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17. Cardiac Repolarization and Stem Cells: An Emerging Path Toward Precision Medicine

Author

El-Sherif, N, Gnecchi, M, Sala, L, Schwartz, P, Gnecchi M., Sala L., Schwartz P. J., El-Sherif, N, Gnecchi, M, Sala, L, Schwartz, P, Gnecchi M., Sala L., and Schwartz P. J.

Abstract

The discovery of a genetic basis for cardiac repolarization disorders has introduced innovative technologies and concepts in the field of cardiac arrhythmias and has revolutionized the knowledge of these disorders as well as patients’ treatment. Conventional methodologies for the in vitro study of cardiac arrhythmias, only indirectly linked to the clinical phenotype, have started to age, and the information they can now provide suddenly appears limited. After the discovery that patient-specific cardiomyocytes can be derived, in virtually unlimited numbers, from pluripotent stem cells, we are now on the edge of another breakthrough with basic science laboratories heavily linked to clinical practice and offering tools with substantially higher translational capabilities. In this chapter, we present an excursus on the path that has led to the discovery, optimization, and implementation of pluripotent stem cell-derived cardiomyocytes for cardiac disease modeling. Then, we cover the major repolarization disorders with genetic bases whose phenotypes have been recapitulated and studied with these cardiomyocytes. Along this, we describe the techniques currently used to study repolarization disorders in vitro, and we offer a glimpse on what will come next in this field. Finally, we analyze the translational relevance of the powerful combination between genetics and stem cell-based approaches for cardiac arrhythmias, in a context of precision medicine.

Published
2019

19. Electrical alternans during rest and exercise as predictors of vulnerability to ventricular arrhythmias

Author

Estes, N. A. 3rd, Michaud, G, Zipes, D. P, El-Sherif, N, Venditti, F. J, Rosenbaum, D. S, Albrecht, P, Wang, P. J, and Cohen, R. J

Subjects
Life Sciences (General)
Abstract

This investigation was performed to evaluate the feasibility of detecting repolarization alternans with the heart rate elevated with a bicycle exercise protocol. Sensitive spectral signal-processing techniques are able to detect beat-to-beat alternation of the amplitude of the T wave, which is not visible on standard electrocardiogram. Previous animal and human investigations using atrial or ventricular pacing have demonstrated that T-wave alternans is a marker of vulnerability to ventricular arrhythmias. Using a spectral analysis technique incorporating noise reduction signal-processing software, we evaluated electrical alternans at rest and with the heart rate elevated during a bicycle exercise protocol. In this study we defined optimal criteria for electrical alternans to separate patients from those without inducible arrhythmias. Alternans and signal-averaged electrocardiographic results were compared with the results of vulnerability to ventricular arrhythmias as defined by induction of sustained ventricular tachycardia or fibrillation at electrophysiologic evaluation. In 27 patients alternans recorded at rest and with exercise had a sensitivity of 89%, specificity of 75%, and overall clinical accuracy of 80% (p <0.003). In this patient population the signal-averaged electrocardiogram was not a significant predictor of arrhythmia vulnerability. This is the first study to report that repolarization alternans can be detected with heart rate elevated with a bicycle exercise protocol. Alternans measured using this technique is an accurate predictor of arrhythmia inducibility.

Published
1997
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24. The kinetics of spontaneous calcium oscillations and arrhythmogenesis in the in vivo heart during ischemia/reperfusion

Author

Lakireddy, V, Lakkireddy, V, Bub, G, Baweja, P, Syed, A, Boutjdir, M, and El-Sherif, N

Subjects
Male, medicine.medical_specialty, Optics and Photonics, Guinea Pigs, Ischemia, chemistry.chemical_element, Action Potentials, Myocardial Reperfusion Injury, Calcium, Ventricular tachycardia, Afterdepolarization, Heart Conduction System, Physiology (medical), Internal medicine, Optical mapping, medicine, Animals, Calcium Signaling, Membrane potential, business.industry, Arrhythmias, Cardiac, medicine.disease, Electrophysiology, Disease Models, Animal, Kinetics, chemistry, Ventricular fibrillation, Cardiology, Cardiology and Cardiovascular Medicine, business
Abstract

Background The correlation between spontaneous calcium oscillations (S-CaOs) and arrhythmogenesis has been investigated in a number of theoretical and experimental in vitro models. There is an obvious lack of studies that directly investigate how the kinetics of S-CaOs correlates with a specific arrhythmia in the in vivo heart. Objectives The purpose of the study is to investigate the correlation between the kinetics of S-CaOs and arrhythmogenesis in the intact heart using an experimental model of ischemia/reperfusion (I/R). Methods Perfused Langendorff guinea pig (GP) hearts were subjected to global I/R (10-15 minutes/10-15 minutes). The heart was stained with a voltage-sensitive dye (RH237) and loaded with a Ca 2+ indicator (Rhod-2 AM). Membrane voltage (Vm) and intracellular calcium transient (Ca i T) were simultaneously recorded with an optical mapping system of two 16 × 16 photodiode arrays. S-CaOs were considered to arise from a localized focal site within the mapped surface when these preceded the associated membrane depolarizations by 2-15 ms. Results In 135 episodes of ventricular arrhythmias from 28 different GP experiments, 23 were linked to S-CaOs that were considered to arise from or close to the mapped epicardial window. Self-limited or sustained S-CaOs had a cycle length of 130-430 ms and could trigger propagated ventricular depolarizations. Self-limited S-CaOs that followed the basic beat action potential (AP)/Ca i T closely resembled phase 3 early afterdepolarizations. Fast S-CaOs could remain confined to a localized site (concealed) or exhibit varying conduction patterns. This could manifest as (1) an isolated premature beat (PB), bigeminal, or trigeminal rhythm; (2) ventricular tachycardia (VT) when a regular 2:1 conduction from the focal site develops; or (3) ventricular fibrillation (VF) when a complex conduction pattern results in wave break and reentrant excitation. Conclusions The study examined, for the first time in the intact heart, the correlation between the kinetics of focal S-CaOs during I/R and arrhythmogenesis. S-CaOs may remain concealed or manifest as PBs, VT, or VF. A "benign looking" PB during I/R may represent "the tip of the iceberg" of an underlying potentially serious arrhythmic mechanism.

Published
2016
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29. Sports and arrhythmias: a report of the International Workshop Venice Arrhythmias 2009

Author

Giada, F, Biffi, A, Cannom, D, Cappato, R, Capucci, A, Corrado, D, Delise, P, Drezner, Ja, El Sherif, N, Estes, M, Furlanello, F, Heidbuchel, H, Inama, G, Lindsay, Bd, Maron, Bj, Maron, M, Mont, L, Olshansky, B, Pelliccia, A, Thiene, G, Viskin, S, Zeppilli, Paolo, Natale, A, Raviele, A., Cannom, Ds, Maron, Ms, Zeppilli, Paolo (ORCID:0000-0002-5228-3634), Giada, F, Biffi, A, Cannom, D, Cappato, R, Capucci, A, Corrado, D, Delise, P, Drezner, Ja, El Sherif, N, Estes, M, Furlanello, F, Heidbuchel, H, Inama, G, Lindsay, Bd, Maron, Bj, Maron, M, Mont, L, Olshansky, B, Pelliccia, A, Thiene, G, Viskin, S, Zeppilli, Paolo, Natale, A, Raviele, A., Cannom, Ds, Maron, Ms, and Zeppilli, Paolo (ORCID:0000-0002-5228-3634)

Abstract

This article is a report of an international symposium, endorsed by the Section on Sports Cardiology of the European Association for Cardiovascular Prevention and Rehabilitation, the Italian Society of Sports Cardiology, and the Italian Federation of Sports Medicine, which was held within the 11th International Workshop on Cardiac Arrhythmias (Venice Arrhythmias 2009, Venice, Italy, October 2009). The following main topics were discussed during the symposium: the role of novel diagnostic examinations to assess the risk of sudden death in athletes, controversies on arrhythmic risk evaluation in athletes, controversies on the relationship between sports and arrhythmias, and controversies on antiarrhythmic treatment in athletes. Eur J Cardiovasc Prev Rehabil 17:607-612 (C) 2010 The European Society of Cardiology

Published
2010

30. Optimal target heart rate for exercise-induced T-wave alternans.

Author

Turitto G, Caref EB, El-Attar G, Helal M, Mohamed A, Pedalino RP, El-Sherif N, Turitto, G, Caref, E B, El-Attar, G, Helal, M, Mohamed, A, Pedalino, R P, and El-Sherif, N

Abstract

Objectives: This study was conducted to determine the optimal target heart rate (HR) for the use of exercise-induced T-wave alternans (TWA) as an index for risk of malignant ventricular tachyarrhythmias.Background: Rate-dependent TWA is an index of vulnerability to ventricular tachyarrhythmias. However, false positive TWA was reported to occur in normal subjects at high HR.Methods: Two groups were evaluated: Group I: 50 patients with malignant ventricular tachyarrhythmias, who received an implantable cardioverter-defibrillator (ICD); and Group II: 55 age-matched normal subjects. In both Groups, TWA was evaluated during symptom-limited bicycle exercise test.Results: Peak HR during exercise test was 103 +/- 17 beats/min in Group I, versus 124 +/- 18 beats/min in Group II (P < 0.001). In Group I, 4 patients were excluded from analysis, due to high noise level or frequent ectopy during exercise. Out of the remaining 46 patients, TWA was present in 28 patients (61%), and absent in 18 (39%). In group II, TWA was present in four subjects (7%), and absent in 51 (93%). HR at the onset of TWA was 91 +/- 11/min in Group I, and 119 +/- 12/min in Group II (P < 0.001). Receiver operated characteristics curves demonstrated that a HR of 115 beats/min was the cutoff with the best sensitivity and specificity for TWA (100 and 96%, respectively). None of the patients in Group I developed TWA at HR > 115 beats/min, while two out of four in Group II had TWA at HR > 115/minutes. However, 13 patients in Group I who had no TWA were unable to exercise to a peak HR > 115 beats/min, compared to nine subjects in Group II.Conclusions: A target HR of 115 beats/min was highly sensitive and specific for determination of exercise-induced TWA as an index of risk of malignant ventricular tachyarrhythmias. However, a significant number of patients may not be able to achieve this target HR, resulting in an indeterminate test. The value of pharmacologic testing in this group should be assessed. [ABSTRACT FROM AUTHOR]

Published
2001

31. Correlation between the signal-averaged electrocardiogram from Holter tapes and from real-time recordings

Author

Kelen, G., Henkin, R., Lannon, M., Bloomfield, D., and el Sherif, N.

Subjects
Heart conduction system, Electrocardiography -- Methods, Arrhythmia -- Diagnosis, Heart beat -- Measurement, Health
Abstract

Readings from a real-time electrocardiograph, a device that measures the heart's electrical output, were compared to recordings from a Holter monitor, a tiny portable electrocardiograph which records heart activity of the person wearing the device, and close correlation between the results of both methods was obtained. Although the Holter systems have trouble with high frequencies, Holter analysis may be very beneficial in that it can record a number of different parameters on the same tape, which is important in analyzing abnormal heartbeats (arrhythmias). It may prove useful in observing transient ischemia (periods of insufficient oxygen to the heart) or spontaneous ventricular fibrillation (erratic contraction of the lower left heart chamber). Diagnostic accuracy using criteria for real-time systems is clinically acceptable for use until specific Holter criteria are established.

Published
1989

33. High resolution Electrocardiography and Magnetocardiography

Author

El-Sherif, N, Turritto, G, Fenici, Riccardo, Masselli, M, Lopez, L, Melillo, G., Fenici, Riccardo (ORCID:0000-0002-4664-2653), El-Sherif, N, Turritto, G, Fenici, Riccardo, Masselli, M, Lopez, L, Melillo, G., and Fenici, Riccardo (ORCID:0000-0002-4664-2653)

Abstract

Not Available

Published
1992

46. Standards for analysis of ventricular late potentials using high-resolution or signal-averaged electrocardiography. A statement by a Task Force Committee of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology.

Author

Breithardt, G, primary, Cain, M E, additional, el-Sherif, N, additional, Flowers, N C, additional, Hombach, V, additional, Janse, M, additional, Simson, M B, additional, and Steinbeck, G, additional

Published
1991
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