Catherine M. Sreenan

Prevention of High Incidence of Neurally Mediated Ventricular Arrhythmias by Afferent Nerve Stimulation in Dogs

BACKGROUND This study tested the hypothesis that the high incidence of ventricular arrhythmias caused by hypothalamic stimulation during acute myocardial ischemia could be attenuated by afferent nerve stimulation and investigated the cardiac mechanisms for those effects. METHODS AND RESULTS In 18 anesthetized dogs, stimulating electrodes were implanted in the hypothalamus and in the isolated left peroneal nerve. The chest was opened and approximately 100 plunge needles were inserted into the ventricles for 3-D activation mapping. Each animal underwent 4 episodes of 2.5 minutes of acute myocardial ischemia. The first and fourth episodes served as controls. During the second and third episodes, animals received either hypothalamic stimulation, peroneal nerve stimulation, or both. Hypothalamic stimulation significantly increased the incidence of ventricular arrhythmias. This high incidence was reduced 34% by simultaneous stimulation of the hypothalamus and peroneal nerve. 3-D mapping showed a focal origin for all ventricular arrhythmias. Hypothalamic stimulation increased the number of arrhythmic beats and decreased the coupling interval between each arrhythmic beat and the preceding beat. These effects were reduced by peroneal nerve stimulation. CONCLUSIONS Alteration in autonomic tone by hypothalamic stimulation causes a high incidence of ventricular arrhythmias during acute myocardial ischemia that can be decreased by afferent nerve stimulation.

Transgenic animals as a tool for studying the effect of the c- myc proto-oncogene on cardiac development

Transgenic animals provide a model system to elucidate the role of specific proteins in development. This model is now being used increasingly in the cardiovascular system to study cardiac growth and differentiation. During cardiac myocyte development a transition occurs from hyperplastic to hypertrophic growth. In the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc functions to regulate myocyte proliferation and/or differentiation, we examined the in vivo effect of increasing c-myc expression during fetal development and of preventing the decrease in c-myc mRNA expression that normally occurs during myocyte development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. Increased c-myc mRNA expression is associated with both atrial and ventricular enlargement in the transgenic mice. This increase in cardiac mass is secondary to myocyte hyperplasia, with the transgenic hearts containing greater than twice as many myocytes as nontransgenic hearts. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth, and suggest a regulatory role for the c-myc protooncogene in cardiac myogenesis

Regional myocyte size in two-kidney, one clip renal hypertension

Regional variations in the size and shape of isolated myocytes were studied using the two-kidney, one clip (2K1C) renal model of hypertension. Weanling male Sprague-Dawley rats (50 to 75 g) were anesthetized by ketamine (100 mg/kg) during renal artery clipping (0.2 mm internal diameter silver clip) and were then allowed to grow for 6 to 8 weeks, when the blood pressure had stabilized at 180 mmHg. Hearts were removed, weighed and then were perfused with a calcium-free Joklik medium containing collagenase. Isolated myocytes were collected from five regions and fixed in isoosmolar glutaraldehyde: right ventricular free wall (RVFW), right and left halves of the interventricular septum (RIVS, LIVS), and epicardial and endocardial halves of the left ventricular free wall (LEPI, LENDO). Myocyte volume was measured by Coulter Counter. Myocyte length was measured by sonic digitizer. Cross-sectional area was calculated from myocyte volume and length. Tailcuff systolic pressure and heart weight were significantly increased in 2K1C rats as compared to control. Body weights were not different. Cell volume was significantly increased in RIVS, LIVS, LEPI, and LENDO, but not in RVFW. Cell length was not significantly increased in any region. Thus, the 2K1C model showed a predominant left ventricular hypertrophy in which the right half of the septum acted in concert with the left ventricle. The shape of the hypertrophied myocytes, having an increase in volume due to an increase in cross-sectional area but not length, was most consistent with a pressure-induced form of cardiac hypertrophy.

Pacing After Shocks Stronger Than the Upper Limit of Vulnerability Impact on Fibrillation Induction

BACKGROUND After upper-limit-of-vulnerability (ULV) shocks of the same strength and coupling interval (CI) during the T wave, (1) the epicardial activation pattern (EAP) for the first postshock cycle is indistinguishable between shocks that do (VF) and do not (NoVF) induce ventricular fibrillation (VF) and (2) >/=3 cycles in rapid succession always occur during VF but not during NoVF episodes. To study the role of these rapid cycles, rapid pacing was performed after a shock stronger than the ULV that by itself did not induce rapid cycles and VF. METHODS AND RESULTS A 504-electrode sock was sutured to the heart in 6 pigs to map EAPs. The S2 shock strength and S1-S2 CI at the ULV were determined by T-wave scanning with an up/down protocol. Ten shocks 50 to 100 V above the ULV (aULV) were delivered at the same S1-S2 CI to confirm that VF was not induced. Then, the postshock interval after aULV shocks was scanned with an S3 pacing stimulus from the LV apex until the shortest S2-S3 CI that captured was reached. This was repeated for S4, S5, etc, until VF was induced. To induce VF, 3 pacing stimuli (S3-S5) with progressively shorter CIs were required; S3 or S3, S4 never induced VF. After cycle S5, which induced VF, 2 EAP types occurred: focal (74%) and reentrant (26%). CONCLUSIONS At least 3 cycles with short CIs are necessary for VF induction after aULV shocks. Cycles S3-S4 may create the substrate for cycle S5 to initiate VF.

Can early timed internal atrial defibrillation shocks reduce the atrial defibrillation threshold

The defibrillation threshold is markedly reduced very early following the initiation of ventricular fibrillation. The purpose of this study was to determine if the same finding holds true for atrial defibrillation. Sustained, reproducible AF was induced with programmed atrial pacing using acetyl‐β‐methylcholine chloride (40–640 μL/min) in six adult sheep (heart weight 245–300 g). Seven timing intervals (125 ms, 200 ms, 1 s, 3 s, 10 s, 30 s, and 5 min after AF induction) and two lead configurations: (1) RA as cathode and CS as anode; and (2) RA as cathode and RV apex as anode were tested. Single capacitor biphasic waveforms (3/1 ms) were delivered and atrial defibrillation thresholds (ADFTs) were determined in random order. No significant differences in leading edge voltage and total energy were detected for the RA‐CS configuration for the seven timing intervals. For the RA‐RV configuration, a significant difference was detected comparing the voltage for 125 ms to the 5‐minute timing interval. For all times except 125 ms, the RA‐RV threshold was significantly higher than the RA‐CS level. In contrast to ventricular defibrillation, the ADFT does not change significantly within the first 5 minutes after the initiation of AF for the RA‐CS configuration. However, if the shock is given very early (125 ms after AF induction) with the RA‐RV configuration, the ADFT is lowered almost to the RA‐CS level.

Effect of Altering the Left Ventricular Pressure on Epicardial Activation Time in Dogs with and without Pacing-Induced Heart Failure

AbstractBackground: The influence of an increased left ventricular end-diastolic pressure (LVEDP) on the development of lethal arrhythmias in chronic heart failure is unclear. We investigated the effect of chronic and acute LVEDP increase on the epicardial activation time of sinus (SB) and paced (PB) beats. Methods: Six dogs underwent rapid ventricular pacing at 220–280[emsp4 ]beats/min for 6–14 weeks for induction of heart failure. On the study day, baseline (ba) LVEDP was determined for the surviving heart failure animals (HF-ba), and for seven control animals (C-ba). The epicardial activation time (EAT, time between the earliest and latest epicardial activation) for five consecutive SB and five ventricular PB during the baseline hemodynamic state were recorded using a 504 electrode mapping-sock. In the control animals a 2-litre volume (vl) was infused over 10[emsp4 ]min to acutely increase the LVEDP (C-vl) to a level comparable to the chronic increased LVEDP of the HF-ba. The same volume challenge was performed in two HF animals (HF-vl) and the EAT for SB and PB was redetermined. Results: Three of six HF animals died during induction of heart failure. In the three remaining HF animals, chronic LVEDP increased from 6±1 to 17±10.8[emsp4 ]mmHg (P=0.07), EAT for SB increased by 68±% compared to control animals (HF-ba vs. C-ba, P<0.05). In contrast, in the control animals the acute rise in LVEDP from 6.8±4.5 to 14.7±6.2 mmHg P<0.05), shortened the EAT for SB (C-ba vs. C-vl, P<0.05). A similar decrease in EAT for SB caused by acute volume load was seen in the HF animals, but did not reach significance due to the small sample size (one of the three remaining HF animals died of spontaneous ventricular fibrillation before the volume load). Chronic LVEDP elevation significantly prolonged the EAT for PB from 72±11 to 120±31[emsp4 ]ms (C-ba vs. HF-ba) while acute LVEDP increase had no significant effect on EAT for PB. Conclusion: Chronic HF increases LVEDP and prolongs EAT, while an acute increase in LVEDP shortens the EAT for sinus beats. A prolongation of EAT in heart failure may make the heart more susceptible to ventricular arrhythmias and electromechanical dissociation.