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.

Utility of a Smartphone Based System (cvrPhone) to Predict Short-term Arrhythmia Susceptibility.

Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. We developed a 12-lead, blue-tooth/Smart-Phone (Android) based electrocardiogram (ECG) acquisition and monitoring system (cvrPhone), and an application to estimate RA, in real-time. In in-vivo swine studies (N = 17), 12-lead ECG signals were recorded at baseline and following coronary artery occlusion. RA was estimated using the Fast Fourier Transform (FFT) method using a custom developed algorithm in JAVA. Underlying ischemia was detected using a custom developed ischemic index. RA from each lead showed a significant (p < 0.05) increase within 1 min of occlusion compared to baseline (n = 29). Following myocardial infarction, spontaneous ventricular tachycardia episodes (n = 4) were preceded by significant (p < 0.05) increase of RA prior to the onset of the tachy-arrhythmias. Similarly, the ischemic index exhibited a significant increase following myocardial infarction (p < 0.05) and preceding a tachy-arrhythmic event. In conclusion, RA can be effectively estimated using surface lead electrocardiograms by analyzing beat-to-beat variability in ECG morphology using a smartphone based platform. cvrPhone can be used to detect myocardial ischemia and arrhythmia susceptibility using a user-friendly, clinically acceptable, mobile platform.

Utility of a smartphone based system (cvrphone) to accurately determine apneic events from electrocardiographic signals.

BACKGROUND: Sleep disordered breathing manifested as sleep apnea (SA) is prevalent in the general population, and while it is associated with increased morbidity and mortality risk in some patient populations, it remains under-diagnosed. The objective of this study was to assess the accuracy of respiration-rate (RR) and tidal-volume (TV) estimation algorithms, from body-surface ECG signals, using a smartphone based ambulatory respiration monitoring system (cvrPhone). METHODS: Twelve lead ECG signals were collected using the cvrPhone from anesthetized and mechanically ventilated swine (n = 9). During ECG data acquisition, the mechanical ventilator tidal-volume (TV) was varied from 250 to 0 to 750 to 0 to 500 to 0 to 750 ml at respiratory rates (RR) of 6 and 14 breaths/min, respectively, and the RR and TV values were estimated from the ECG signals using custom algorithms. RESULTS: TV estimations from any two different TV settings showed statistically significant difference (p < 0.01) regardless of the RR. RRs were estimated to be 6.1±1.1 and 14.0±0.2 breaths/min at 6 and 14 breaths/min, respectively (when 250, 500 and 750 ml TV settings were combined). During apnea, the estimated TV and RR values were 11.7±54.9 ml and 0.0±3.5 breaths/min, which were significantly different (p<0.05) than TV and RR values during non-apnea breathing. In addition, the time delay from the apnea onset to the first apnea detection was 8.6±6.7 and 7.0±3.2 seconds for TV and RR respectively. CONCLUSIONS: We have demonstrated that apnea can reliably be detected using ECG-derived RR and TV algorithms. These results support the concept that our algorithms can be utilized to detect SA in conjunction with ECG monitoring.

A Novel Point-of-Care Smartphone Based System for Monitoring the Cardiac and Respiratory Systems.

Cardio-respiratory monitoring is one of the most demanding areas in the rapidly growing, mobile-device, based health care delivery. We developed a 12-lead smartphone-based electrocardiogram (ECG) acquisition and monitoring system (called "cvrPhone"), and an application to assess underlying ischemia, and estimate the respiration rate (RR) and tidal volume (TV) from analysis of electrocardiographic (ECG) signals only. During in-vivo swine studies (n = 6), 12-lead ECG signals were recorded at baseline and following coronary artery occlusion. Ischemic indices calculated from each lead showed statistically significant (p < 0.05) increase within 2 min of occlusion compared to baseline. Following myocardial infarction, spontaneous ventricular tachycardia episodes (n = 3) were preceded by significant (p < 0.05) increase of the ischemic index ~1-4 min prior to the onset of the tachy-arrhythmias. In order to assess the respiratory status during apnea, the mechanical ventilator was paused for up to 2 min during normal breathing. We observed that the RR and TV estimation algorithms detected apnea within 7.9 ± 1.1 sec and 5.5 ± 2.2 sec, respectively, while the estimated RR and TV values were 0 breaths/min and less than 100 ml, respectively. In conclusion, the cvrPhone can be used to detect myocardial ischemia and periods of respiratory apnea using a readily available mobile platform.

On the efficiency and accuracy of the single equivalent moving dipole method to identify sites of cardiac electrical activation.

We have proposed an algorithm to guide radiofrequency catheter ablation procedures. This algorithm employs the single equivalent moving dipole (SEMD) to model cardiac electrical activity. The aim of this study is to investigate the optimal time instant during the cardiac cycle as well as the number of beats needed to accurately estimate the location of a pacing site. We have evaluated this algorithm by pacing the ventricular epicardial surface and inversely estimating the locations of pacing electrodes from the recorded body surface potentials. Two pacing electrode arrays were sutured on the right and left ventricular epicardial surfaces in swine. The hearts were paced by the electrodes sequentially at multiple rates (120-220 bpm), and body surface ECG signals from 64 leads were recorded for the SEMD estimation. We evaluated the combined error of the estimated interelectrode distance and SEMD direction at each time instant during the cardiac cycle, and found the error was minimum when the normalized root mean square (RMS n ) value of body surface ECG signals reached 15 % of its maximum value. The beat-to-beat variation of the SEMD locations was significantly reduced (p < 0.001) when estimated at 15 % RMS n compared to the earliest activation time (EAT). In addition, the 5-95 % interval of the estimated interelectrode distance error decreased exponentially as the number of beats used to estimate a median beat increased. When the number of beats was 4 or larger, the 5-95 % interval was smaller than 3.5 mm (the diameter of a commonly used catheter). In conclusion, the optimal time for the SEMD estimation is at 15 % of RMS n , and at that time instant a median beat estimated from 4 beats is associated with a beat-to-beat variability of the SEMD location that is appropriate for catheter ablation procedures.

A method to noninvasively identify cardiac bioelectrical sources.

BACKGROUND: We have introduced a method to guide radiofrequency catheter ablation (RCA) procedures that estimates the location of a catheter tip used to pace the ventricles and the target site for ablation using the single equivalent moving dipole (SEMD). OBJECTIVE: To investigate the accuracy of this method in resolving epicardial and endocardial electrical sources. METHODS: Two electrode arrays, each of nine pacing electrodes at known distances from each other, sutured on the left- and right-ventricular (LV and RV) epicardial surfaces of swine, were used to pace the heart at multiple rates, while body surface potentials from 64 sites were recorded and used to estimate the SEMD location. A similar approach was followed for pacing from catheters in the LV and RV. RESULTS: The overall (RV & LV) error in estimating the interelectrode distance of adjacent epicardial electrodes was 0.38 ± 0.45 cm. The overall endocardial (RV & LV) interelectrode distance error, was 0.44 ± 0.26 cm. Heart rate did not significantly affect the error of the estimated SEMD location (P > 0.05). The guiding process error became progressively smaller as the SEMD approached an epicardial target site and close to the target, the overall absolute error was ∼ 0.28 cm. The estimated epicardial SEMD locations preserved their topology in image space with respect to their corresponding physical location of the epicardial electrodes. CONCLUSION: The proposed algorithm suggests one can efficiently and accurately resolve epicardial electrical sources without the need of an imaging modality. In addition, the error in resolving these sources is sufficient to guide RCA procedures.

The single equivalent moving dipole model does not require spatial anatomical information to determine cardiac sources of activation.

Radio-frequency catheter ablation (RCA) is an established treatment for ventricular tachycardia (VT). A key feature of the RCA procedure is the need for a mapping approach that facilitates the identification of the target ablation site. In this study, we investigate the effect of the location of the reference potential and spatial anatomical constraints on the accuracy of an algorithm to identify the target site for ablation therapy of VT. This algorithm involves processing body surface potentials using the single equivalent moving dipole (SEMD) model embedded in an infinite homogeneous volume conductor to model cardiac electrical activity. We employed a swine animal model and an electrode array of nine electrodes that was sutured on the epicardial surface of the right ventricle. We identified two potential reference electrode locations: at an electrode most far away from the heart (R1) and at the average of all 64 body surface electrode potentials (R2). Also, we developed three spatial "constraining" schemes of the algorithm used to obtain the SEMD location: one that does not impose any constraint on the inverse solution (S1), one that constrains the solution into a volume that corresponds to the heart (S2), and one that constrains the solution into a volume that corresponds to the body surface (S3). We have found that R2S1 is the most accurate approach (p < 0.05 versus R1S1 at earliest activation time-EAT) for localizing epicardial electrical sources of known locations in vivo. Although the homogeneous volume conductor introduces systematic error in the estimated compared to the true dipole location, we have observed that the overall error of the estimated interelectrode distance compared to the true one was 0.4 ± 0.4 cm and 0.4 ± 0.1 cm for the R1S1 and R2S1 combinations, respectively, at the EAT (p = N.S.) and 1.0 ± 0.6 and 0.5 ± 0.4 cm, respectively, at the pacing spike time (PST, ). In conclusion, our algorithm to estimate the SEMD parameters from body surface potentials can potentially be a useful method to rapidly and accurately guide the catheter tip to the target site during a RCA procedure without the need for spatial anatomical information obtained by conventional imaging modalities.

Absence of glucose transporter 4 diminishes electrical activity of mouse hearts during hypoxia.

Insulin resistance, which characterizes type 2 diabetes, is associated with reduced translocation of glucose transporter 4 (GLUT4) to the plasma membrane following insulin stimulation, and diabetic patients with insulin resistance show a higher incidence of ischaemia, arrhythmias and sudden cardiac death. The aim of this study was to examine whether GLUT4 deficiency leads to more severe alterations in cardiac electrical activity during cardiac stress due to hypoxia. To fulfil this aim, we compared cardiac electrical activity from cardiac-selective GLUT4-ablated (G4H-/-) mouse hearts and corresponding control (CTL) littermates. A custom-made cylindrical 'cage' electrode array measured potentials (Ves) from the epicardium of isolated, perfused mouse hearts. The normalized average of the maximal downstroke of Ves ( (|d Ves/dt(min)|na), which we previously introduced as an index of electrical activity in normal, ischaemic and hypoxic hearts, was used to assess the effects of GLUT4 deficiency on electrical activity. The |d Ves/dt(min)|na of G4H −/− and CTL hearts decreased by 75 and 47%, respectively (P < 0.05), 30 min after the onset of hypoxia. Administration of insulin attenuated decreases in values of |d Ves/dt(min)|na in G4H −/− hearts as well as in CTL hearts, during hypoxia. In general, however, G4H −/− hearts showed a severe alteration of the propagation sequence and a prolonged total activation time. Results of this study demonstrate that reduced glucose availability associated with insulin resistance and a reduction in GLUT4-mediated glucose transport impairs electrical activity during hypoxia, and may contribute to cardiac vulnerability to arrhythmias in diabetic patients.

The maximal downstroke of epicardial potentials as an index of electrical activity in mouse hearts.

The maximal upstroke of transmembrane voltage (dV(m)/dt(max)) has been used as an indirect measure of sodium current I(Na) upon activation in cardiac myocytes. However, sodium influx generates not only the upstroke of V(m), but also the downstroke of the extracellular potentials V(e) including epicardial surface potentials V(es). The purpose of this study was to evaluate the magnitude of the maximal downstroke of V(es) (|dV(es)/dt (min)|) as a global index of electrical activation, based on the relationship of dV(m)/dt(max) to I(Na). To fulfill this purpose, we examined |dV(es)/dt(min)| experimentally using isolated perfused mouse hearts and computationally using a 3-D cardiac tissue bidomain model. In experimental studies, a custom-made cylindrical "cage" array with 64 electrodes was slipped over mouse hearts to measure V(es) during hyperkalemia, ischemia, and hypoxia, which are conditions that decrease I(Na). Values of |dV(es)/dt(min)| from each electrode were normalized (|dV(es)/dt (min)|(n)) and averaged (|dV(es)/dt(min)|(na)). Results showed that |dV(es)/dt(min)|(na) decreased during hyperkalemia by 28, 59, and 79% at 8, 10, and 12 mM [K(+)](o), respectively. |dV(es)/dt(min)| also decreased by 54 and 84% 20 min after the onset of ischemia and hypoxia, respectively. In computational studies, |dV(es)/dt(min)| was compared to dV(m)/dt(max) at different levels of the maximum sodium conductance G(Na), extracellular potassium ion concentration [K(+)](o), and intracellular sodium ion concentration [Na(+)](i), which all influence levels of I(Na). Changes in |dV(es)/dt(min)|(n) were similar to dV(m)/dt (max) during alterations of G(Na), [K(+)](o), and [Na(+)](i). Our results demonstrate that |dV(es)/dt(min)|(na) is a robust global index of electrical activation for use in mouse hearts and, similar to dV(m)/dt(max), can be used to probe electrophysiological alterations reliably. The index can be readily measured and evaluated, which makes it attractive for characterization of, for instance, genetically modified mouse hearts and drug effects on cardiac tissue.

Propagation and electrical impedance changes due to ischemia, hypoxia and reperfusion in mouse hearts.

The purpose of this study is to quantitatively characterize major electrical markers of cardiac ischemia in normal mouse hearts to establish a set of baseline parameters for evaluation of genetically altered mouse hearts. Optical and electrical imaging techniques were coupled with impedance measurements to quantify changes induced by global ischemia. Optical and electrical mapping studies revealed the time course of conduction slowing and local inactivation during 30 minutes of ischemia or hypoxia. Measures of myocardial electrical impedance (MEI) were made during 30 and 120 minutes of global ischemia and proved to be qualitatively similar yet quantitatively distinct when compared to results reported from other mammals. The results of this study can now be applied in the analysis of genetically altered mouse hearts that are currently becoming available to help us understand cardiac death in disease.

Acoustic and visual characteristics of cavitation induced by mechanical heart valves.

BACKGROUND AND AIM OF THE STUDY: A sudden pressure drop and recovery can induce cavitation in liquids. Mechanical heart valves (MHVs) generate such a pressure drop at closure, and cavitation generation around MHVs has been demonstrated many times. Cavitation is suspected as being a cause of blood and valve material damage. METHODS: In this in-vitro experiment, visual images and acoustic signals associated with MHV cavitation were studied to reveal cavitation characteristics. Björk-Shiley Convex-Concave valves, one with a pyrolytic carbon occluder and one with a Delrin occluder, were installed in a single-shot valve chamber. Cavitation intensity was controlled by load (dP/dt) and air content of water. The acoustic signal was measured using a hydrophone and visual images recorded with a high-speed digital camera system. RESULTS: Cavitation images showed that 10 ppm water rarely developed cavitation, unlike the 16 ppm water. A distinct peak pressure was observed at cavitation collapse that was a good indicator of MHV cavitation intensity. The average of the peak pressures revealed that cavitation intensity increased faster with increasing load for the 16 ppm water. CONCLUSION: The use of the peak pressure may be the preferred method for correlating cavitation intensity in structures for which the separation of valve closure noise and cavitation signal is difficult, as for the valves studied here.

Postoperative adjuvant chemotherapy and radiotherapy for stage II and III non-small cell lung cancer (NSCLC).

The role of postoperative adjuvant chemo-radiotherapy in the treatment of patients with non-small cell lung cancer (NSCLC) remains unclear. This study was undertaken to evaluate the survival outcomes, relapse patterns, prognostic factors and complications of postoperative adjuvant MVP chemotherapy and radiotherapy. The study involved some 96 patients who had undergone curative resection of stage II and III NSCLC between 1991 and 1996. Among these, 94 patients who completed their adjuvant treatment were analyzed. Surgery consisted of pneumonectomy (33%), single lobectomy (54%) or bilobectomy (13%). Within 4 weeks of curative resection, two cycles of MVP chemotherapy (mitomycinC 8 mg/m(2), vinblastine 8 mg/m(2), cisplatin 60 mg/m(2)) were started at 4 weeks intervals. Conventionally fractionated radiotherapy was given 3 weeks after chemotherapy to a total dose of 50 Gy in completely resected patients and 55-60 Gy in patients with positive resection margins. The TNM classification of the AJCC, as revised in 1997, was used for pathologic staging. The number of patients at AJCC stages IIa, IIb, IIIa, and IIIb were four, 40, 45, and five, respectively. A pathologically positive bronchial resection margin was found in nine patients. At the time of analysis, death was recorded in 29 patients (31%), though five had died without evidence of lung cancer. Overall 2, 3, and 5-year-survival rates for all patients were 74.2, 70.2, and 65%, respectively, and locoregional disease-free survival (LRDFS) rates were 88.6, 83.7, 74.3%, at 2, 3, and 5-years, distant metastasis disease-free survival (DMDFS) rates were 67.7, 65.0, and 63.6%, respectively. In the multivariate model, a primary tumor size of more than 5 cm and the level of pathologically positive nodes were found to be associated with poor overall survival, LRDFS and DMDFS. Although positive bronchial resection margin affected overall survival, LRDFS and DMDFS were unaffected. With respect to the first site of relapse, distant metastasis occurred more frequently (N=33, 35%) than locoregional recurrence (N=15, 16%). Grade 3 esophagitis in two patients and weight loss of more than 10% in five patients were observed during adjuvant treatment. Grade 4 pulmonary toxicity was observed in one patient after radiotherapy and this patient ultimately died 5 months after treatment. The postoperative adjuvant MVP chemotherapy and radiotherapy regimen showed relatively low locoregional recurrence and distant metastasis rates and good survival with acceptable toxicity. A prospective randomized trial, which compares this regimen to surgery alone or postoperative adjuvant radiotherapy is needed.