels of xenobiotics. The aim of the present study was to evaluate the role of genetic variants in initiation of PCT and to analyze the genetic basis of the PCT-HIV association. Control individuals, and HIV, PCT and PCT-HIV patients were recruited, PCR-restriction fragment length polymorphism was used to genotype the ABCB1 and GSTP1 variants, and multiplex PCR was used to study the GSTM1 and GSTT1 variants. The high frequency of c.3435C>T (PCT and PCT-HIV) and c.1236C>T (PCT) suggested that the onset of PCT were not specifically related to HIV infection or antiretroviral therapy for these variants. c.2677G>T/A frequencies in the PCT-HIV patients were higher compared with the other groups, suggesting that a mechanism involving antiretroviral therapy served a role in this association. PCT-HIV patients also had a high frequency of GSTT1 null and low frequency for GSTM1 null variants; thus, the genetic basis for PCT onset may involve a combination between the absence of GSTT1 and the presence of GSTM1 . In conclusion, genes encoding for proteins involved in the flow and metabolism of xenobiotics may influence the PCT-HIV association. The present study is the first to investigate the possible role of GST and ABCB1 gene variants in the triggering of PCT in HIV-infected individuals, to the best of our knowledge, and may provide novel insights into the molecular basis of the association between PCT and HIV., (Copyright: © Pagnotta et al.)

The optimal antiplatelet strategy after left atrial appendage (LAA) occlusion able to protect from device-related thrombosis, paying the lowest price in terms of bleeding increase, is unclear. In a real-world, observational study we performed a head-to-head comparison of single versus dual antiplatelet therapy (SAPT vs DAPT) in patients who underwent LAA occlusion. We included 610 consecutive patients, stratified according to the type of post-procedural antiplatelet therapy (280 on SAPT and 330 on DAPT). Primary outcome measure was the incidence of the net composite end point including Bleeding Academic Research Consortium classification 3-5 bleeding, major adverse cardiovascular events or device-related thrombosis at 1-year follow-up. The use of SAPT compared with DAPT was associated with similar incidence of the primary net composite end point (9.3% vs 12.7% p = 0.22), with an adjusted hazard ratio (HR) of 0.69, 95% confidence interval 0.41 to 1.15; p = 0.15) at multivariate analysis. However, SAPT significantly reduced Bleeding Academic Research Consortium classification 3-5 bleeding (2.9% vs 6.7%, p = 0.038; adjusted HR 0.37, 0.16 to 0.88; p = 0.024). The occurrence of ischemic events (major adverse cardiovascular events or device-related thrombosis) was not significantly different between the 2treatment strategies (7.8% vs 7.4%; adjusted HR 1.34, 0.70 to 2.55; p = 0.38). In patients who underwent LAA occlusion, post-procedural use of SAPT instead of DAPT was associated with reduction of bleeding complications, with no significant increase in the risk of thrombotic events. These hypothesis-generating findings should be confirmed in a specific, randomized study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Risk stratification is crucial to optimise treatment strategies in patients with COVID-19. We aimed to evaluate the impact on mortality of an early assessment of cardiac biomarkers in patients with COVID-19., Methods: Humanitas Clinical and Research Hospital (Rozzano-Milan, Lombardy, Italy) is a tertiary centre that has been converted to the management of COVID-19. Patients with confirmed COVID-19 were entered in a dedicated database for cohort observational analyses. Outcomes were stratified according to elevated levels (ie, above the upper level of normal) of high-sensitivity cardiac troponin I (hs-TnI), B-type natriuretic peptide (BNP) or both measured within 24 hours after hospital admission. The primary outcome was all-cause mortality., Results: A total of 397 consecutive patients with COVID-19 were included up to 1 April 2020. At the time of hospital admission, 208 patients (52.4%) had normal values for cardiac biomarkers, 90 (22.7%) had elevated both hs-TnI and BNP, 59 (14.9%) had elevated only BNP and 40 (10.1%) had elevated only hs-TnI. The rate of mortality was higher in patients with elevated hs-TnI (22.5%, OR 4.35, 95% CI 1.72 to 11.04), BNP (33.9%, OR 7.37, 95% CI 3.53 to 16.75) or both (55.6%, OR 18.75, 95% CI 9.32 to 37.71) as compared with those without elevated cardiac biomarkers (6.25%). A multivariate analysis identified concomitant elevation of both hs-TnI and BNP as a strong independent predictor of all-cause mortality (OR 3.24, 95% CI 1.06 to 9.93)., Conclusions: An early detection of elevated hs-TnI and BNP predicts mortality in patients with COVID-19. Cardiac biomarkers should be systematically assessed in patients with COVID-19 at the time of hospital admission in order to optimise risk stratification., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients presenting with cardiogenic shock and severe combined aortic and mitral regurgitation represent a major clinical challenge. Therapeutic options are limited in this setting as they are often deemed inoperable due to prohibitive risk for surgery, while mechanical circulatory support is usually contraindicated or technically challenging. Medical therapy, on the other hand, is associated with high-mortality rates. Therefore, percutaneous therapies may represent an appealing alternative. Here, we present a "one-stop-shop" totally percutaneous approach for severe aortic and mitral regurgitation in a patient with cardiogenic shock., (© 2019 Wiley Periodicals, Inc.)

Objectives: The aim of this study was to evaluate and compare the outcomes of transcatheter self-expandable prostheses in patients with small annuli., Background: Transcatheter aortic heart valves appear to have better performance than surgical valves in terms of prosthesis-patient mismatch, especially in patients with aortic stenosis with small aortic annuli., Methods: TAVI-SMALL (International Multicenter Registry to Evaluate the Performance of Self-Expandable Valves in Small Aortic Annuli) is a retrospective registry of patients with severe aortic stenosis and small annuli (annular perimeter <72 mm or area <400 mm 2 on computed tomography) treated with transcatheter self-expandable valves (n = 859; Evolut R, n = 397; Evolut PRO, n = 84; ACURATE, n = 201; Portico, n = 177). Primary endpoints were post-procedural mean aortic gradient, indexed effective orifice area, and rate of severe prosthesis-patient mismatch., Results: Pre-discharge gradients were consistently low in every group, with a slight benefit with the Evolut R (8.1 mm Hg; 95% confidence interval [CI]: 7.7 to 8.5 mm Hg) and Evolut PRO (6.9 mm Hg; 95% CI: 6.3 to 7.6 mm Hg) compared with the ACURATE (9.6 mm Hg; 95% CI: 8.9 to 10.2 mm Hg) and Portico (8.9 mm Hg; 95% CI: 8.2 to 9.6 mm Hg) groups (p < 0.001). Mean indexed effective orifice area was 1.04 cm 2 /m 2 (95% CI: 1.01 to 1.08 cm 2 /m 2 ) with a trend toward lower values with the Portico. No significant differences were reported in terms of severe prosthesis-patient mismatch (overall rate 9.4%; p = 0.134), permanent pacemaker implantation (15.6%), and periprocedural and 1-year adverse events. Pre-discharge more than mild paravalvular leaks were significantly more common with the Portico (19.2%) and less common with the Evolut PRO (3.6%) compared with the Evolut R (11.8%) and ACURATE (9%) groups., Conclusions: Transcatheter self-expandable valves showed optimal clinical and echocardiographic results in patients with small aortic annuli, although supra-annular functioning transcatheter heart valves seemed to slightly outperform intra-annular functioning ones. The role of transcatheter aortic valve replacement with self-expandable valves for the treatment of aortic stenosis in patients with small annuli needs to be confirmed in larger trials., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Left atrial appendage (LAA) closure is considered an effective option in patients with non-valvular atrial fibrillation (NVAF) and contraindications to long-term oral anticoagulant (OAC) therapy. However, there are some concerns about safety of currently available devices. Our aim is to provide an initial assessment on feasibility and safety of the novel LAA closure Ultraseal device in patients with NVAF and contraindications to long-term OAC therapy., Methods: Twenty-three consecutive patients with NVAF undergoing Ultraseal device implantation between July 2016 and February 2018 at two institutions were included. All patients performed transesophageal echocardiography and computed tomography angiography prior to LAA closure., Results: Procedural success was achieved in all patients except two who experienced incorrect device deployment with incomplete LAA closure. Procedure duration halved from first to last procedure performed. The only periprocedural adverse events observed were a myocardial infarction and an in-hospital death due pneumonia. At mean follow-up (166 ± 80 days) all other patients were alive and free from major bleedings and ischaemic strokes., Conclusions: Our results suggest that the Ultraseal device is a feasible option for LAA occlusion. Notably, the learning curve in this registry was fast, paralleled by extremely low complication rates. These results should be considered hypothesis generating and larger studies are mandatory., (© 2018 Wiley Periodicals, Inc.)

Objectives: This study sought to evaluate the feasibility, safety, and efficacy of the Ultraseal device for left atrial appendage closure (LAAC) (Cardia, Eagan, Minnesota) in patients with nonvalvular atrial fibrillation at high bleeding risk., Background: The Ultraseal device is a novel bulb-and-sail designed LAAC device, with an articulating joint enabling conformability to heterogeneous angles and shapes of appendage anatomy., Methods: This was a multicenter study including consecutive patients undergoing LAAC with the Ultraseal device at 15 Canadian and European sites. Periprocedural and follow-up events were systematically collected, and transesophageal echocardiography at 45 to 180 days post-procedure was routinely performed in all centers but 3., Results: A total of 126 patients (mean age 75 ± 8 years; mean CHA 2 DS 2 -VASc score 5 ± 2; mean HAS-BLED score 4 ± 1) were included. The device was successfully implanted in 97% of patients. A major periprocedural adverse event occurred in 3 (2.4%) patients (clinically relevant pericardial effusion [n = 1], stroke [n = 1], device embolization [n = 1]). Ninety percent of patients were discharged on single or dual antiplatelet therapy. Follow-up transesophageal echocardiography was available in 89 (73%) patients, with no cases of large (>5 mm) residual leak and 5 (5.6%) cases of device-related thrombosis (all successfully treated with anticoagulation therapy). At a median follow-up of 6 (interquartile range: 3 to 10) months, the rates of stroke and transient ischemic attack were 0.8% and 0.8%, respectively, with no systemic emboli. None of the events occurred in patients with device-related thrombosis., Conclusions: In this initial multicenter experience, LAAC with the Ultraseal device was associated with a high implant success rate and a very low incidence of periprocedural complications. There were no late device-related clinical events and promising efficacy results were observed regarding thromboembolic prevention at midterm follow-up. Larger studies are further warranted to confirm the long-term safety and efficacy of this novel device., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Coronary artery disease and aortic stenosis frequently coexist. The pathophysiology of both conditions is similar where atherosclerosis is the hallmark feature. Risk factors for aortic stenosis are also similar for coronary artery disease. The standard therapy in the past decades has been coronary artery bypass grafting and aortic valve replacement; however, with the introduction of transcatheter aortic valve implantation their management is probably going to shift towards a percutaneous strategy.

Aims: The aim of this study was to evaluate the safety and efficacy profile of new-generation, SYNERGY everolimus-eluting stents (S-EES) as compared to XIENCE everolimus-eluting stents (X-EES) with a durable polymer coating in "complex patients"., Methods and Results: We included 2,001 consecutive patients treated with S-EES (n=400) or X-EES (n=1,601) at two Italian centres between May 2013 and May 2015. We used propensity score matching to obtain two cohorts of patients with similar baseline risk profiles. Patients were stratified according to baseline complexity based on the EVOLVE II trial exclusion criteria. The primary outcome was major adverse cardiac events (MACE), defined as the composite of all-cause death, myocardial infarction (MI), and target lesion revascularisation (TLR), at one year. Among 391 matched pairs of patients treated with S-EES or X-EES, we identified 253 (63%) as complex. At one-year follow-up, among "complex" patients, MACE rates did not differ between the S-EES and X-EES groups (9.9% vs. 9.5%, p=0.830, HR 1.04, CI: 0.72-1.48). Similarly, death, MI, and TLR, stratified for complexity, were comparable between S-EES and X-EES treated patients at one year. Of note, no definite ST was observed in either the S-EES or the X-EES cohort., Conclusions: New-generation S-EES with a bioresorbable polymer coating appear to be safe and effective irrespective of patient complexity as compared to X-EES.

Percutaneous coronary interventions (PCI) were proposed in the late 1970s as an alternative to surgical coronary artery bypass grafting for the treatment of coronary artery disease. Important technological progress has been made since. Balloon angioplasty was replaced by bare metal stents, which allowed to permanently scaffold the coronary vessel avoiding acute recoil and abrupt occlusion. Thereafter, the introduction of early generation drug-eluting stents (DES) has significantly improved clinical outcomes, primarily by markedly reducing the risk of restenosis. New generation DES with thinner stent struts, novel durable or biodegradable polymer coatings, and new limus antiproliferative agents, have further improved upon the safety and efficacy profile of early generation DES. The present article aims to review the impact of technological advances on clinical outcomes in the field of PCI with coronary stents, and to provide a brief overview on clinical margins of improvement and unmet needs of available DES.