Psychologic stress and threshold for repetitive ventricular response.

A psychologically stressful environment reduced the threshold of the dog's ventricle for repetitive response. Elicitation of such a response indicates the presence of electrical instability and a predisposition to ventricular fibrillation, the mechanism of sudden death.

Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave.

A link is found between T wave alternans and vulnerability to ventricular fibrillation, and a new approach is provided for quantification of susceptibility to malignant arrhythmias. Complex demodulation reveals that alternation of the electrocardiogram is concentrated during the first half of the T wave, coinciding with the vulnerable period of the cardiac cycle. During myocardial ischemia and reperfusion, there are marked increases in the degree of T wave alternans that parallel the established time course of changes in vulnerability. The influence of the sympathetic nervous system in arrhythmogenesis is also accurately detected. Ultimately, complex demodulation of the electrocardiogram could provide a technique for identification and management of individuals at risk for sudden cardiac death.

Ambient pollution and heart rate variability.

BACKGROUND: We investigated associations between ambient pollution levels and cardiovascular function in a repeated measures study including 163 observations on twenty-one 53- to 87-year-old active Boston residents observed up to 12 times from June to September 1997. Particles with aerodynamic diameter

Intrinsic sympathomimetic activity and the effects of beta-adrenergic blocking drugs on vulnerability to ventricular fibrillation.

Beta-adrenergic blocking agents differ considerably in their effects on myocardial excitable properties. The possibility that intrinsic sympathomimetic activity might contribute to such differences has not been adequately explored. This study examined the influence of intrinsic sympathomimetic activity on the electrophysiologic effects of three agents with varying degrees of such activity. Intravenous propranolol (0.5 mg/kg), oxprenolol (0.5 mg/kg) and pindolol (0.05 mg/kg) were administered in 16 anesthetized dogs. The effects of the drugs on ventricular vulnerability were studied over a 2 hour period. Propranolol and oxprenolol raised the ventricular fibrillation threshold by 42 and 56%, respectively. In contrast, pindolol resulted in an elevation of only 25%. After depletion of endogenous norepinephrine stores using reserpine, pindolol led to a decrease of the ventricular fibrillation threshold, which was reversed by propranolol. These data indicate that intrinsic sympathomimetic activity of beta-adrenergic blocking agents substantially alters their ultimate effect on myocardial excitable properties.

Angerlike behavioral state potentiates myocardial ischemia-induced T-wave alternans in canines.

OBJECTIVES: The main goal of this study was to determine whether induction of an angerlike state can result in significant levels of T-wave alternans, a marker of electrical instability, in the normal and ischemic heart. BACKGROUND: Outbursts of anger have been implicated in the occurrence of myocardial infarction and sudden cardiac death, but the pathophysiologic mechanisms remain unknown. METHODS: A standardized behavioral challenge of eliciting an angerlike state was conducted before and during a 3-min period of coronary artery occlusion in six canines. RESULTS: Precordial T-wave alternans increased from 0.04 +/- 0.02 at baseline to 1.40 +/- 0.32 mV X ms (p < 0.05) during the angerlike response. When the angerlike state and myocardial ischemia were superimposed, the augmentation in T-wave alternans magnitude (to 3.27 +/- 0.61 mV X ms, p < 0.05) exceeded their additive effects, increasing by 130% over the angerlike state alone (p < 0.05) and by 390% over occlusion alone (p < 0.05). Adrenergic influences were reduced by the beta1-adrenergic receptor blocking agent metoprolol (1.5 mg/kg, intravenous), which diminished T-wave alternans magnitude (p < 0.0004 for all) during the angerlike response (from 1.40 +/- 0.32 to 0.80 +/- 0.17 mV x ms) and during the combined intervention (from 3.27 +/- 0.61 to 1.23 +/- 0.13 mV X ms). In five additional normal anesthetized canines, atrial pacing at 180 beats/min did not increase T-wave alternans magnitude monitored from lead II electrocardiogram. CONCLUSIONS: Provocation of an angerlike state results in T-wave alternans in the normal heart and potentiates the magnitude of ischemia-induced T-wave alternans. Elevation in heart rate during arousal does not appear to be the main factor in the development of alternans in the normal heart but may be an important component during myocardial ischemia. Enhanced adrenergic activity appears to mediate the effects in both the normal and ischemic hearts. T-wave alternans may constitute a useful electrophysiologic measure for clinical use in conjunction with behavioral stress testing or ambulatory monitoring.

Persistent primary coronary dilation induced by transatrial delivery of nitroglycerin into the pericardial space: a novel approach for local cardiac drug delivery.

OBJECTIVES: We compared the effects of intrapericardial and intracoronary nitroglycerin on coronary cross-sectional area as assessed by intravascular ultrasound and demonstrated the feasibility of local cardiac drug delivery by a newly developed method to access the normal pericardial space through the right atrial appendage. BACKGROUND: Studies of nitric oxide (NO) donors have suggested that their antiarrhythmic and antiproliferative properties are more effective when administered by the intrapericardial rather than intravascular route. We postulated that NO donors delivered intrapericardially would also cause sustained coronary vasodilation without significant systemic hypotension. METHODS: Intrapericardial nitroglycerin (200 microg) was administered in five Yorkshire pigs. Coronary cross-sectional luminal area was measured with intravascular ultrasound at various time intervals. The effects of intracoronary nitroglycerin on coronary luminal area were used for comparison. RESULTS: Transatrial pericardial access required 1 to 3 min in all animals. Intrapericardial nitroglycerin was associated with a mean 31.7% increase in luminal area at 5 min (p < 0.001). Vasodilation peaked between 5 and 10 min and persisted for 15 min. In contrast, intracoronary nitroglycerin was associated with a smaller mean increase in luminal area (20.3% at 5 min, p < 0.01) that disappeared by 10 min. Significant systemic hypotension was observed at 3 min with intracoronary but not with intrapericardial nitroglycerin. CONCLUSIONS: Sustained coronary vasodilation can be achieved with intrapericardial delivery of nitroglycerin without systemic hypotension. Nitric oxide donors with longer half-lives could prove beneficial in the treatment of myocardial ischemic syndromes when administered through this route. Transatrial pericardial access offers a novel route for local cardiac drug delivery.

Effects of adrenergic and muscarinic receptor stimulation on serum potassium concentrations and myocardial electrical stability.

The influence of adrenergic and muscarinic receptor activation on cardiac electrical stability and on serum potassium concentrations was studied in 23 anaesthetised dogs. The ventricular fibrillation threshold was assessed using the single stimulus technique. Adrenaline (1.0 microgram X kg-1 X min-1) caused a brief rise and a subsequent prolonged fall in serum potassium concentration, which was accompanied by a decline in ventricular fibrillation threshold when baroreceptor activation was prevented. After pretreatment with the beta1 adrenoceptor blocking agent metoprolol (0.5 mg X kg-1), adrenaline did not alter vulnerability to ventricular fibrillation but still elicited hypokalaemia. In contrast, selective beta2 adrenoceptor blockade (ICI 118551, 100 micrograms X kg-1) prevented the adrenaline induced lowering of serum potassium concentration but not of ventricular vulnerability. Muscarinic receptor activation by methacholine (3.0 micrograms X kg-1 X min-1) had no effect on serum potassium concentration but increased the ventricular fibrillation threshold by 30%. When methacholine was administered concomitantly with adrenaline the decline in serum potassium concentration persisted, but the increase in ventricular vulnerability was completely prevented. It is concluded that in the normal canine myocardium adrenaline produces an increase in vulnerability that is mediated through beta 1 adrenoceptors and that the beta 2 adrenoceptor mediated hypokalaemia is dissociated from electrophysiological effects of adrenaline. Parasympathetic nervous system activation does not influence serum potassium concentrations but opposes the effects of adrenaline on susceptibility to ventricular fibrillation.

Comparative effects of the opioids fentanyl and buprenorphine on ventricular vulnerability during acute coronary artery occlusion.

Fentanyl, a mu selective opioid agonist in wide clinical use, raises the ventricular fibrillation threshold in the normal canine myocardium. We have previously shown that this effect is amplified by haemorrhagic stress. In order to determine if mu receptor activation is antifibrillatory during acute myocardial ischaemia, we compared the effects of two mu selective agents, fentanyl and buprenorphine, in open chest chloralose anaesthetised dogs. Each drug was administered intravenously in two doses 1 h apart (fentanyl 30 micrograms.kg-1.dose; buprenorphine 0.3 mg.kg-1.dose). Ventricular fibrillation threshold was measured during right ventricular pacing using the single stimulus technique. The threshold was determined before and during a 10 min left anterior descending coronary artery occlusion. Prior to fentanyl administration, ventricular fibrillation threshold decreased from a control value of 19(SEM 2) mA to 12(1) mA during coronary artery occlusion. After the first dose of this drug an attenuation in the ischaemia induced fall in fibrillation threshold from 23(4) mA to 15(2) mA was observed. After the second dose of fentanyl the decline in fibrillation threshold was significantly blunted at 22(4) mA during control and 18(3) mA during occlusion, p less than 0.05 compared to no drug. In an additional series of experiments atropine sulphate abolished the antifibrillatory action of fentanyl, indicating that vagal efferent activation is responsible for the protective effect of the drug during acute myocardial ischaemia. This is in contrast with its mode of action during haemorrhage, when it enhances vagal afferent inhibition of sympathetic tone, and atropine pretreatment is without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased vulnerability to ventricular fibrillation by vasodilator-induced baroreceptor sensitisation.

Vulnerability to ventricular fibrillation (VF) is affected by changes in systemic arterial blood pressure which are mediated through the sympathetic nervous system. We determined that small doses of a vasodilator drug can abolish the enhanced ventricular vulnerability induced by norepinephrine infusion. Noradrenaline (0.5 micrograms X kg-1 X min-1) caused a fall in ventricular fibrillation threshold from 30 to 20 mA (P less than 0.001). Pretreatment with prostaglandin E1, I2 or nitroglycerin at doses which reduced mean arterial blood pressure by 0.7 to 1.3 kPa (5 to 10 mmHg) abolished the enhanced vulnerability produced by noradrenaline. Following baroreceptor denervation, these agents no longer afforded protection against the profibrillatory action of noradrenaline. We conclude that small doses of vasodilator agents can augment ventricular electrical stability. The mechanism for this protective action appears to be a decrease in cardiac sympathetic tone resulting from vasodilatation of baroreceptor areas.

Protective effect of verapamil on vulnerability to ventricular fibrillation during myocardial ischaemia and reperfusion.

The effects of verapamil on vulnerability to ventricular fibrillation were studied in 55 chloralose-anaesthetised dogs. Ventricular fibrillation threshold was measured before and during a 10 min period of left anterior descending coronary artery occlusion and following abrupt release of occlusion. The action of intravenous verapamil (0.01 mg.kg-1.min-1, following a 0.1 mg.kg-1 bolus) on vulnerability to fibrillation was examined before and during coronary artery occlusion and reperfusion. While the infusion of verapamil did not alter the ventricular fibrillation threshold in the nonischaemic myocardium, the vulnerable period threshold was raised and the incidence of spontaneous ventricular fibrillation was reduced both after coronary artery occlusion and release. Since cardiocardiac sympathetic reflexes are elicited in response to coronary artery occlusion, the effect of verapamil on vulnerability during left stellate ganglion stimulation and during noradrenaline infusion was investigated. Verapamil completely prevented the reduction in vulnerable period threshold during sympathetic nerve stimulation or noradrenaline infusion. This study suggests that the antifibrillatory action of verapamil during coronary artery occlusion may be, in part, related to antagonism of enhanced adrenergic input to the heart, while the mechanism of protection during reperfusion is as yet uncertain.

Protective effect of the vagotonic action of morphine sulphate on ventricular vulnerability.

Administration of morphine sulphate to 16 anaesthetised dogs resulted in significant reduction in ventricular vulnerability to fibrillation. The repetitive extrasystole threshold was used as an index of vulnerability to ventricular fibrillation. In 14 dogs, atropine or vagotomy abolished this response. This suggests that central vagal activation by morphine sulphate may be protective against ventricular fibrillation.

Influence of autonomic nervous system stimulation on the protective zone.

The effect of sympathetic and parasympathetic stimulation on the vulnerable period threshold and the protective zone was studied in chloralose-anaesthetised dogs. Sympathetic stimulation substantially decreased the repetitive extrasystole threshold and shifted the timing of the protective zone earlier into diastole. Vagus nerve excitation exerted the opposite effect on both electrophysiological properties. During concurrent sympathetic nerve stimulation, the changes produced by vagal activation were accentuated. These findings suggest that parasympathetic influences on the protective zone are due, in part, to an antagonism of adrenergic effects on ventricular electrical properties.

Quantification of ischaemia induced vulnerability by precordial T wave alternans analysis in dog and human.

OBJECTIVE: The aim was to examine the regional specificity of T wave alternans and the value of precordial ECG monitoring for non-invasive tracking of cardiac vulnerability during acute coronary artery occlusion and reperfusion in animals and humans. METHODS: The left ventricular ECG was monitored during two acute occlusions of the left anterior descending coronary artery and subsequent reperfusion in each of 61 chloralose anaesthetised dogs, and over 150,000 beats were analysed. In subgroups of these animals, lead II and precordial lead V5 were monitored or epicardial electrograms were recorded. In seven patients, lead II and precordial leads V1-6 were monitored during angioplasty. T wave alternans magnitude was quantified by complex demodulation. The same recording equipment and analytical methods were used in the clinical and experimental studies. RESULTS: A close temporal correspondence and linear correlation was found between T wave alternans magnitude--but not ST segment depression or ventricular premature beat incidence--and the incidence of spontaneous ventricular tachycardia and fibrillation during acute coronary artery occlusion and reperfusion. Epicardial electrograms showed alternans to be regionally specific, occurring in the ischaemic but not in the normal zones, and to predict spontaneous ventricular fibrillation and ventricular tachycardia (sensitivity = 79%, specificity = 86%). A significant linear relationship (r2 = 0.86, p < 0.01) between alternans magnitude detected in V5 and the left ventricular intracavitary lead indicates that the precordial leads could be used to assess cardiac vulnerability from the body surface. Lead V5 showed greater resolution than lead II. In humans, the precordial leads overlying the ischaemic zone were superior to lead II or Frank leads for alternans detection during both the occlusion and the reperfusion phases. In both animals and humans, alternation invariably occurred during the first half of the T wave, coinciding with the vulnerable period of the cardiac cycle and suggesting an important electrophysiological link to cardiac vulnerability. CONCLUSIONS: Alternans is regionally specific and is linearly projected to the precordium. Quantification of its magnitude in the precordial ECG may provide a non-invasive means for tracking cardiac vulnerability during acute myocardial ischaemia and reperfusion in both animals and humans.

Hypoperfusion of the myocardium relative to myocardial metabolism during delayed coronary constriction.

OBJECTIVE: The aim was to test the hypothesis that the myocardium becomes hypoperfused, relative to its metabolic demands, during the delayed coronary constriction which is observed following termination of a period of sympathetic stimulation. METHODS: This was tested by beat by beat analysis of the ratio of coronary blood flow to the product of heart rate and systolic blood pressure (HR x SBP), an index of myocardial metabolism, in acutely instrumented open chest canine preparations, before, during, and after direct electrical stimulation of the left stellate ganglion. RESULTS: Myocardial metabolism increased in response to stellate stimulation, as evidenced by increases in heart rate, aortic blood pressure, and HR x SBP. These were accompanied by increased blood flow and decreased vascular resistance in the left anterior descending coronary artery. Delayed coronary constriction, defined as the period with the lowest coronary blood flow observed after the end of the stimulation, occurred 1 to 3 min after stimulation was terminated and was characterised by recovery of heart rate, blood pressure, HR x SBP, and coronary blood flow toward control levels, while coronary vascular resistance overshot to above control levels. The ratio of coronary blood flow to HR x SBP fell progressively in the poststimulation period to significantly less (mean 0.715, range of +/- 1 SEM 0.638 to 0.800, p < 0.05) than control (1.0, by definition) in experiments performed with partial prestenosis of the left anterior descending coronary artery. In a selected subgroup of observations with a mean reduction in coronary blood flow during delayed coronary constriction comparable to that reported previously, the flow/metabolism ratio was even lower (mean 0.239, range of +/- 1 SEM 0.202 to 0.284). CONCLUSIONS: The phenomenon of delayed coronary constriction clearly involves a mismatch between myocardial supply and demand: coronary blood flow becomes inappropriately low for the prevailing level of myocardial metabolism.

Effect of vagus nerve stimulation upon excitability of the canine ventricle. Role of sympathetic-parasympathetic interactions.

The effect of vagus nerve stimulation on ventricular excitability was studied in 28 dogs under various conditions of adrenergic neural tone. Strength-interval curves were delineated from the apex of the right ventricular endocardium with a transvenous bipolar catheter. Vagus nerve stimulation in both closed chest and open chest dogs shifted the strength-interval curve 6 to 8 msec later into electrical diastole (P less than 0.001). Left stellate ganglion stimulation shifted the strength-interval curve 9 to 11 msec earlier into diastole (P less than 0.001). The effect of simultaneous left stellate ganglion and vagus nerve stimulation was not significantly different from that of left stellate ganglion stimulation alone. The influence of vagus nerve stimulation on the strength-interval curve under basal conditions was abolished by acute beta adrenergic blockade with propranolol. It is concluded that vagus nerve stimulation affects ventricular excitability as well as vulnerability by opposing the effects of sympathetic neural tone.

Precordial mechanical stimulation for exposing electrical instability in the ischemic heart.

Sequenital mechanical pulsing of the chest wall with three stimuli failed to induce arrhythmias in normal dogs. After coronary arterial occlusion, this technique evoked in 11 of 12 animals repetitive ventricular tachycardia in 2. These responses corresponded closely to those elicited by electrical testing. In four conscious animals after recovery from myocardial infarction, precordial pulsing induced repetitive ventricular arrhythmias. The type of arrhythmia produced depended on the degree of prematurity of the third pulse in the sequence. The use of precordial mechanical stimulation can perhaps be modified and adapted as a method of detecting persons at high risk for sudden cardiac death.

Acute blood pressure elevation and ventricular fibrillation threshold during coronary occlusion and reperfusion in the dog.

The effect of acute elevation of arterial blood pressure on the ventricular fibrillation threshold was examined in 19 closed chest dogs anesthetized with chloralose during 10 minutes of occlusion followed by abrupt reperfusion of the left anterior descending coronary artery. Ventricular fibrillation threshold was determined using two methods of electrical testing: sequential R/T pulsing and the train of stimuli method. Blood pressure was increased with an intravenous injection of the alpha adrenergic stimulator phenylephrine. Acute hypertension significantly diminished the enhanced vulnerability associated with coronary occlusion. After denervation of the carotid sinus and aortic arch baroreceptors, elevation of blood pressure failed to affect vulnerability during occlusion. In both intact and denervated animals, the predisposition to ventricular fibrillation after reperfusion was unchanged by the increase in blood pressure. It is suggested that withdrawal of sympathetic tone mediated by the baroreceptor reflex is the basis for the protection against ventricular fibrillation resulting from elevation of blood pressure. The failure of acute hypertension to alter vulnerability during reperfusion suggests that the predisposition to ventricular fibrillation during reperfusion is due to mechanisms other than those operating during coronary occlusion.

Neural and psychologic mechanisms and the problem of sudden cardiac death.

Brain stimulation can provoke a variety of arrhythmias and lower the ventricular vulnerable threshold. In the animal with acute myocardial ischemia such stimuli suffice to provoke ventricular fibrillation. Vagal neural traffic or adrenal catecholamines are not the conduits for this brain-heart linkage. Accompanying increases in heart rate or blood pressure are not prerequisites for the changes in cardiac excitability. Increased sympathetic activity, whether induced by neural or neurohumoral action, predisposes the heart to ventricular fibrillation. Protection can be achieved with surgical and pharmacologic denervation or reflex reduction in sympathetic tone. With acute myocardial ischemia, augmented sympathetic activity accounts for the early surge of ectopic activity frequently precipitating ventricular fibrillation. Asymmetries in sympathetic neural discharge may also contribute to the genesis of serious arrhythmias. The vagus nerve, through its muscarinic action, exerts an indirect effect on cardiac vulnerability, the consequence of annulment of concomitant adrenergic influence, rather than of any direct cholinergic action on the ventricles. There exist anatomic, physiologic as well as molecular bases for such interactions. Available experimental evidence indicates that environmental stresses of diverse types can injure the heart, lower the threshold of cardiac vulnerability to ventricular fibrillation and, in the animal with coronary occlusion, provoke potentially malignant ventricular arrhythmias. Available evidence indicates that in man, as in the experimental animal, administration of catecholamines can induce ventricular arrhythmia, whereas vagal activity exerts an opposite effect. Furthermore, in certain subjects diverse stresses and various psychologic states provoke ventricular ectopic activity.

Vulnerability to ventricular fibrillation during acute coronary arterial occlusion and release.

The effect of 10 minutes of occlusion, and release of occlusion, of the left anterior descending coronary artery on vulnerability to ventricular fibrillation was studied in 15 dogs. Ventricular fibrillation threshold was determined by inducing a sequence of three closely coupled extrasystoles (sequential R/T pulsing). Within 3 minutes of occlusion the current required to induce fibrillation decreased from a control value of 56 +/- 7 ma (mean +/- standard error) to 1.6 +/- 0.3 ma (P less than 0.001). It remained at this level for about 4 minutes and then rapidly returned to the control level in 8 of 10 dogs. Upon release of occlusion at 10 minutes, the ventricular fibrillation threshold was again greatly reduced; this period of reduction occurred shortly after reperfusion and was of brief duration. After both occlusion and release the duration of the ventricular vulnerable period was prolonged. The time course of change in cardiac vulnerability parallels the altered susceptibility to ventricular fibrillation after coronary arterial occlusion and release. These results recommend sequential R/T pulsing as a useful technique for probing changes in cardiac vulnerability under diverse experimental conditions.

Effects of sulfinpyrazone on ventricular vulnerability in the normal and the ischemic heart.

The effects of sulfinpyrazone were studied in 33 chloralose-anesthetized dogs. Ventricular fibrillation thresholds, mid diastolic thresholds and duration of the effective refractory period were determined in the normal heart after intravenous administration of sulfinpyrazone, 30 mg/kg body weight. The drug significantly raised the ventricular fibrillation threshold by 24 percent and the mid diastolic threshold by 36 percent and prolonged the effective refractory period by seven percent. The influence of sulfinpyrazone during acute myocardial ischemia was evaluated before and during a 10 minute occlusion of the left anterior descending coronary artery and after abrupt release of the occlusion. Although the drug afforded significant protection during coronary occlusion, it had no effect on the ventricular fibrillation threshold after reperfusion. Because potent cardiocardiac reflexes are elicited during ischemia, the influence of sulfinpyrazone on the ventricular fibrillation threshold was studied during norepinephrine infusion. Sulfinpyrazone attenuated the reduction of the ventricular fibrillation threshold during sympathetic humoral stimulation. Its effect was additive to beta adrenergic blockade with practolol and membrane stabilization with lidocaine. This investigation suggests that sulfinpyrazone exerts significant effects on ventricular vulnerability of both the normal and the ischemic myocardium. Further studies are needed to elucidate its precise mechanism of action.