Real-Time Closed-Loop Suppression of Repolarization Alternans Reduces Arrhythmia Susceptibility In Vivo.

BACKGROUND: Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. METHODS: We have developed a real-time, closed-loop system to record and analyze RA from multiple intracardiac leads, and deliver dynamically R-wave triggered pacing stimuli during the absolute refractory period. We have evaluated the ability of this system to control RA and reduce arrhythmia susceptibility, in vivo. RESULTS: R-wave triggered pacing can induce RA, the magnitude of which can be modulated by varying the amplitude, pulse width, and size of the pacing vector. Using a swine model (n=9), we demonstrate that to induce a 1 µV change in the alternans voltage on the body surface, coronary sinus and left ventricle leads, requires a delivered charge of 0.04±0.02, 0.05±0.025, and 0.06±0.033 µC, respectively, while to induce a one unit change of the Kscore, requires a delivered charge of 0.93±0.73, 0.32±0.29, and 0.33±0.37 µC, respectively. For all body surface and intracardiac leads, both Δ(alternans voltage) and ΔKscore between baseline and R-wave triggered paced beats increases consistently with an increase in the pacing pulse amplitude, pulse width, and vector spacing. Additionally, we show that the proposed method can be used to suppress spontaneously occurring alternans (n=7), in the presence of myocardial ischemia. Suppression of RA by pacing during the absolute refractory period results in a significant reduction in arrhythmia susceptibility, evidenced by a lower Srank score during programmed ventricular stimulation compared with baseline before ischemia. CONCLUSIONS: We have developed and evaluated a novel closed-loop method to dynamically modulate RA in a swine model. Our data suggest that suppression of RA directly reduces arrhythmia susceptibility and reinforces the concept that RA plays a critical role in the pathophysiology of arrhythmogenesis.

An optimized method for estimating the tidal volume from intracardiac or body surface electrocardiographic signals: implications for estimating minute ventilation.

The ability to accurately monitor tidal volume (TV) from electrocardiographic (ECG) signals holds significant promise for improving diagnosis treatment across a variety of clinical settings. The objective of this study was to develop a novel method for estimating the TV from ECG signals. In 10 mechanically ventilated swine, we collected intracardiac electrograms from catheters in the coronary sinus (CS), left ventricle (LV), and right ventricle (RV), as well as body surface electrograms, while TV was varied between 0 and 750 ml at respiratory rates of 7-14 breaths/min. We devised an algorithm to determine the optimized respirophasic modulation of the amplitude of the ECG-derived respiratory signal. Instantaneous measurement of respiratory modulation showed an absolute error of 72.55, 147.46, 85.68, 116.62, and 50.89 ml for body surface, CS, LV, RV, and RV-CS leads, respectively. Minute TV estimation demonstrated a more accurate estimation with an absolute error of 69.56, 153.39, 79.33, 122.16, and 48.41 ml for body surface, CS, LV, RV, and RV-CS leads, respectively. The RV-CS and body surface leads provided the most accurate estimations that were within 7 and 10% of the true TV, respectively. Finally, the absolute error of the bipolar RV-CS lead was significantly lower than any other lead configuration (P < 0.0001). In conclusion, we have demonstrated that ECG-derived respiratory modulation provides an accurate estimation of the TV using intracardiac or body surface signals, without the need for additional hardware.

An optimized method for the estimation of the respiratory rate from electrocardiographic signals: implications for estimating minute ventilation.

It is well-known that respiratory activity influences electrocardiographic (ECG) morphology. In this article we present a new algorithm for the extraction of respiratory rate from either intracardiac or body surface electrograms. The algorithm optimizes selection of ECG leads for respiratory analysis, as validated in a swine model. The algorithm estimates the respiratory rate from any two ECG leads by finding the power spectral peak of the derived ratio of the estimated root-mean-squared amplitude of the QRS complexes on a beat-by-beat basis across a 32-beat window and automatically selects the lead combination with the highest power spectral signal-to-noise ratio. In 12 mechanically ventilated swine, we collected intracardiac electrograms from catheters in the right ventricle, coronary sinus, left ventricle, and epicardial surface, as well as body surface electrograms, while the ventilation rate was varied between 7 and 13 breaths/min at tidal volumes of 500 and 750 ml. We found excellent agreement between the estimated and true respiratory rate for right ventricular (R(2) = 0.97), coronary sinus (R(2) = 0.96), left ventricular (R(2) = 0.96), and epicardial (R(2) = 0.97) intracardiac leads referenced to surface lead ECGII. When applied to intracardiac right ventricular-coronary sinus bipolar leads, the algorithm exhibited an accuracy of 99.1% (R(2) = 0.97). When applied to 12-lead body surface ECGs collected in 4 swine, the algorithm exhibited an accuracy of 100% (R(2) = 0.93). In conclusion, the proposed algorithm provides an accurate estimation of the respiratory rate using either intracardiac or body surface signals without the need for additional hardware.

SERCA Cys674 sulphonylation and inhibition of L-type Ca2+ influx contribute to cardiac dysfunction in endotoxemic mice, independent of cGMP synthesis.

The goal of this study was to identify the cellular mechanisms responsible for cardiac dysfunction in endotoxemic mice. We aimed to differentiate the roles of cGMP [produced by soluble guanylyl cyclase (sGC)] versus oxidative posttranslational modifications of Ca(2+) transporters. C57BL/6 mice [wild-type (WT) mice] were administered lipopolysaccharide (LPS; 25 µg/g ip) and euthanized 12 h later. Cardiomyocyte sarcomere shortening and Ca(2+) transients (ΔCai) were depressed in LPS-challenged mice versus baseline. The time constant of Ca(2+) decay (τCa) was prolonged, and sarcoplasmic reticulum Ca(2+) load (CaSR) was depressed in LPS-challenged mice (vs. baseline), indicating decreased activity of sarco(endo)plasmic Ca(2+)-ATPase (SERCA). L-type Ca(2+) channel current (ICa,L) was also decreased after LPS challenge, whereas Na(+)/Ca(2+) exchange activity, ryanodine receptors leak flux, or myofilament sensitivity for Ca(2+) were unchanged. All Ca(2+)-handling abnormalities induced by LPS (the decrease in sarcomere shortening, ΔCai, CaSR, ICa,L, and τCa prolongation) were more pronounced in mice deficient in the sGC main isoform (sGCα1(-/-) mice) versus WT mice. LPS did not alter the protein expression of SERCA and phospholamban in either genotype. After LPS, phospholamban phosphorylation at Ser(16) and Thr(17) was unchanged in WT mice and was increased in sGCα1(-/-) mice. LPS caused sulphonylation of SERCA Cys(674) (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα1(-/-) versus WT mice. Taken together, these results suggest that cardiac Ca(2+) dysregulation in endotoxemic mice is mediated by a decrease in L-type Ca(2+) channel function and oxidative posttranslational modifications of SERCA Cys(674), with the latter (at least) being opposed by sGC-released cGMP.

A novel pacing method to suppress repolarization alternans in vivo: implications for arrhythmia prevention.

BACKGROUND: Repolarization alternans (RA), a pattern of ventricular repolarization that repeats on an every other beat basis, has been closely linked with the substrate associated with ventricular tachycardia/ventricular fibrillation. OBJECTIVE: To evaluate a novel method to suppress RA. METHODS: We have developed a novel method to dynamically (on R-wave detection) trigger pacing pulses during the absolute refractory period. We have tested the ability of this method to control RA in a structurally normal swine heart in vivo. RESULTS: RA induced by triggered pacing can be measured from both intracardiac and body surface leads and the amplitude of R-wave triggered pacing-induced alternans can be locally modulated by varying the amplitude and width of the pacing pulse. We have estimated that to induce a 1 µV change in alternans voltage on the body surface, coronary sinus, and left ventricle leads, a triggered pacing pulse delivered in the right ventricle of 0.04±0.02, 0.05±0.025, and 0.06±0.033 µC, respectively, is required. Similarly, to induce a 1 unit change in Kscore (ratio of alternans peak to noise), a pacing stimulus of 0.93±0.73, 0.32±0.29, and 0.33±0.37 µC, respectively, is required. We have been able to demonstrate that RA can be suppressed by R-wave triggered pacing from a site that is within or across ventricles. Lastly, we have demonstrated that the proposed method can be used to suppress spontaneously occurring alternans in the diseased heart. CONCLUSION: We have developed a novel method to suppress RA in vivo.

A novel lead configuration for optimal spatio-temporal detection of intracardiac repolarization alternans.

BACKGROUND: Electric alternans is a pattern of variation in the shape of ECG waveform that occurs every other beat. In humans, alternation in ventricular repolarization, known as repolarization alternans (RA), has been associated with increased vulnerability to ventricular tachycardia/fibrillation and sudden cardiac death. METHODS AND RESULTS: This study investigates the spatio-temporal variability of intracardiac RA and its relationship to body surface RA in an acute myocardial ischemia model in swine. We developed a real-time multichannel repolarization signal acquisition, display, and analysis system to record ECG signals from catheters in the right ventricle, coronary sinus, left ventricle, and epicardial surface before and after circumflex coronary artery balloon occlusion. We found that RA is detectable within 4 minutes after the onset ischemia and is most prominently seen during the first half of the repolarization interval. Ischemia-induced RA was detectable on unipolar and bipolar leads (both in near- and far-field configurations) and on body surface leads. Far-field bipolar intracardiac leads were more sensitive for RA detection than body surface leads, with the probability of body surface RA detection increasing as the number of intracardiac leads detecting RA increased, approaching 100% when at least three intracardiac leads detected RA. We developed a novel, clinically applicable intracardiac lead system based on a triangular arrangement of leads spanning the right ventricular and coronary sinus catheters, which provided the highest sensitivity for intracardiac RA detection when compared with any other far-field bipolar sensing configurations. CONCLUSIONS: In conclusion, intracardiac alternans, a complex spatio-temporal phenomenon associated with arrhythmia susceptibility and sudden cardiac death, can be reliably detected through a novel triangular right ventricular-coronary sinus lead configuration.