Isolation and Characterization of Cardiac Mesenchymal Stromal Cells from Endomyocardial Bioptic Samples of Arrhythmogenic Cardiomyopathy Patients

A normal adult heart is composed of several different cell types, among which cardiac mesenchymal stromal cells represent an abundant population. The ...

Centro Cardiologico Monzino-IRCCS

Uncommon ventricular tachycardia originating from an interventricular septal aneurism: Mapping and ablation guided by real-time image integration.

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.

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

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.

Electrical storm: A clinical and electrophysiological overview.

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.

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

Ventricular arrhythmias (VAs) arising from the right ventricular outflow tract (RVOT) are a common and heterogeneous entity. Idiopathic right ventricular arrhythmias (IdioVAs) are generally benign, with excellent ablation outcomes and long-term arrhythmia-free survival, and must be distinguished from other conditions associated with VAs arising from the right ventricle: the differential diagnosis with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is therefore crucial because VAs are one of the most important causes of sudden cardiac death (SCD) in young individuals even with early stage of the disease. Radiofrequency catheter ablation (RFCA) is a current option for the treatment of VAs but important differences must be considered in terms of indication, purposes and procedural strategies in the treatment of the two conditions. In this review, we comprehensively discuss clinical and electrophysiological features, diagnostic and therapeutic techniques in a compared analysis of these two entities.

Right Ventricular Outflow Tract Arrhythmias: Benign Or Early Stage Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia?

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.

Cell therapy for heart disease after 15 years: Unmet expectations.

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.

Electroanatomical mapping systems and intracardiac echo integration for guided endomyocardial biopsy.

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.

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

Electrophysiology procedures are traditionally performed under fluoroscopic guidance. Nowadays a growing interest in the radiation risk associated to these procedures has been cultivated, since radiation exposure has non-negligible stochastic and deterministic effects on health. A correlation between radiation exposure and lifetime malignancy effect is difficult to establish and the threshold of a completely safe exposure dose is unknown. Thus, electrophisiologists have become aware of the use of fluoroscopy and they have tried to use all the complementary imaging technologies available in order to reduce the radiological exposure. This review is aimed at evaluating the radiation exposure risk, both for the patients and the operators. We describe electroanatomical mapping systems and technologies, which allow the reduction of radiation exposure. We review the main literature based on different catheter ablation procedures with the use of the abovementioned technologies, specifically focusing on feasibility, safety, and radiation exposure. Finally, we highlight the necessity of increasing the radiological risk awareness among operators and cardiological scientific societies.

Benefits of electroanatomic ablation of conventional cardiac arrhytmias: from fluoroscopy to zero X-ray mapping.

Arrhythmogenic cardiomyopathy (ACM) is a genetic cardiac condition characterized by the replacement of the ventricular myocardium with fibro-fatty tissue, by arrhythmias and sudden death. Adipogenesis in ACM is considered an aberrant remodeling following myocardial loss. Which cell type(s) is (are) responsible for the adipose replacement is still matter of debate. A systematic overview of the different cells that have been, over time, considered as main players in adipose replacement is provided. The comprehension of the cellular component giving rise to arrhythmogenic cardiomyopathy substrate defects may represent both an essential tool for mechanistic studies of disease pathogenesis and a novel possible therapeutic target.

Arrhythmogenic Cardiomyopathy: the Guilty Party in Adipogenesis.

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.

Cell Therapy for Refractory Angina: A Reappraisal.

Based on a plenty of different applications, intracardiac echocardiography (ICE) is now a well-established technology in complex electrophysiological procedures. Recently, ICE has become the most widely used ultrasound-based imaging tool to guide diagnostic endomyocardial biopsy (EMB). EMB of cardiac mass guided by ICE is an interesting application of ICE. Allowing a correct positioning of the bioptome, ICE reduce the procedure-related risks and the need of a diagnostic open-chest procedure reserving the more invasive approach to selected cases.

Valentina Catto

Heart Rhythm Center

Centro Cardiologico Monzino-IRCCS

Isolation and Characterization of Cardiac Mesenchymal Stromal Cells from Endomyocardial Bioptic Samples of Arrhythmogenic Cardiomyopathy Patients

Valentina Catto

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Centro Cardiologico Monzino-IRCCS

Isolation and Characterization of Cardiac Mesenchymal Stromal Cells from Endomyocardial Bioptic Samples of Arrhythmogenic Cardiomyopathy Patients

Heart Rhythm Center