Immunomodulation Therapies for Atherosclerosis: The Past, the Present, and the Future.

Atherosclerotic cardiovascular disease is the most common cause of morbidity and death worldwide. Recent studies have demonstrated that this chronic inflammatory disease of the arterial wall can be controlled through the modulation of immune system activity. Many patients with cardiovascular disease remain at elevated risk of recurrent events despite receiving current, state-of-the-art preventive medical treatment. Much of this residual risk is attributed to inflammation. Therefore, finding new treatment strategies for this category of patients became of common interest. This review will discuss the experimental and clinical data supporting the possibility of developing immune-based therapies for lowering cardiovascular risk, explicitly focusing on vaccination strategies.

Serum uric acid in patients with ST-segment elevation myocardial infarction: An innocent bystander or leading actor?

Elevated serum uric acid (SUA) levels have been associated with several cardiovascular risk factors and the progression of coronary artery disease. In the setting of acute myocardial infarction, increasing evidence suggests that high SUA levels could be related to adverse outcomes. Interestingly elevated SUA levels have been linked to endothelial dysfunction, inflammation and oxidative stress. The aim of this review is to discuss the potential negative effects of SUA in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, analyzing the possible underlying pathophysiological mechanisms.

A thymic hyperplasia-related reversible complete atrioventricular block: When compression is more important than compressor.

A 19-year-old patient presented for syncope with third-degree AV block (TDAVB) at ECG. A chest-CT showed a thymic mass that could be responsible for TDAVB due to extrinsic vagal nerve compression. Thymectomy led to complete AV block resolution. An extrinsic vagal compression mechanism should be considered among causes of complete atrioventricular block.

Altered CD31 expression and activity in helper T cells of acute coronary syndrome patients.

In acute coronary syndrome (ACS), T cell abnormalities are associated to a worse outcome. Loss of inhibitory activity of CD31, an Ig-like adhesion molecule, on peripheral leukocytes has been found to enhance atherosclerosis in experimental models. In this study, we examined the expression of CD31 on T cells, and its role on TCR signaling in 35 patients with non-ST elevation ACS, in 35 patients with stable angina (SA), and in 35 controls. Furthermore, 10 ACS and 10 SA patients were re-analyzed at 1-year follow-up. Flow-cytometry analysis showed that in ACS patients, CD31 expression was reduced on total CD4(+) and CD4(+)CD28(null) (P < 0.001, ACS vs. SA), on naïve (P < 0.001, ACS vs. SA) and on central-memory and effector-memory CD4(+) T cells (P < 0.05, ACS vs. SA and controls). The immunomodulatory effect of CD31 on TCR signaling of CD4(+) and CD4(+)CD28(null) T cells, was lower in ACS than SA patients (P < 0.05, for both comparisons). At 1-year follow-up, CD31 expression and function increased in ACS becoming similar to that found in SA. CD31 recruitment in the immunological synapse was lower in ACS than controls (P = 0.012). Moreover, CD31 modulated MAPK signaling and reduced the expression of T bet and Rorγ-t, necessary for Th1 and Th17 differentiation. Finally, we studied TCR signaling in CD31(+) naïve and primed T cell subsets observing a different pattern of protein phosphorylation. A CD31-mediated regulatory pathway is enhanced in SA and temporarily downregulated in ACS. As CD31 modulates both T cell activation, by increasing the threshold for TCR stimulation, and T cell differentiation, it might represent a novel molecular target to treat T cell abnormalities in ACS.

Holographic mixed reality for planning transcatheter aortic valve replacement.

BACKGROUND: Using three-dimensional (3D) modalities for optimal pre-procedure planning in transcatheter aortic valve replacement (TAVR) is critical for procedural success. However, current methods rely on visualizing images on a two-dimensional screen, using shading and colors to create the illusion of 3D, potentially impeding the accurate comprehension of the actual anatomy structures. In contrast, a new Mixed Reality (MxR) based software enables accurate 3D visualization, imaging manipulation, and quantification of measurements. AIMS: The study aims to evaluate the feasibility, reproducibility, and accuracy of dimensions of the aortic valve complex as measured with a new holographic MxR software (ARTICOR®, Artiness srl, Milano, Italy) compared to a widely used software for pre-operative sizing and planning (3mensio Medical Imaging BV, Bilthoven, The Netherlands) . METHODS: This retrospective, observational, double-center study enrolled 100 patients with severe aortic stenosis who underwent cardiac computed tomography (CCT) before TAVR. The CCT datasets of volumetric aortic valve images were analyzed using 3Mensio and newly introduced MxR-based software. RESULTS: 98% of the CCT datasets were successfully converted into holographic models. A higher level of agreement between the two software systems was observed for linear metrics (short, long, and average diameter). In comparison, agreement was lower for area, perimeter, and annulus-to-coronary ostia distance measurements. Notably, the annulus area, annular perimeter, LVOT area, and LVOT perimeter were significantly and consistently smaller with the MxR-based software compared to the 3Mensio. Excellent interobserver reliability was demonstrated for most measurements, especially for direct linear measurements. CONCLUSIONS: Linear Measurements of the aortic valve complex using MxR-based software are reproducible compared to the standard CCT dataset analyzed with 3Mensio. MxR-based software could represent an accurate tool for the pre-procedural planning of TAVR.

Intermittent Normal Ventricular Conduction in Left Bundle Branch Block After TAVR.

In a patient who previously developed left bundle branch block after transcatheter aortic valve replacement, intermittent narrow QRS complexes were recorded on ambulatory electrocardiography monitoring. The peculiar distribution of wide and narrow QRS complexes suggested the presence of a window of supernormality in the refractory period of a branch block that on other occasions exhibited the Wenckebach phenomenon. (Level of Difficulty: Intermediate.).

Successful percutaneous catheter-directed treatment of high-risk pulmonary embolism: a case report.

Background: Pulmonary embolism (PE) is an acute cardiovascular syndrome characterized by high incidence and mortality. The therapy of this condition is based on anticoagulation and hemodynamic support, but in case of high-risk mortality, the European Society of Cardiology (ESC) guidelines recommend systemic thrombolytic therapy and surgical embolectomy if thrombolysis is contraindicated or has failed; nowadays several percutaneous catheter-directed treatments for local thrombolysis or mechanical embolectomy are available, but they have IIa class of recommendation, because of lack of robust scientific evidence favoring their use. Case Description: We described a case of high-risk PE treated with a novel percutaneous system for mechanical embolectomy, which consists of a large aspiration catheter that was advanced in the pulmonary artery, capturing and removing a vast thrombus, of 15 centimeters in length. This therapeutic strategy avoided the risk of hemorrhagic complications related to systemic thrombolysis, exiting in the achievement of fast patient hemodynamic stabilization and symptoms resolution, without complications. Computed tomography (CT) pulmonary angiography after 10 days from the intervention revealed the complete resolution of pulmonary artery filling defects, and the patient was discharged asymptomatic. Conclusions: Percutaneous catheter-directed treatments represent an effective alternative therapy for PE, but further studies are needed to demonstrate safety and superiority over the actually recommended therapy.

Rationale and design of the sirolimus eluting balloon utilization for treatment of vasculogenic erectile dysfunction: the SUASION Registry.

BACKGROUND: Conventional angioplasty balloon catheter, drug coated balloon (DCB), or angioplasty with drug eluting stent (DES) have been used on the percutaneous treatment of erectile dysfunction (ED). Currently available DCBs are paclitaxel eluting balloon (PEB), very recently, sirolimus eluting balloon (SEB). Although endovascular revascularization with balloon resulted in improvement of ED, there have been no prior reports on the feasibility of SEB treatment for ED. METHODS: We present an observational, retrospective-prospective multicentre registry in patients evaluating the use of SEB for the treatment of de novo stenosis in native internal pudendal arteries. We will include 100 patients affected by vasculogenic ED non responder to PDE5i with up to two lesions requiring treatment. ED patients should present a IIEF-5 Score<15, positive dynamic doppler (PSV <25 cm/s) and/or evidence at basal CT angiography. At 30 days, 180, 240, and 365 days following the index procedure, IIEF-5 score will be assessed, and medication regimen and adverse event monitoring will be assessed. At 8 months a dynamic Doppler will be performed. Patients will be followed up for 2 years. The primary endpoints are the Delta IIEF-5 Score and a Delta PSV between basal and 8 months follow-up. The secondary endpoint is the incidence of major adverse event (MAE), binary restenosis and late loss in patients who will repeat control angiography if clinically indicated. CONCLUSIONS: Considering the limitations and safety concerns of PEB, POBA and DES used so far in ED clinical investigations, we hypothesize that sirolimus nanocarriers-coated balloon can potentially be an improved next-generation treatment for ED patients.

Treatment with gentamicin-impregnated collagen sponges in reducing infection of implantable cardiac devices: 10-year analysis with propensity score matching.

INTRODUCTION AND OBJECTIVES: The incidence of device infection has increased over time and is associated with increased mortality in patients with cardiac implantable electronic devices (CIEDs). Gentamicin-impregnated collagen sponges (GICSs) are useful in preventing surgical site infection (SSI) in cardiac surgery. Nevertheless, to date, there is no evidence concerning their use in CIED procedures. Our study aims to determine the effectiveness of treatment with GICSs in preventing CIED infection. METHODS: A total of 2986 adult patients who received CIEDs between 2010 and 2020 were included. Before device implantation, all patients received routine periprocedural systemic antibiotic prophylaxis. The study endpoints were the CIED infection rate at one year and the effectiveness of the use of GICSs in reducing CIED infection. RESULTS: Among 1524 pacemaker, 942 ICD and 520 CRT implantations, CIED infection occurred in 36 patients (1.2%). Early reintervention (OR 9 [95% CI 3.180-25.837], p<0.001), pocket hematoma (OR 11 [95% CI 4.195-28.961], p<0.001), diabetes (OR 2.9 [95% CI 1.465-5.799], p=0.002) and prolonged procedural time (OR 1.02 [95% CI 1.008-1.034], p=0.001) were independent risk factors for CIED infection. Treatment with GICSs reduced CIED infections significantly ([95% CI -0.031 to -0.001], p<0.001). CONCLUSIONS: The use of GICSs may help in reducing infections associated with CIED implantation.

Clinical Features and Management of COVID-19-Associated Hypercoagulability.

COVID-19 is an acute respiratory disease of viral origin caused by SARS-CoV-2. This disease is associated with a hypercoagulable state resulting in arterial and venous thrombotic events. The latter are more frequent, especially in patients who develop a severe form of the disease and are associated with an increased mortality rate. It is therefore essential to identify patients at higher risk to initiate antithrombotic therapy. Hospitalized patients treated with treatment dose of anticoagulants had better outcomes than those treated with prophylactic dose. However, several trials are ongoing to better define the therapeutic and prevention strategies for this insidious complication.

Autologous Immune Cell-Based Regenerative Therapies to Treat Vasculogenic Erectile Dysfunction: Is the Immuno-Centric Revolution Ready for the Prime Time?

About 35% of patients affected by erectile dysfunction (ED) do not respond to oral phosphodiesterase-5 inhibitors (PDE5i) and more severe vasculogenic refractory ED affects diabetic patients. Innovative approaches, such as regenerative therapies, including stem cell therapy (SCT) and platelet-rich plasma (PRP), are currently under investigation. Recent data point out that the regenerative capacity of stem cells is strongly influenced by local immune responses, with macrophages playing a pivotal role in the injury response and as a coordinator of tissue regeneration, suggesting that control of the immune response could be an appealing approach in regenerative medicine. A new generation of autologous cell therapy based on immune cells instead of stem cells, which could change regenerative medicine for good, is discussed. Increasing safety and efficacy data are coming from clinical trials using peripheral blood mononuclear cells to treat no-option critical limb ischemia and diabetic foot. In this review, ongoing phase 1/phase 2 stem cell clinical trials are discussed. In addition, we examine the mechanism of action and rationale, as well as propose a new generation of regenerative therapies, evolving from typical stem cell or growth factor to immune cell-based medicine, based on autologous peripheral blood mononuclear cells (PBMNC) concentrates for the treatment of ED.

Unequal opportunities in Italian cardiovascular research: focus on gender.

BACKGROUND: Despite unanimous calls for more equitable access and support to female researchers, there are persistent barriers to women's career progression and professional fulfillment. These discriminative hurdles undermine female gender in science and have detrimental effects on research activities and female professionals and patients. There is no data on women's outlook in cardiovascular research in Italy, which limits appropriate remedial actions. We aimed at providing an updated perspective on top Italian cardiovascular researchers, focusing on women versus men comparisons. METHODS: Top Italian cardiovascular researchers were retrieved from a dedicated and validated Scopus query. Researchers' sex was assigned according to the given name with a consensus process. Several metrics were compared, including global rank, total cites, total cites adjusted by academic age, H-index, and self-citation percentage. Bivariate and propensity score-adjusted analyses were used for inferential purposes. RESULTS: Our analysis shows the existence of a gender gap: the number of scientific articles published by Italian male researchers in their careers is significantly higher than their female counterparts (P=0.002). For men, the year of first publication is earlier (P=0.001); they also published more articles as a single author, or single + first author or single + first + last author. Men's papers cited at least once were more than those of women (P≤0.001), and the total number of citations was significantly higher for men (P=0.002). These results remain significant both in the analysis excluding self-citations as well as in the analysis including self-citations. The single-year analysis (2019) confirms the significance of the career analysis, adding that men have a higher rank based on composite score (P=0.041, or P=0.005 if including self-citation). Finally, men have a higher percentage of self-citation in 2019 than women (P=0.008). CONCLUSIONS: The gender disparity is still a limiting factor in Italian cardiovascular research. Despite career advancement, women continue to be underrepresented. Men retain more leadership positions in academia and maintain the edge for scientific work productions. More efforts are needed to ensure equity between men and women.

Cardiovascular medicine: a year in review.

Cardiovascular medicine is facing several challenges in the current era, dominated by the rapid spread of a previously unknown virus around the world. Indeed, the 2020 COVID-19 pandemic set the course of cardiovascular science and education in an extraordinary way, hogging the attention of the medical community. Notably, while COVID-19 impacted research progress, there has been considerable effort in exploring topics of great interest, from the management of acute coronary syndromes to new horizons in the treatment of heart failure, from novelties in the surgical treatment of cardiovascular disease to new data on implantable cardiac devices, and from new diagnostic applications of multimodal imaging techniques to relevant basic science findings. Minerva Cardiology and Angiology, formerly Minerva Cardioangiologica, has strived to inform its readers on these topics and novelties, aiming for a succinct yet poignant melding of timeliness and accuracy. Accordingly, the purpose of this narrative review is to highlight and summarize the major research and review articles published during 2020. In particular, we provide a broad overview of the novelties identifying six major areas of interest in the field of cardiovascular sciences in which new evidences have contributed to improving prevention, diagnosis and treatment of heart and vessels diseases.

The Transaxillary Route as a Second Access Option in TAVI Procedures: Experience of a Single Centre.

Background: The aim of our study was to determine the feasibility and efficacy of transaxillary (TAX) TAVI in patients not eligible for the transfemoral route. Methods: This is a retrospective study of a single center. We analysed 262 patients treated with TAVI. In 17 patients (6.5%), the procedure was performed with the TAX approach. Procedural and hospital data, 30-day safety, and clinical efficacy were assessed and compared between the transfemoral and TAX groups. Results: In the TAX groups, we found a higher prevalence of men (p = 0.001), smokers (p = 0.033), and previous strokes (p = 0.02). The EUROSCORE II was higher in the TAX group (p = 0.014). The success rate of the device was 100%. TAX was associated with a longer procedure time (p = 0.001) and shorter median device time (p = 0.034) in minutes. Patients treated with TAX had a longer hospital stay (p = 0.005) and higher overall bleeding rate (p = 0.001). Peripheral neurological complications were more frequent with TAX (p = 0.001), which almost completely resolved by 30 days. Conclusions: TAX TAVI is safe and effective and should be considered as a second choice when transfemoral TAVI is not feasible due to severe comorbidities.

Acute effect of edge-to-edge repair of mitral regurgitation on left heart mechanics and health status.

AIMS: Examine the impact of acute changes in left heart strain and volumes with percutaneous edge-to-edge MitraClip repair on improvement in health status assessed using Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score. METHODS: Changes in left atrial strain, left ventricular (LV) global longitudinal strain (LVGLS), LV end-systolic volume (LVESV), and end-diastolic volume (LVEDV) were evaluated in 50 patients undergoing MitraClip repair for symptomatic primary mitral regurgitation (PMR) and secondary mitral regurgitation (SMR) on transthoracic echocardiography before and 1 month after MitraClip. Multivariable regression was used to evaluate changes in left heart strain and volumes as predictors of change in KCCQ-12 scores, adjusting for baseline clinical and echocardiographic characteristics. RESULTS: Both PMR and SMR patients had significant increase in LVGLS and reduction in LVEDV and LVESV ( P  < 0.05) after MitraClip, reduction trend in left atrial conduit strain (PMR P  = 0.053; SMR P  = 0.12) but no significant change in LV ejection fraction. KCCQ-12 score improved significantly in both PMR ( P  < 0.001) and SMR cohorts ( P  < 0.001). Higher delta KCCQ-12 tertiles were associated with greater reduction in LVEDV ( P  = 0.022) after MitraClip. On multiple regression analysis, lower preprocedural Society of Thoracic Surgeons for Mitral Valve Replacement and KCCQ-12 score, and greater reduction in LVESV and left atrial strain conduit phase were associated with KCCQ-12 score improvement ( P  < 0.001). CONCLUSION: There is a significant increase in LVGLS and reduction in LVEDV, LVESV and left atrial strain conduit after edge-to-edge MitraClip repair in both PMR and SMR. Lower preprocedural Society of Thoracic Surgeons for Mitral Valve Replacement and KCCQ-12 score, and greater reduction in LVESV and left atrial conduit strain were associated with KCCQ-12 score improvement after MitraClip. Further studies are warranted to understand the mechanism and significance of our findings.

Home Management of Heart Failure and Arrhythmias in Patients with Cardiac Devices during Pandemic.

BACKGROUND: The in-hospital management of patients with cardiac implantable electronic devices (CIEDs) changed early in the COVID-19 pandemic. Routine in-hospital controls of CIEDs were converted into remote home monitoring (HM). The aim of our study was to investigate the impact of the lockdown period on CIEDs patients and its influence on in-hospital admissions through the analysis of HM data. METHODS: We analysed data recorded from 312 patients with HM during the national quarantine related to COVID-19 and then compared data from the same period of 2019. RESULTS: We observed a reduction in the number of HM events in 2020 when compared to 2019. Non-sustained ventricular tachycardia episodes decreased (18.3% vs. 9.9% p = 0.002) as well as atrial fibrillation episodes (29.2% vs. 22.4% p = 0.019). In contrast, heart failure (HF) alarm activation was lower in 2019 than in 2020 (17% vs. 25.3% p = 0.012). Hospital admissions for critical events recorded with CIEDs dropped in 2020, including those for HF. CONCLUSIONS: HM, combined with telemedicine use, has ensured the surveillance of CIED patients. In 2020, arrhythmic events and hospital admissions decreased significantly compared to 2019. Moreover, in 2020, patients with HF arrived in hospital in a worse clinical condition compared to previous months.

Electrocardiographic modifications and cardiac involvement in COVID-19 patients: results from an Italian cohort.

AIM: The aim of this study was to detect predisposing CV risks factors and ECGs changes in COVID-19 patients. METHODS: The study population included 60 noncritically ill patients with COVID-19 pneumonia admitted to our hospital between 16 March and 11 May 2020. Electrographic changes, evaluated from ECGs acquired at admission and at 7 days after starting COVID-19 therapy, were analysed. We also compared 45 patients without CV involvement with 15 patients with new onset of cardiac adverse events during hospitalization. RESULTS: ECGs under treatment showed a lower heart rate (HR) (69.45 ±â€Š8.06 vs 80.1 ±â€Š25.1 beats/min, P = 0,001) and a longer QRS (102.46 ±â€Š15.08 vs 96.75 ±â€Š17.14, P = 0.000) and QT corrected (QTc) interval (452.15 ±â€Š37.55 vs 419.9 ±â€Š33.41, P = 0,000) duration than ECGs before therapy. Fifteen patients (25%) showed clinical CV involvement. Within this group, female sex, lower ejection fraction (EF), low serum haemoglobin, high Troponin I levels (TnI), low lymphocytes count, high serum IL-6 levels, or use of Tocilizumab (TCZ) were more represented. CONCLUSIONS: Patients admitted for SARS-CoV2 infection and treated with anti-COVID-19 drug therapy develop ECG changes such as reduction in HR and increase in QRS duration and QTc interval. One in four patients developed CV events. Gender, EF, heamoglobin values, TnI, lymphocytes count, IL-6 and use of TCZ can be considered as predisposing factors for CV involvement.

Challenges and Open Issues in Transcatheter Mitral Valve Implantation: Smooth Seas Do Not Make Skillful Sailors.

According to the European and American guidelines, surgery represents the treatment of choice for mitral valve (MV) disease. However, a number of patients are deemed unsuitable for surgery due to a prohibitive/high operative risk. In such cases, transcatheter therapies aiming at MV repair have been proven to be a valuable alternative and have been recently introduced in the latest American guidelines on valvular heart disease. Indeed, percutaneous repair techniques, particularly transcatheter edge-to-edge, have gained a broad experience and demonstrated to be safe and effective. However, given the complexity and heterogeneity of MV anatomy and pathology, transcatheter MV implantation (TMVI) has grown as a possible alternative to percutaneous MV repair. Current data about TMVI are still limited and come from different settings: valve-in-native MV, valve-in-valve (ViV), valve-in-ring (ViR), and valve-in-mitral annular calcification. Preliminary data are promising although several open issues still need to be addressed. This paper provides a comprehensive review of the available devices in the different clinical settings, to discuss potentialities, limitations, and future directions for TMVI.

MiR-423 is differentially expressed in patients with stable and unstable coronary artery disease: A pilot study.

Coronary artery disease (CAD) and acute myocardial infarction (AMI) are the leading causes of death worldwide. Since only a subset of CAD patients develops myocardial infarction, it is likely that unique factors predispose to AMI. Circulating microRNAs represent diagnostic powerful biomarkers for detection of heart injuries and patients' risk stratification. Using an array-based approach, the expression of 84 circulating miRNAs was analyzed in plasma of pooled stable CAD patients (CAD; n = 5) and unstable CAD patients (AMI_T0; n = 5) enrolled within 24 hours from an AMI event. The array experiments showed 27 miRNAs differentially expressed with a two-fold up- or down-regulation (10 up- and 17 down-regulated miRNAs). Among them, miR-423-5p dis-regulation was confirmed in a larger case study (n = 99). Circulating miR-423-5p resulted to be significantly down-regulated within 24 hours from the AMI event (FC = -2, p≤0.05). Interestingly, miR-423-5p expression resulted to be increased (FC = +2; p≤0.005) in a subgroup of the same AMI patients (AMI_T1; n = 11) analyzed after 6 months from the acute event. We extended miR-423-5p expression study on PBMCs (peripheral blood mononuclear cells), confirming also in this tissue its up-regulation at 6 months post-AMI. Receiver operating characteristic analyses (ROC) were performed to detect the power of miR-423-5p to discriminate stable and unstable CAD. In plasma, miR-423-5p expression accurately distinguishes stable and unstable CAD patients (AUC = 0.7143, p≤0.005). Interestingly, the highest discriminatory value (AUC = 0.8529 p≤0.0005) was identified in blood cells, where miR-423-5p expression is able to differentiate unstable CAD patients during an acute event (AMI_T0) from those at six months post-AMI (AMI_T1). Furthermore, cellular miR-423-5p may discriminate also stable CAD patients from unstable CAD patients after six months post-AMI (AUC = 0.7355 p≤0.05). The results of this pilot-study suggest that miR-423-5p expression level both in plasma and blood cells, could represent a new promising biomarker for risk stratification of CAD patients.