Assessment of ventricular repolarization instability and cardiac risk stratification in different pathological and abnormal conditions

Cardiovascular diseases (CVDs) represents the leading cause of mortality worldwide [1,2]. These pathological conditions are mainly characterized by a structurally abnormal heart, that is, a vulnerable substrate, prone to the abnormal generation and/or propagation of the electrical impulse, determining the onset of ventricular arrhythmias, which can result in sudden cardiac death (SCD) [3]. In this context, the assessment of ventricular repolarization from the electrocardiogram (ECG) signal has been shown to provide with valuable information for risk stratification and several electrocardiographic indices have been proposed in the literature [4]. The main objective of this thesis is to propose methodological advances for the assessment of ventricular repolarization instability in pathological and abnormal conditions. These contributions are aimed at improving the prediction of ventricular arrhythmias and, consequently, better identifying SCD risk. In particular, we have addressed this objective by developing robust methodologies for the assessment of T-wave alternans (TWA) and ventricular repolarization instability, in invasive and non-invasive cardiac signals, that have been evaluated in both experimental and clinical conditions. In the first part of the thesis, TWA was simultaneously characterized (prevalence, magnitude, time-course, and alternans waveform) in body-surface ECG and intracardiac electrograms (EGMs) signals during coronary artery occlusion. Signals from both body surface ECG and intracardiac EGMs recorded from 4 different anatomical heart locations (coronary sinus, epicardial space and left and right ventricles) were analyzed following a multilead strategy. Leads were linearly combined using the periodic component analysis (πCA) [5], which maximizes the 2-beat periodicity (TWA periodicity) content present on the available leads. Then the Laplacian Likelihood Ratio method (LLRM) [6] was applied for TWA detection and estimation. A sensitivity study for TWA detection from the 5 different locations of leads was performed, revealing that it is the combination of the ECG leads that better performs. In addition, this multilead approach allowed us to find the optimal combination of intracardiac leads usable for in-vivo monitorization of TWA directly from an implantable device, with a sensitivity comparable to the ECG analysis. These results encourage further research to determine the feasibility of predicting imminent VT/VF episodes by TWA analysis implemented in implantable cardioverter defibrillator’s (ICD) technology.Then, we have studied the potential changes induced by a prolonged exposure to simulated microgravity on ventricular repolarization in structurally normal hearts. It is well known that this environmental condition affects the control of autonomic and cardiovascular systems [7], with a potential increase on cardiac electrical instability. The effects of short- (5 days), mid- (21 days) and long- (60 days) exposure to simulated microgravity on TWA using the head-down bed-rest (HDBR) model [8] were assessed. TWA was evaluated before (PRE), during and after (POST) the immobilization period, by the long-term averaging technique in ambulatory ECG Holter recordings [9]. Additionally, we proposed an adapted short-term averaging approach for shorter, non-stationary ECG signals obtained during two stress manoeuvres (head-up tilt-table and bicycle exercise tests). Both approaches are based on the multilead analysis used in the previous study. The absence of significant changes between PRE and POST-HDBR on TWA indices suggests that a long-term exposure to simulated microgravity is not enough to induce alterations in healthy myocardial substrate up to the point of reflecting electrical instability in terms of TWA on the ECG. Finally, methodological advances were proposed for the assessment of ventricular repolarization instability from the ECG signal in the presence of sporadic (ventricular premature contractions, VPCs) and sustained (atrial fibrillation) rhythm disturbances.On the one hand, a methodological improvement for the estimation of TWA amplitude in ambulatory ECG recordings was proposed, which deals with the possible phase reversal on the alternans sequence induced by the presence of VPCs [10]. The performance of the algorithm was first evaluated using synthetic signals. Then, the effect of the proposed method in the prognostic value of TWA amplitude was assessed in real ambulatory ECG recordings from patients with chronic heart failure (CHF). Finally, circadian TWA changes were evaluated as well as the prognostic value of TWA at different times of the day. A clinical study demonstrated the enhancement in the predictive value of the index of average alternans (IAA) [9] for SCD stratification. In addition, results suggested that alternans activity is modulated by the circadian pattern, preserving its prognostic information when computed just during the morning, which is also the day interval with the highest reported SCD incidence. Thus, suggesting that time of the day should be considered for SCD risk prediction. On the other hand, the high irregularity of the ventricular response in atrial fibrillation (AF) limits the use of the most common ECG-derived markers of repolarization heterogeneity, including TWA, under this clinical condition [11]. A new method for assessing ventricular repolarization changes based on a selective averaging technique was developed and new non-invasive indices of repolarization variation were proposed. The positive impact in the prognostic value of the computed indices was demonstrated in a clinical study, by analyzing ECG Holter recordings from CHF patients with AF. To the best of our knowledge, this is the first study that attempts a non-invasive SCD stratification of patients under AF rhythm by assessing ventricular repolarization instability from the ECG signal. To conclude, the research presented in this thesis sheds some light in the identification of pro-arrhythmic factors, which plays an important role in adopting efficient therapeutic strategies. In particular, the optimal configuration for real-time monitoring of repolarization alternans from intracardiac EGMs, together with the prognostic value of the proposed non-invasive indices of alternans activity and ventricular instability variations in case of AF rhythms demonstrated in two clinical studies, would increase the effectiveness of (ICD) therapy. Finally, the analysis of ECG signals recorded during HDBR experiments in structurally healthy hearts, also provides interesting information on cardiovascular alterations produced in immobilized or bedridden patients.<br /

Evaluation of T-wave alternans activity under stress conditions after 5 d and 21 d of sedentary head-down bed rest

It is well known that prolonged microgravity leads to cardiovascular deconditioning, inducing significant changes in autonomic control of the cardiovascular system. This may adversely influence cardiac repolarization, and provoke cardiac rhythm disturbances. T-wave alternans (TWA), reflecting temporal and spatial repolarization heterogeneity, could be affected. The aim of this work was to test the hypothesis that 5 d and 21 d head-down (-6°) bed rest (HDBR) increases TWA, thus suggesting a higher underlying electrical instability and related arrhythmogenic risk.Forty-four healthy male volunteers were enrolled in the experiments as part of the European Space Agency's HDBR studies. High-fidelity ECG was recorded during orthostatic tolerance (OT) and aerobic power (AP) tests, before (PRE) and after HDBR (POST). A multilead scheme for TWA amplitude estimation was used, where non-normalized and T-wave amplitude normalized TWA indices were computed. In addition, spectral analysis of heart rate variability during OT was assessed.Both 5 d and 21 d HDBR induced a reduction in orthostatic tolerance time (OTT), as well as a decrease in maximal oxygen uptake and reserve capacity, thus suggesting cardiovascular deconditioning. However, TWA indices were found not to increase. Interestingly, subjects with lower OTT after 5 d HDBR also showed higher TWA during recovery after OT testing, associated with unbalanced sympathovagal response, even before the HDBR. In contrast with previous observations, augmented ventricular heterogeneity related to 5 d and 21 d HDBR was not sufficient to increase TWA under stress conditions

Weightlessness and Cardiac Rhythm Disorders: Current Knowledge from Space Flight and Bed-Rest Studies

Isolatedepisodesofheartrhythmdisordershavebeenreportedduring40yearsofspaceflight,triggeringresearchtoevaluatetheriskofdevelopinglife-threateningarrhythmiasinducedbyprolongedexposuretoweightlessness.Infact,theseeventscouldcompromiseastronautperformanceduringexploratorymissions,aswellasposeatrisktheastronauthealth,duetolimitedoptionsofcareonboardtheInternationalSpaceStation.Startingfromoriginalobservations,thisminireviewwillexplorethelatestresearchinthisfield,consideringresultsobtainedbothduringspaceflightandonEarth,thelatterbysimulatinglong-termexposuretomicrogravitybyhead-downbedrestmaneuverinordertoelicitcardiovasculardeconditioningonnormalvolunteers

Evaluation of Cardiac Circadian Rhythm Deconditioning Induced by 5-to-60 Days of Head-Down Bed Rest

Head-down tilt (HDT) bed rest elicits changes in cardiac circadian rhythms, generating possible adverse health outcomes such as increased arrhythmic risk. Our aim was to study the impact of HDT duration on the circadian rhythms of heart beat (RR) and ventricular repolarization (QTend) duration intervals from 24-h Holter ECG recordings acquired in 63 subjects during six different HDT bed rest campaigns of different duration (two 5-day, two 21-day, and two 60-day). Circadian rhythms of RR and QTend intervals series were evaluated by Cosinor analysis, resulting in a value of midline (MESOR), oscillation amplitude (OA) and acrophase (f). In addition, the QTc (with Bazett correction) was computed, and day-time, night-time, maximum and minimum RR, QTend and QTc intervals were calculated. Statistical analysis was conducted, comparing: (1) the effects at 5 (HDT5), 21 (HDT21) and 58 (HDT58) days of HDT with baseline (PRE); (2) trends in recovery period at post-HDT epochs (R) in 5-day, 21-day, and 60-day HDT separately vs. PRE; (3) differences at R + 0 due to bed rest duration; (4) changes between the last HDT acquisition and the respective R + 0 in 5-day, 21-day, and 60-day HDT. During HDT, major changes were observed at HDT5, with increased RR and QTend intervals’ MESOR, mostly related to day-time lengthening and increased minima, while the QTc shortened. Afterward, a progressive trend toward baseline values was observed with HDT progression. Additionally, the f anticipated, and the OA was reduced during HDT, decreasing system’s ability to react to incoming stimuli. Consequently, the restoration of the orthostatic position elicited the shortening of RR and QTend intervals together with QTc prolongation, notwithstanding the period spent in HDT. However, the magnitude of post-HDT changes, as well as the difference between the last HDT day and R + 0, showed a trend to increase with increasing HDT duration, and 5/7 days were not sufficient for recovering after 60-day HDT. Additionally, the f postponed and the OA significantly increased at R + 0 compared to PRE after 5-day and 60-day HDT, possibly increasing the arrhythmic risk. These results provide evidence that continuous monitoring of astronauts’ circadian rhythms, and further investigations on possible measures for counteracting the observed modifications, will be key for future missions including long periods of weightlessness and gravity transitions, for preserving astronauts’ health and mission success

Publications of the Space Physiology and Countermeasures Program, Cardiopulmonary Discipline: 1980-1990

A 10-year cumulative bibliography of publications resulting from research supported by the Cardiopulmonary Discipline of the Space Physiology and Countermeasures Program of NASA's Life Sciences Division is provided. Primary subjects included in this bibliography are Fluid Shifts, Cardiovascular Fitness, Cardiovascular Physiology, and Pulmonary Physiology. General physiology references are also included. Principal investigators whose research tasks resulted in publication are identified. Publications are identified by a record number corresponding with their entry in the Life Sciences Bibliographic Database, maintained at the George Washington University

Life Sciences Program Tasks and Bibliography for FY 1996

This document includes information on all peer reviewed projects funded by the Office of Life and Microgravity Sciences and Applications, Life Sciences Division during fiscal year 1996. This document will be published annually and made available to scientists in the space life sciences field both as a hard copy and as an interactive Internet web page

Aerospace medicine and biology: A cumulative index to a continuing bibliography (supplement 358)

This publication is a cumulative index to the abstracts contained in Supplements 346 through 357 of Aerospace Medicine and Biology: A Continuing Bibliography. It includes seven indexes: subject, personal author, corporate source, foreign technology, contract number, report number and accession number

Life Sciences Program Tasks and Bibliography for FY 1997

This document includes information on all peer reviewed projects funded by the Office of Life and Microgravity Sciences and Applications, Life Sciences Division during fiscal year 1997. This document will be published annually and made available to scientists in the space life sciences field both as a hard copy and as an interactive internet web page

UWOMJ Volume 70, Number 1, Spring 2000

Schulich School of Medicine & Dentistryhttps://ir.lib.uwo.ca/uwomj/1018/thumbnail.jp