Valentina Catto

Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy

Fibro-adipose substitution has a double detrimental effect on the myocardium in arrhythmogenic cardiomyopathy (ACM), worsening arrhythmogenesis by creating a non-conductive substrate, and causing ventricular dysfunction leading to heart failure. Notably, to-date no etiological therapy is available. This work introduces, for the first time, the stromal cardiac compartment as a key player in ACM ventricular adipose substitution: we demonstrated that cardiac human mesenchymal stromal cells undergo adipogenic differentiation both in ACM explanted hearts and in culture through a PKP2-dependent mechanism. Cardiac mesenchymal stromal cells constitute a suitable cellular platform for future mechanistic studies and a potential target for future therapies.

Cell therapy for heart disease after 15 years: Unmet expectations

Graphical abstract Figure. No Caption available. ABSTRACT Over the past two decades cardiac cell therapy (CCT) has emerged as a promising new strategy to cure heart diseases at high unmet need. Thousands of patients have entered clinical trials for acute or chronic heart conditions testing different cell types, including autologous or allogeneic bone marrow (BM)‐derived mononuclear or selected cells, BM‐ or adipose tissue‐derived mesenchymal cells, or cardiac resident progenitors based on their potential ability to regenerate scarred or dysfunctional myocardium. Nowadays, the original enthusiasm surrounding the regenerative medicine field has been cushioned by a cumulative body of evidence indicating an inefficient or modest efficacy of CCT in improving cardiac function, along with the continued lack of indisputable proof for long‐term prognostic benefit. In this review, we have firstly comprehensively outlined the positive and negative results of cell therapy studies in patients with acute myocardial infarction, refractory angina and chronic heart failure. Next, we have discussed cell therapy‐ and patient‐related variables (e.g. cell intrinsic and extrinsic characteristics as well as criteria of patient selection and proposed methodologies) that might have dampened the efficacy of past cell therapy trials. Finally, we have addressed critical factors to be considered before embarking on further clinical trials.

Electrical storm: A clinical and electrophysiological overview

Electrical storm (ES) is a clinical condition characterized by three or more ventricular arrhythmia episodes leading to appropriate implantable cardioverter-defibrillator (ICD) therapies in a 24 h period. Mostly, arrhythmias responsible of ES are multiple morphologies of monomorphic ventricular tachycardia (VT), but polymorphic VT and ventricular fibrillation can also result in ES. Clinical presentation is very dramatic in most cases, strictly related to the cardiac disease that may worsen electrical and hemodynamic decompensation. Therefore ES management is challenging in the majority of cases and a high mortality is the rule both in the acute and in the long-term phases. Different underlying cardiomyopathies provide significant clues into the mechanism of ES, which can arise in the setting of structural arrhythmogenic cardiomyopathies or rarely in patients with inherited arrhythmic syndrome, impacting on pharmacological treatment, on ICD programming, and on the opportunity to apply strategies of catheter ablation. This latter has become a pivotal form of treatment due to its high efficacy in modifying the arrhythmogenic substrate and in achieving rhythm stability, aiming at reducing recurrences of ventricular arrhythmia and at improving overall survival. In this review, the most relevant epidemiological and clinical aspects of ES, with regard to the acute and long-term follow-up implications, were evaluated, focusing on these novel therapeutic strategies of treatment.

Comparison between First- and Second-Generation Cryoballoon for Paroxysmal Atrial Fibrillation Ablation

Introduction. Cryoballoon (CB) ablation has emerged as a novel treatment for pulmonary vein isolation (PVI) for patients with paroxysmal atrial fibrillation (PAF). The second-generation Arctic Front Advance (ADV) was redesigned with technical modifications aiming at procedural and outcome improvements. We aimed to compare the efficacy of the two different technologies over a long-term follow-up. Methods. A total of 120 patients with PAF were enrolled. Sixty patients underwent PVI using the first-generation CB and 60 patients with the ADV catheter. All patients were evaluated over a follow-up period of 2 years. Results. There were no significant differences between the two groups of patients. Procedures performed with the first-generation CB showed longer fluoroscopy time (36.3 ± 16.8 versus 14.2 ± 13.5 min, resp.; p = 0.00016) and longer procedure times as well (153.1 ± 32 versus 102 ± 24.8 min, resp.; p = 0.019). The overall long-term success was significantly different between the two groups (68.3 versus 86.7%, resp.; p = 0.017). No differences were found in the lesion areas of left and right PV between the two groups (resp., p = 0.61 and 0.57). There were no significant differences in procedural-related complications. Conclusion. The ADV catheter compared to the first-generation balloon allows obtaining a significantly higher success rate after a single PVI procedure during the long-term follow-up. Fluoroscopy and procedural times were significantly shortened using the ADV catheter.

An easy-to-use, operator-independent, clinical model to predict the left vs. right ventricular outflow tract origin of ventricular arrhythmias

AIMS To identify clinical characteristics able to predict a left ventricular outflow tract (LVOT) origin in outflow tract ventricular arrhythmias (OTVAs). METHODS AND RESULTS We included 117 consecutive patients (training sample) with successful radiofrequency ablation of OTVA in one centre. A predictive model for LVOT origin was obtained using clinical data. The model was prospectively validated in a second population (testing sample) of 143 patients from two additional centres. In training sample, mean age was 54 ± 17 years, 72 patients (61%) were male, and 63 (54%) had cardiovascular risk factors. Sixty (51%) patients had LVOT origin. Independent predictors for LVOT origin were the presence of hypertension [odds ratio (OR) 2.17, confidence interval (CI) 0.91-6.20, P = 0.09], male gender (OR 4.83, 95% CI 1.89-12.33, P < 0.001), and age >50 years (OR 4.46, 95% CI 1.57-12.7, P = 0.005). A simple score was constructed with these three variables to predict LVOT origin (mean predicted probability of 15% for score 0, 26% for score 1, 60% for score 2, and 87% for score 3, P < 0.001) and reached 80% sensitivity and 75% specificity. The score was validated in the testing sample and was not inferior to previously described electrocardiogram algorithms. CONCLUSION Patients currently referred for OTVA ablation are older, more frequently men, and with a higher probability for LVOT origin than previously described. A LVOT origin is associated with the presence of hypertension, male gender, and older age, and can be anticipated by using a simple clinical score.

Novel Application of 3-Dimensional Real-Time Cardiac Imaging to Guide Stem Cell-Based Therapy

Stem cell-based therapy is an emerging treatment for refractory ischemic cardiomyopathy. The transendocardial approach represents the most attractive method that allows direct percutaneous injections of the cell product into the ischemic territories. This clinical case shows a novel strategy designed to optimize cell endocardial delivery, based on the implementation of the 3-dimensional electroanatomical map with the intracardiac-echocardiographic reconstruction of the left ventricle, using acquired multiple slice recordings. Combined imaging was efficacious to detail the anatomical and functional characteristics of the target areas and to guide cell delivery supported by direct real-time visualization of the needle to improve procedural effectiveness and safety.

MiR-320a as a Potential Novel Circulating Biomarker of Arrhythmogenic CardioMyopathy

Diagnosis of Arrhythmogenic CardioMyopathy (ACM) is challenging and often late after disease onset. No circulating biomarkers are available to date. Given their involvement in several cardiovascular diseases, plasma microRNAs warranted investigation as potential non-invasive diagnostic tools in ACM. We sought to identify circulating microRNAs differentially expressed in ACM with respect to Healthy Controls (HC) and Idiopathic Ventricular Tachycardia patients (IVT), often in differential diagnosis. ACM and HC subjects were screened for plasmatic expression of 377 microRNAs and validation was performed in 36 ACM, 53 HC, 21 IVT. Variable importance in data partition was estimated through Random Forest analysis and accuracy by Receiver Operating Curves. Plasmatic miR-320a showed 0.53 ± 0.04 fold expression difference in ACM vs. HC (p < 0.01). A similar trend was observed when comparing ACM (n = 13) and HC (n = 17) with athletic lifestyle, a ACM precipitating factor. Importantly, ACM patients miR-320a showed 0.78 ± 0.05 fold expression change vs. IVT (p = 0.03). When compared to non-invasive ACM diagnostic parameters, miR-320a ranked highly in discriminating ACM vs. IVT and it increased their accuracy. Finally, miR-320a expression did not correlate with ACM severity. Our data suggest that miR-320a may be considered a novel potential biomarker of ACM, specifically useful in ACM vs. IVT differentiation.

Electroanatomical mapping systems and intracardiac echo integration for guided endomyocardial biopsy

ABSTRACT Introduction: During the past years, endomyocardial biopsy (EMB) has gradually spread into clinical practice. However, the role of EMB in the diagnosis and treatment of cardiovascular diseases remains a controversial issue, especially in the setting of unexplained ventricular arrhythmias. Areas covered: This review describes the methodology of EMB guided by combined use of three-dimensional electroanatomical mapping systems and intracardiac echo and summarizes the classical, fluoroscopy-guided EMB technique. Finally, the personal experience acquired with the ‘electrophysiologist-made’ integration methodology has been reported. Expert commentary: Since EMB has been considered in the setting of arrhythmogenic cardiomyopathy, myocarditis, cardiac sarcoidosis, drug toxicity, and/or other diseases causing malignant ventricular arrhythmias, the electrophysiologists have started to perform firsthand biopsy. The electrophysiologists introduced the use of electroanatomical mapping systems and intracardiac echo. This new methodology improved significantly biopsy diagnostic yield and allowed to reduce complications.

X‐Ray Exposure in Cardiac Electrophysiology: A Retrospective Analysis in 8150 Patients Over 7 Years of Activity in a Modern, Large‐Volume Laboratory

Background Only a few studies have systematically evaluated fluoroscopy data of electrophysiological and device implantation procedures. Aims of this study were to quantify ionizing radiation exposure for electrophysiological/device implantation procedures in a large series of patients and to analyze the x‐ray exposure trend over years and radiation exposure in patients undergoing atrial fibrillation ablation considering different technical aspects. Methods and Results We performed a retrospective analysis of all electrophysiological/device implantation procedures performed during the past 7 years in a modern, large‐volume laboratory. We reported complete fluoroscopy data on 8150 electrophysiological/device implantation procedures (6095 electrophysiological and 2055 device implantation procedures); for each type of procedure, effective dose and lifetime attributable risk of cancer incidence and mortality were calculated. Over the 7‐year period, we observed a significant trend reduction in fluoroscopy time, dose area product, and effective dose for all electrophysiological procedures (P<0.001) and a not statistically significant trend reduction for device implantation procedures. Analyzing 2416 atrial fibrillation ablations, we observed a significant variability of fluoroscopy time, dose area product and effective dose among 7 different experienced operators (P<0.0001) and a significant reduction of fluoroscopy use over time (P<0.0001) for all of them. Considering atrial fibrillation ablation techniques, fluoroscopy time was not different (P = 0.74) for radiofrequency catheter ablation in comparison with cryoablation, though cryoablation was still associated with higher dose area product and effective dose values (P<0.001). Conclusions Electrophysiological procedures involve a nonnegligible x‐ray use, leading to an increased risk of malignancy. Awareness of radiation‐related risk, together with technological advances, can successfully optimize fluoroscopy use.

Cell Therapy for Refractory Angina: A Reappraisal

Cardiac cell-based therapy has emerged as a novel therapeutic option for patients dealing with untreatable refractory angina (RA). However, after more than a decade of controlled studies, no definitive consensus has been reached regarding clinical efficacy. Although positive results in terms of surrogate endpoints have been suggested by early and phase II clinical studies as well as by meta-analyses, the more recent reports lacked the provision of definitive response in terms of hard clinical endpoints. Regrettably, pivotal trials designed to conclusively determine the efficacy of cell-based therapeutics in such a challenging clinical condition are therefore still missing. Considering this, a comprehensive reappraisal of cardiac cell-based therapy role in RA seems warranted and timely, since a number of crucial cell- and patient-related aspects need to be systematically analysed. As an example, the large variability in efficacy endpoint selection appears to be a limiting factor for the advancement of cardiac cell-based therapy in the field. This review will provide an overview of the key elements that may have influenced the results of cell-based trials in the context of RA, focusing in particular on the understanding at which the extent of angina-related endpoints may predict cell-based therapeutic efficacy.