Hyperpolarized cardiac arrest with a potassium-channel opener, aprikalim.

Cardioplegic solutions that arrest the heart at or near the resting membrane potential may provide better myocardial protection than standard depolarizing hyperkalemic cardioplegia by reducing both metabolic demand and harmful transmembrane ion fluxes. This hypothesis was investigated in an isolated, blood-perfused, rabbit heart Langendorff model during 30 minutes of normothermic global ischemia. Hyperpolarized cardiac arrest induced by aprikalim, an opener of adenosine triphosphate-dependent potassium channels, was compared with hyperkalemic depolarized arrest and with unprotected global ischemia. Left ventricular pressure was recorded over a wide range of balloon volumes before ischemia and 30 minutes after reperfusion. End-diastolic pressure versus balloon volume data were fitted to a two-coefficient exponential relationship. Changes in the diastolic compliance of the left ventricle were assessed by comparison of preischemic and postischemic coefficients within each cardioplegia group. Postischemic recovery of developed pressure was used to assess changes in left ventricular systolic function. The tissue water content of each heart was also determined. Myocardial protection with aprikalim resulted in better postischemic recovery of developed pressure (90% +/- 9%) than either protection with hyperkalemic cardioplegia (73% +/- 11%) or no protection (62% +/- 9%). Myocardial tissue water content in hearts protected with hyperkalemic cardioplegia (77.4% +/- 1.4%) was less than the tissue water content of either unprotected hearts (79.4% +/- 1.2%) or hearts protected with aprikalim (78.7% +/- 0.9%). Despite these differences, neither hyperkalemic cardioplegia (p = 0.15) nor aprikalim cardioplegia (p = 0.30) was associated with a significant postischemic decrease in ventricular compliance. By contrast, unprotected global ischemia was associated with a significant decrease in ventricular compliance (p < 0.001).

Myocardial protection in the acutely injured heart: hyperpolarizing versus depolarizing hypothermic cardioplegia.

OBJECTIVES: The superiority of hyperpolarized arrest with adenosine triphosphate-sensitive potassium channel openers over standard hyperkalemic depolarizing cardioplegia during normothermic ischemia has been documented. This study examined the hypothesis that pinacidil would provide superior protection in a more clinically relevant model of an acutely injured heart and hypothermic cardioplegic arrest. METHODS: In a blood-perfused, parabiotic, rabbit heart Langendorff model, hearts underwent 15 minutes of unprotected global normothermic ischemia before the administration of 50 ml of cardioplegic solution at 4 degrees C, followed by 50 minutes of hypothermic (15 degrees C) ischemia and 30 minutes of reperfusion. The cardioplegic solutions administered consisted of Krebs-Henseleit solution alone (N = 6), Krebs-Henseleit solution with pinacidil (50 mumol/L; N = 10), Krebs-Henseleit solution with pinacidil (50 mumol/L) and glibenclamide (a potassium channel blocker, 10 mumol/L; N = 8), or St. Thomas' Hospital solution (N = 8). The percent recovery of developed pressure, linear diastolic pressure-volume relationships, and coronary blood flow were compared. RESULTS: The percent recovery of developed pressure was 32.8% +/- 2.8%, 43.0% +/- 4.3%, 46.5% +/- 2.2%, and 49.3% +/- 2.7% for the Krebs-Henseleit, the Krebs-Henseleit with pinacidil and glibenclamide, the St. Thomas' Hospital, and the Krebs-Henseleit with pinacidil groups, respectively. No hearts had ventricular fibrillation on reperfusion. CONCLUSIONS: During hypothermic hyperpolarized arrest, as opposed to normothermic ischemia as in our previous studies, there was neither an increased incidence of ventricular fibrillation nor prolonged electrical activity when compared with results during traditional hyperkalemic arrest. Myocardial protection by St. Thomas' Hospital solution and pinacidil was superior (p = 0.009) to that with Krebs-Henseleit solution alone. The protection provided by pinacidil was lost with the addition of glibenclamide, indicating that the drug has adenosine triphosphate-sensitive potassium channel activity during hypothermia.

The adenosine-triphosphate-sensitive potassium-channel opener pinacidil is effective in blood cardioplegia.

BACKGROUND: This study was designed to evaluate the adenosine-triphosphate-sensitive potassium channel opener pinacidil as a blood cardioplegic agent. METHODS: Using a blood-perfused, parabiotic, Langendorff rabbit model, hearts underwent 30 minutes of normothermic ischemia protected with blood cardioplegia (St. Thomas' solution [n = 8] or Krebs-Henseleit solution with pinacidil [50 micromol/L, n = 81) and 30 minutes of reperfusion. Percent recovery of developed pressure, mechanical arrest, electrical arrest, reperfusion ventricular fibrillation, percent tissue water, and myocardial oxygen consumption were compared. RESULTS: The percent recovery of developed pressure was not different between the groups (52.3 +/- 5.9 and 52.8 +/- 6.9 for hyperkalemic and pinacidil cardioplegia, respectively). Pinacidil cardioplegia was associated with prolonged electrical and mechanical activity (14.4 +/- 8.7 and 6.1 +/- 3.9 minutes), compared with hyperkalemic cardioplegia (1.1 +/- 0.6 and 1.1 +/- 0.6 minutes, respectively; p < 0.05). Pinacidil cardioplegia was associated with a higher reperfusion myocardial oxygen consumption (0.6 +/- 0.1 versus 0.2 +/- 0.0 mL/100 g myocardium/beat; p < 0.05) and a higher percent of tissue water (79.6% +/- 0.7% versus 78.6% +/- 1.2%; p < 0.05). CONCLUSIONS: Systolic recovery was not different between groups, demonstrating comparable effectiveness of pinacidil and hyperkalemic warm blood cardioplegia.

Myocardial protection with potassium-channel openers is as effective as St. Thomas' solution in the rabbit heart.

BACKGROUND: Previous work from our laboratory has demonstrated the advantage of adenosine triphosphate-sensitive potassium-channel openers as cardioplegic agents when compared with hyperkalemic (20 mmol/L KCl) Krebs-Henseleit solution. However, Krebs-Henseleit with 20 mmol/L KCl is not an ideal hyperkalemic cardioplegia. Therefore, we investigated the hypothesis that hyperpolarized arrest with pinacidil and aprikalim could provide equal or superior myocardial protection to hyperkalemic arrest with the widely accepted St. Thomas' solution. METHODS: Myocardial protection was compared in the blood-perfused isolated parabiotic rabbit heart Langendorff model. Twenty-four hearts were protected with a 50-mL infusion of cardioplegia for a 30-minute global normothermic ischemic period followed by 30 minutes of reperfusion. Systolic function (percent recovery of developed pressure) and the diastolic properties of the left ventricle were measured. Coronary blood flow was measured throughout each experiment. RESULTS: The percent recovery of developed pressure (mean +/- standard error of the mean) for St. Thomas' solution, pinacidil, and aprikalim was 53.1% +/- 5.4%, 64.0% +/- 3.0%, and 62.4% +/- 3.2%, respectively. The time (minutes) until mechanical and electrical arrest was significantly longer in the pinacidil (4.82 +/- 0.10 and 12.06 +/- 1.07) and aprikalim (3.33 +/- 0.28 and 11.12 +/- 0.94) groups when compared with the St. Thomas group (1.84 +/- 0.74, and 3.17 +/- 1.44). Coronary blood flow upon reperfusion was significantly greater in the pinacidil (16.4 +/- 2.1 mL/min) and aprikalim (19.4 +/- 2.8 mL/min) groups compared with the St. Thomas' solution group (8.0 +/- 1.0 mL/min), and this returned to baseline after 15 minutes of reperfusion. CONCLUSIONS: Myocardial protection with pinacidil and aprikalim is comparable with that of St. Thomas' solution in the blood-perfused isolated rabbit heart despite prolonged mechanical and electrical activity during ischemia.

Myocardial protection with pinacidil cardioplegia in the blood-perfused heart.

BACKGROUND: Adenosine triphosphate-sensitive potassium-channel openers are potent vasodilators that have been found to be cardioprotective during myocardial ischemia. The potassium-channel opener pinacidil was investigated to determine its efficacy as a cardioplegic agent. METHODS: A blood-perfused, parabiotic, isolated rabbit heart Langendorff preparation was used. Fifty-six hearts underwent 30 minutes of global normothermic ischemia after a 50-mL infusion of cardioplegia, followed by 60 minutes of reperfusion. The cardioplegia consisted of Krebs-Henseleit solution with either vehicle alone (control), 20 mmol KCl, or pinacidil (10, 50, 100, 150, or 200 mumol/L). The developed pressure was measured at baseline and after reperfusion. Coronary blood flow was measured with an in-line ultrasonic probe. RESULTS: Pinacidil (50 mumol/L), as opposed to potassium cardioplegia, provided significantly better postischemic percentage recovery of developed pressure compared with controls (68.3% +/- 4.0% versus 44.6% +/- 5.5%; p < 0.05). The time until electrical arrest was significantly shorter in the hyperkalemic group than in all other groups. Linear end-diastolic pressure-volume relationships revealed an increase in slope after ischemia in all groups. Coronary flow after 5 minutes of reperfusion was significantly higher in both the 50-mumol/L and 100-mumol/L pinacidil groups compared with traditional hyperkalemic arrest, and this returned to baseline after 15 minutes. CONCLUSIONS: The potassium channel opener pinacidil provided dose-dependent myocardial protection during global ischemia in the blood-perfused rabbit heart model. Potassium-channel openers are a promising class of drugs that may provide an alternative to traditional hyperkalemic cardioplegia.

Electrophysiologic consequences of hyperkalemic cardioplegia during surgical ischemia.

Myocardial protection strategies use cardioplegic solutions to reduce the injury induced by surgical ischemia and reperfusion. However, there is a high incidence of electrophysiologic abnormalities after cardioplegic arrest. A computerized epicardial mapping system in a porcine cardiopulmonary bypass model was used to measure the electrophysiologic consequences of different myocardial protection techniques. Both warm and cold, crystalloid and blood cardioplegic solutions were compared. The effects of hypothermia and prolonged cardiopulmonary bypass were examined in a control group that underwent a 2-hour period of hypothermia without cardioplegia or aortic cross-clamping, followed by 2 hours of normothermic reperfusion. Isochronous activation maps, unipolar electrograms, ventricular refractory periods, and pacing thresholds were measured before cardioplegic arrest and during reperfusion. Compared with the control group, crystalloid cardioplegia, but not blood cardioplegia, was accompanied by large changes in the pattern of ventricular activation and by persistent (> 2 hours) and significant slowing of the time required for complete ventricular activation. This was not the result of hypoxia. Moreover, the effective refractory period and the pacing threshold were unchanged by any cardioplegia. Our data suggest that crystalloid cardioplegia increases myocardial resistance to current flow leading to a derangement of electrical impulse propagation that may underlie arrhythmogenesis.

Integration of absolute ventricular fibrillation voltage correlates with successful defibrillation.

Previous work has suggested that at higher absolute ventricular fibrillation voltages (AVFV), the heart is more amenable to defibrillation. This study investigated in a canine model whether voltage integration of the AVFV is associated with the defibrillation success rate. The moving-average filter was used to process the ventricular fibrillation (VF) waveform recorded from Lead II of the electrocardiogram (ECG). In seven animals, defibrillation trials were analyzed using a dc shock (DCS) successful approximately 50% of the time when delivered randomly. For each of a total of 84 DCS (40% successes, 60% failures), the fibrillation waveform just prior to DCS was analyzed. The integration of the AVFV waveform was performed over various sample sizes including 1, 4, 8, 16, 64, and 128 ms, as well as the time equal to the mean VF cycle length. The results suggest that dc shocks delivered at instants of higher values of integrated AVFV over the various window sizes are associated with successful defibrillation. Window sizes less than 16 ms appeared to offer the best discrimination. The integration of AVFV over the entire VF cycle length was significantly higher for successful rather than unsuccessful DCS. This interesting observation is consistent with the clinical observation that "coarse" VF (high AVFV) is easier to defibrillate than "fine" VF (low AVFV). The use of voltage integration of AVFV may have potential implications in the improvement of defibrillation success in implantable devices.

Vector magnitude using orthogonal ECG leads during ventricular fibrillation is associated with defibrillation outcome.

Random fluctuations of ventricular fibrillation (VF) affect defibrillation; in addition, the heart is more susceptible to defibrillation at a higher absolute VF voltage (AVFV). Shocks delivered at higher AVFV waveforms from a single lead of the electrocardiogram (ECG) are more effective than conventional shocks. The authors investigated a new sensing method using multiple leads for better representation of the depolarization state of the heart. In this non-thoracotomy defibrillation study, a vector waveform derived from three orthogonal surface leads X, Y, and Z was analyzed in real time using two distinct defibrillation lead configurations, P1: RV-coil electrode (-) <--> (SVC-coil electrode + SCP) (+); and P2: RV-coil electrode (+) <--> (SVC-coil electrode + SCP) (-), where (-) represents cathode and (+) anode for the first phase of biphasic shock (RV = right ventricle, SVC = superior vena cava, SCP = subcutaneous patch). A PC-based closed-loop waveform-processing system, the peak-shock method (PSM), was developed to analyze the vector waveforms and trigger a biphasic shock at an AVFV peak. In using this defibrillation technique, an empirical threshold was applied to a weight function consisting of short-term and long-term moving averages of the vector VF waveform. A total of 340 shock trials in nine canine studies resulted in a significantly higher defibrillation success rate for the PSM compared with the conventional random-shock method (RSM), which involved shocking after a fixed VF time (54% for the PSM versus 42% for the RSM, p < 0.03). This further confirms that a susceptible period for defibrillation occurs during VF. The hardware/software design satisfied the requirements for processing the VF vector waveform in real time, and with the help of signal-processing techniques the high VF voltage could be detected at it occurred in real time. In addition, the P2 defibrillation lead configuration was significantly better than the P1 (p < 0.006).

Genesis of sigmoidal dose-response curve during defibrillation by random shock: a theoretical model based on experimental evidence for a vulnerable window during ventricular fibrillation.

The sigmoidal dose-response curve (percent success vs shock energy) suggests a probabilistic nature of defibrillation. The mechanism is still largely unknown, however, random variation in the excitable state during ventricular fibrillation (VF) is suspected. A canine defibrillation study was designed to determine whether random variation in absolute VF voltage (AVFV) (a crude marker of number of excitable cells) was related to success of defibrillation, using a DC shock successful at the 50% level. The results were: (a) transmyocardial resistance (73.4 +/- 1.4 vs 73.6 +/- 1.5 ohms) and delivered energy (6.1 +/- 1.2 vs 6.2 +/- 1.2 joules) were similar; however, (b) AVFV 2 msec prior to DC shock was greater for successful as compared to unsuccessful attempts (0.5 +/- 0.1 vs 0.3 +/- 0.0 mV, P less than 0.01). A mathematical model was subsequently developed based on fluctuation in the number of excitable cells. Variation in the state of excitability resulted in a cyclic window potentially vulnerable to defibrillation. The vulnerable window occurred at a point when the number of excitable cells was low, i.e., a higher state of total depolarization, which was in agreement with the experimental finding. For a given VF pattern, duration of the vulnerable window was regulated by the shock energy. A larger shock energy generated a wider vulnerable window and, in turn, a higher success rate. Finally, the sigmoidal dose-response curve of defibrillation was theoretically constructed by calculating the variable chances of a random DC shock occurring either in a vulnerable window or elsewhere during VF. It is concluded that a vulnerable window susceptible to defibrillation can be demonstrated in the early stages (10 sec) of VF. The mathematical model provides a theoretical basis for the vulnerable window and helps elucidate the probabilistic nature of defibrillation.

Spatial coherence: a new method of quantifying myocardial electrical organization using multichannel epicardial electrograms.

A new technique has been developed to quantify the organization of myocardial electrical activity. The spatial coherence technique employs the use of the magnitude-squared coherence (MSC) spectrum to analyze multichannel electrograms obtained during cardiac mapping. In this study, MSC values for all possible pairs of electrograms recorded from an epicardial plaque consisting of 112 electrodes were computed and systematically integrated to form a three-dimensional coherence surface, that is, a graphical representation of average coherence values versus the spatial orientation of one electrode to another. From this surface, two-dimensional graphs of average coherence versus electrode separation distance were derived, and the data were fitted to an exponentially decaying curve. Two novel parameters indicative of myocardial organization were then extracted from the curves, the coherence length parameter and the coherence plateau parameter. Higher values for these parameters were hypothesized to reflect greater levels of organization of the rhythm. A total of 164 mapping sessions were performed on nine dogs. Three-second data segments of normal sinus rhythm (NSR) and ventricular fibrillation (VF) were analyzed by using spatial coherence. Coherence lengths were found to be significantly longer (24.3 +/- 13.4 vs 0.165 +/- 0.053 mm, P = .0001) and coherence plateau values significantly higher (0.896 +/- 0.104 vs 0.098 +/- 0.008, P = .0001) for NSR than for VF. In addition, one instance of ventricular tachycardia, a rhythm more organized than VF, had coherence parameter values greater than those for VF but less than those for NSR (coherence length = 1.23 mm, coherence plateau value = 0.597). These results suggest that spatial coherence may be an effective means of quantifying the electrical organization of a particular cardiac rhythm. The advantages of this technique are (1) it extracts a single parameter from the vast amount of data that is generated in a typical mapping study, thus allowing easy characterization of different cardiac rhythms in terms of their level of organization, and (2) it does not require activation time detection, a process that is difficult when studying arrhythmias such as ventricular fibrillation.

Variation of spectral power immediately prior to spontaneous onset of ventricular tachycardia/ventricular fibrillation in implantable cardioverter defibrillator patients.

INTRODUCTION: Short-term heart rate variability (HRV) may change immediately before onset of a ventricular arrhythmia (ONSET). METHODS AND RESULTS: Power spectrum analysis was performed on instantaneous heart rate (IHR; including all beats) and normal heart rate (NHR; excluding ectopics) curves obtained at equally spaced 0.5-second intervals using a cubic spline. The database consisted of 135 sets of 1,024 RR intervals leading to ventricular arrhythmia (VA) and controls from 78 patients. Total periodogram and time course of spectral power were obtained. Ten spectral bands of 0.1-Hz bandwidth (0 to 1 Hz) were analyzed. A simple threshold technique was retrospectively used to predict the onset of a VA. RR intervals that led to VA ONSET had significantly higher total spectral power than controls (P < 0.001 for both NHR and IHR for every band). Spectral power remained constant until 100 seconds before ONSET and then increased significantly in the time window immediately preceding ONSET (P < 0.02 compared with others). Using a simple threshold method, a predictive accuracy of 68%+/-1.4% was obtained with different window sizes. Using specific spectral bands, the predictive accuracy of VA ONSET could be improved to 76% for IHR and 71% for NHR (0.8- to 0.9-Hz band). CONCLUSION: Our results suggest that a sustained higher power increase in NHR and IHR occurs during the course of 12.11+/-.57 minutes, followed by a sudden elevation in spectral power within 100 seconds of ONSET, and may be a precursor to ventricular tachycardia/ventricular fibrillation episodes.

Hyperpolarized cardioplegic arrest with nicorandil: advantages over other potassium channel openers.

BACKGROUND: Our laboratory has demonstrated that the potassium channel openers (PCOs) aprikalim and pinacidil are effective cardioplegic agents but exhibit toxicity at high doses. In this study, the effectiveness of another PCO, nicorandil, was investigated for several reasons. The chemical structure of nicorandil is distinct from other PCOs, in part because of a nitrate moiety, which may confer additional cardioprotection. Moreover, nicorandil has been approved for human use and has not been shown to exhibit significant toxicity in clinical trials. METHODS AND RESULTS: Using a blood-perfused, parabiotic, isolated rabbit heart model, 45 hearts underwent 30 minutes of global normothermic ischemia after infusion of 50 mL of cardioplegia, followed by 30 minutes of reperfusion. Cardioplegia consisted of Krebs-Henseleit solution either alone (control) or with nicorandil (100 micromol/L, 300 micromol/L, or 1 mmol/L), 20 mmol/L KCl, or nicorandil (100 micromol/L) plus glibenclamide (10 micromol/L), a potassium channel blocker. Over a wide range of volumes, left ventricular systolic function and diastolic compliance were measured at baseline and after reperfusion. The percentage of recovery of developed pressure (mean+/-SEM) for control, glibenclamide plus nicorandil, 100 micromol/L nicorandil, 1 mmol/L nicorandil, and 20 mmol/L KCl was 44.1+/-3.4%, 44.9+/-2.9%, 61.1+/-4.7%, 58.4+/-3.0%, and 63.2+/-1.5%, respectively. Postreperfusion end-diastolic pressures were significantly increased in control, 300 micromol/L nicorandil, and nicorandil plus glibenclamide groups. CONCLUSIONS: Nicorandil (100 micromol/L and 1 mmol/L) significantly improved functional recovery compared with control and was as effective as KCl cardioplegia. The protective effect of nicorandil was eliminated by glibenclamide, indicating that nicorandil is cardioprotective primarily through its capability as a PCO. In contrast to other PCOs, nicorandil produced mechanical arrest as quickly as KCl and did not show toxicity.

Defibrillation success is associated with myocardial organization. Spatial coherence as a new method of quantifying the electrical organization of the heart.

The relationship between the degree of electrical organization of ventricular fibrillation (VF) and defibrillation success was investigated in this study using a new technique to quantify organization--spatial coherence. This technique employs the use of the magnitude-squared coherence spectrum to analyze multichannel electrograms obtained during a cardiac mapping study. Magnitude-squared coherence values for all possible pairs of electrograms recorded from an epicardial plaque consisting of 112 electrodes were computed. Average coherence was plotted versus electrode separation distance, and the data were fit with an exponentially decaying curve. Two parameters indicative of myocardial organization were extracted from the curve. The coherence length (d) was defined as the distance (mm) at which the average coherence dropped to a given level, and the coherence strength was defined as the average coherence value at a given distance. Higher values for these parameters were hypothesized to indicate higher levels of organization. The spatial coherence technique was tested previously in a canine study of ventricular fibrillation (VF) and normal sinus rhythm, and the results suggested that spatial coherence parameters may be used to compare cardiac rhythms in terms of their organization. To test the hypothesis that organization is related to defibrillation success, 164 mapping sessions recorded during repeated VF induction and defibrillation trials using a monophasic waveform were performed in a close-chested canine study (n = 9) using a fixed energy and VF duration (10 seconds). Three coherence lengths and five coherence strengths were calculated for each VF episode. Results using a two-way analysis of variance with blocking between dogs showed that all of the coherence length and three of the coherence strength parameters were higher for those VF episodes that were successfully defibrillated than for those that were not (P < .05). Energy delivered and transmyocardial impedance were not significantly different between the groups. The authors conclude (1) the organization of a VF episode, as reflected in the spatial coherence parameters, is related to defibrillation success and may be partially responsible for the probabilistic nature of defibrillation and (2) the spatial coherence technique provides a means of quantifying myocardial electrical organization and is an important experimental tool that may be used to obtain a better understanding of VF and its termination.

Changes in transmyocardial impedance during prolonged ventricular fibrillation. Implications for current flow and delivered energy during DC countershock.

Transthoracic resistance (TTR) and transmyocardial resistance (TMR) were measured during 10 minutes of uninterrupted ventricular fibrillation (VF) in a canine model. TMR was measured at 10- to 50-second intervals with two wire-mesh patch electrodes in 16 dogs. TTR was measured through two identical low-impedance electrodes. A monophasic exponentially truncated pulse with a duration of 5 msec was used for measurement of TMR as well as TTR. Low-energy pulses of 100 V were used for TMR measurements and pulses of 300 V for TTR measurements. TMR showed an increase of 22.8 +/- 5.14 omega (from 96.2 +/- 12.3 omega) after 600 seconds of uninterrupted VF (p less than 0.0006). TTR showed a change of 2.4 +/- 1.94 omega, which was not statistically significant in comparison with the initial value of 69.0 +/- 11.4 omega. A mathematical model was developed to predict energy delivered to the heart after a transthoracic shock. Observed values of TMR and TTR were used in this model. With the use of this model, the predicted fall in transmyocardial current after 600 seconds of uninterrupted VF and 19.3%, and the fall in energy delivered to the heart was 14%. Our study suggests that increase in TMR may contribute to the observed lack of successful defibrillation during prolonged VF.

Quantification of acute aortic regurgitation by color Doppler flow in an experimental animal model.

Color Doppler flow studies were performed on ten anesthetized open-chest dogs. Acute aortic regurgitation was created in the dogs by a special valve-spreading catheter. The magnitude of valvular regurgitation was determined by aortic electromagnetic flow recordings of regurgitant fraction. Arbitrarily-designated grades of aortic regurgitation: mild (4%-10%), moderate (11%-30%), and severe ( greater than 30%) were assigned on the basis of electromagnetic flow. We attempted to obtain studies of varying degrees of AR in each animal. Mean regurgitant fraction for the three grades were 6.8 +/- 0.6% (n = 11), 22.0 +/- 2.4% (n = 7), and 40.4 +/- 2.5 (n = 20), respectively (each P less than 0.05). By color Doppler flow assessment, the ratio of regurgitant jet height to the left ventricular dimension at the junction of the left ventricular outflow tract and the aortic annulus (JH/LVOH) was measured in each study. AR was classified by Doppler as grade I (mild), 1%-24%; II (moderate), 25%-64%; and III (severe), greater than or equal to 65% jet height/left ventricular outflow tract height. Color Doppler flow correlated well with flowmeter assessment of regurgitant fraction. Color Doppler flow tests had a calculated sensitivity of 88%, specificity of 83%, and predictive value of 85% for significant (moderate + severe) aortic regurgitation. Our data support the concept that this method of color Doppler flow assessment provides a quantitative noninvasive evaluation of aortic regurgitation.

Changes in muscle mechanics during chronic conditioning for cardiomyoplasty.

Chronic repetitive stimulation of skeletal muscle causes significant changes in contractile mechanics and makes the muscle fatigue resistant. The purpose of this study was to quantify the magnitude and time course of these changes. One latissimus dorsi muscle from each of 28 mongrel dogs was stimulated in situ at 1 Hz for 0, 3, 7, 14, 21, 42, or 70 days. Changes in isometric and isotonic mechanical performance were measured as a function of conditioning time. Isotonic force and velocity data were fitted to the Hill equation to obtain Vmax. The most striking early change was a 30 and 26% decline in muscle mass and cross-sectional area, respectively. Coincident with this was an approximate 40% decline in tetanic and twitch tension. There was a similar decline in the rates of rise and fall of twitch and tetanus tensions (+dT/dt and -dT/dt). The decline in tetanus +dT/dt and -dT/dt followed a similar time course, suggesting that these muscle functions were under similar influences. Calculation of the isometric force data per unit of cross-sectional area minimized the effect of stimulation on isometrically measured muscle function but did not eliminate it. Fusion frequency declined 52% with conditioning. The increases in time-to-peak twitch tension and half-relaxation time were independent of cross-sectional area. Time-to-peak twitch tension and half-relaxation time increased after 7 days of stimulation and became maximal after 42 or 70 days, respectively. Time-to-peak tetanus tension was unchanged by muscle conditioning. Changes in the force-velocity relationship began after 3 days of stimulation, changed very little between 3 and 21 days of stimulation, and showed another change after 42 and 70 days of stimulation. It may be possible to better modify the muscle for dynamic cardiomyoplasty by pharmacological or stimulation regimens once the mechanism of fiber switching is better understood.

Myocardial oxygen consumption in the rabbit heart after ischemia: hyperpolarized arrest with pinacidil versus depolarized hyperkalemic arrest.

BACKGROUND: This study was designed to test the hypothesis that adenosine triphosphate-sensitive potassium channel opener (PCO)-induced hyperpolarized arrest with pinacidil minimizes cellular energy requirements during global ischemia compared with traditional, hyperkalemic depolarized arrest, which is known to be associated with ongoing energy-consuming ion transport. METHODS AND RESULTS: Using a blood-perfused parabiotic rabbit heart Langendorff model, myocardial oxygen consumption (MVO2) was compared in hearts protected with either Krebs-Henseleit solution (K-H), pinacidil (50 micromol/L in K-H), or hyperkalemic St. Thomas' solution during a 30-minute period of global, normothermic (37 degrees C) ischemia followed by 30 minutes of reperfusion. MVO2 (mL/100 g of myocardium per beat) was calculated at baseline and continuously during reperfusion with the use of an in-line flow probe and an in-line coronary sinus oximetric catheterizationeter. Systolic function (percentage recovery of developed pressure) was measured over a range of volumes using a balloon in the left ventricle. Percentage recovery of developed pressure with pinacidil (60.3%+/-3.1%) was not statistically different from that with St Thomas' solution (53.3%+/-2.8%). Pinacidil provided superior protection versus K-H (44.4%+/-4.8%, P<.05). The MVO2 was significantly (P<.05) elevated in the pinacidil group (0.77+/-0.12) compared with the St Thomas group (0.29+/-0.04) during the first 6 minutes of reperfusion. CONCLUSIONS: The cardioprotective properties of PCOs are associated with an increased myocardial oxygen demand on reperfusion. This may be related to reparative processes of viable myocytes or to a higher oxygen debt generated during ischemia that presents a significant limitation to PCO cardioplegia.

A critical period of ventricular fibrillation more susceptible to defibrillation: real-time waveform analysis using a single ECG lead.

Previous studies have suggested that variations in the underlying ventricular fibrillation (VF) waveform may be one of the factors responsible for the probabilistic nature of defibrillation. The heart appeared to be more susceptible to defibrillation at higher absolute VF voltages (AVFV). This study investigated in an open-chest canine model (n = 8), a newly developed system that analyzed the VF waveform in real-time, instantaneously determined the time to shock, and immediately delivered a fixed low energy DC shock. A two parameter tracking technique using a running long-term and short-term AVFV average was devised to automatically identify a high voltage peak area of the VF waveform, which has been hypothesized to represent a critical period susceptible to defibrillation. Using a DC shock estimated at the 50% success level, the performance using this technique in 58 defibrillation trials was compared to the performance of the conventional method of shocking at a fixed time (random shock method) in 62 trials. Patch size, electrode location, and discharge voltage were kept constant while VF duration, transmyocardial resistance (TMR), energy delivered, and AVFV at the point of shock were measured. Shock energy and current, TMR, and VF duration were similar with both shock methods. A significantly higher AVFV was observed for trials performed with the peak shock method (0.66 +/- 0.02 mV) as compared to trials performed with the random shock method (0.25 +/- 0.09 mV) (P < 0.003). Using lead II as the only sensing lead, the success rate was increased in 6 of 8 dogs (75%) with the new method. One animal showed identical performance, and one animal a worse performance. The overall increase in success rate was 24% using a single ECG lead (range 0%-100%; P < 0.04). Our data document that using this algorithm a period of high VF voltage can be detected in real-time. The improved success in the majority of animals supports the hypothesis that a critical period susceptible to defibrillation exists during VF. However, the high AVFV detected using a single ECG lead did not translate to an improved success rate in all animals. This suggests that other factors in addition to the VF voltage measured on a single lead of the ECG are important in characterizing this critical period.

Improved nonthoracotomy defibrillation based on ventricular fibrillation waveform characteristics.

The heart has been shown to be more susceptible to defibrillation at a higher absolute ventricular fibrillation voltage (AVFV) measured on the surface ECG. This study evaluated in a closed-chest canine model (n = 7) the clinical applicability of using a real-time VF waveform analysis system using an electrogram defined between the generator can and an RV endocardial electrode. Under fluoroscopic guidance, superior vena cava and RV spring coil catheter electrodes were inserted through the external jugular vein. A subcutaneous patch was placed on the left chest. A two-parameter tracking algorithm was used to dynamically identify the high AVFV area, and a biphasic shock was triggered synchronously at the next peak. The performance of this new peak shock method (PSM) was compared to the conventional method of shocking at a fixed time in 175 paired trials. Five shocks per voltage and five voltages per animal were randomized between the two methods to permit the generation of sigmoidal dose response curves for the estimation of 50% (E50), 75% (E75), and 100% (E100) success energies. Induction of VF and discharge voltage were kept constant while energy delivered, impedance (R), and AVFV at the point of shock were measured. Energy (8.63 +/- 0.40 vs 8.64 +/- 0.40 J), R (48.60 +/- 0.30 vs 48.59 +/- 0.30 omega), and current (7.50 +/- 0.18 vs 7.51 +/- 0.16 A) were not significantly different between trials for either the conventional or the PSM. The time from the onset of VF until the defibrillation shock was 7.98 +/- 1.44 seconds. Higher overall successes (46.3% vs 33.1%; P < 0.01) and lower E50, E75, and E100 were observed for the PSM. Finally, the significantly higher AVFV (9.12 +/- 0.32 vs 4.73 +/- 0.34 mV; P < 0.0001) with the peak method suggests that the high VF voltage could be detected as it occurred in real-time. The improved defibrillation success supports the use of this method for nonthoracotomy defibrillation.