Development Of Fatal Arrhythmias Research Articles

Osborn Wave Is Related to Ventricular Fibrillation and Tachycardia in Hypothermic Patients.

The Osborn wave (OW) is often observed in hypothermic patients; however, whether OW in hypothermic patients is related to the development of fatal ventricular arrhythmia, including ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT), remains undetermined. This study aimed to estimate the association between OW and the incidence of fatal ventricular arrhythmias.Methods and Results: This retrospective study used the Japanese Accidental Hypothermia Network registry database and included 572 hypothermic patients. Patients were divided into the OW group (those with OW) and non-OW group (those without OW). The relationship between the development of fatal arrhythmias and presence of OW was assessed using the chi-squared test. All patients who developed VF/VT (n=10) had OW on electrocardiogram upon hospital arrival. The presence of OW had a sensitivity of 100%, specificity of 47.8%, positive predictive value of 4.0%, and negative predictive value of 100% for VF/VT development. The in-hospital mortality rate was 22.3% in the OW group and 21.2% in the non-OW group (P=0.781). OW was observed in all hypothermic patients with VF/VT. The occurrence of ventricular arrhythmias is highly unlikely in the absence of OW on the electrocardiogram. Although the presence of OW might be used to predict these fatal arrhythmias in hypothermic patients, there was no association between the presence of OW and in-hospital mortality.

Effects of an hERG Activator, ICA-105574, on Electrophysiological Properties of Canine Hearts

In short QT syndrome, inherited gain-of-function mutations in the human ether a-go-go-related gene (hERG) K+ channel have been associated with development of fatal arrhythmias. This implies that drugs that activate hERG as a side effect may likewise pose significant arrhythmia risk. hERG activators have been found to have diverse mechanisms of activation, which may reflect their distinct binding sites. Recently, the new hERG activator ICA-105574 was introduced, which disables inactivation of the hERG channel with very high potency. We explored characteristics of this new drug in several experimental models. Patch clamp experiments were used to verify activation of hERG channels by ICA-105574 in human embryonic kidney cells stably-expressing hERG channels. ICA-105574 significantly shortened QT and QTc intervals and monophasic action potential duration (MAP90) in Langendorff-perfused guinea-pig hearts. We also administered ICA-105574 to anesthetized dogs while recording ECG and drug plasma concentrations. ICA-105574 (10 mg/kg) significantly shortened QT and QTc intervals, with a free plasma concentration of approximately 1.7 μM at the point of maximal effect. Our data showed that unbound ICA-105574 caused QT shortening in dogs at concentrations comparable to the half maximal effective concentration (EC50, 0.42 μM) of hERG activation in the patch clamp studies.

Calcium Independent Positive Inotropy By Fast Cardiac Myosin Motor Gene Transfer In Slow Myosin Dominant Ventricular Myocytes

Current inotropic drug therapies used to boost cardiac muscle performance focus on elevating the amount of calcium that is mobilized for activation of the myofilaments. These calcium based therapies can provide short term benefits, but when administered long term can actually increase mortality due to calcium overload and the development of fatal arrhythmias. Calcium mobilization has also been the key target for current gene therapy strategies (i.e. SERCA2a over-expression, PLN knockdown, S100 protein expression) to treat the failing heart. Here we present a novel form of calcium independent positive inotropy by fast cardiac myosin motor gene transfer. We designed a recombinant adenovirus to express the full length human α-myosin heavy chain (α-MyHC, MYH6) gene in rabbit or human ventricular myocytes that endogenously express almost exclusively β-MyHC. Healthy or diseased adult cardiac myocytes were isolated by enzymatic digestion and maintained in primary culture for 48 hours. Highly efficient α-MyHC gene transfer was confirmed by fluorescent immunocytochemistry and Western blotting. In all cases contractility of single cardiac myocytes was measured 48 hours after gene transfer of α-MyHC by measuring sarcomere shortening and intracellular calcium transients. Sarcomere shortening was ∼35% greater in cardiac myocytes transduced with the α-MyHC adenovirus when α-MyHC made up ∼30% of the total myosin protein. Intracellular calcium transient amplitudes, however, were not affected by α-MyHC gene transfer. In permeabilized myocyte experiments we found that α-MyHC gene transfer did not affect myofilament calcium sensitivity, but did speed the kinetics of myosin cross bridge transitions from weakly-bound to strongly-bound states. We conclude that α-MyHC gene transfer offers a novel form of calcium independent positive inotropy for β-MyHC dominant adult ventricular myocytes.

Telemetrically monitored arrhythmogenic effects of doxorubicin in a dog model of heart failure

A model of chronic heart failure has been induced in dogs by repeated intracoronary infusion of doxorubicin, which is an antineoplastic medication that has dose-limiting cardiotoxic side effects. Although many of the dogs receiving doxorubicin develop typical signs of dilated cardiomypathy over 4–6 weeks, some of them suddenly die before completing the four weekly infusions of the drug. The present study was undertaken to determine whether such sudden death may be caused by the development of fatal arrhythmias during doxorubicin treatment. This was assessed by telemetrically monitoring the EKG of seven dogs, which received intracoronary infusion of 1 mg/kg doxorubicin given in four divided weekly doses. The recordings were obtained for 8–10 h on alternate days up to 4 weeks. Echo-cardiographic recordings were obtained once a week. The acute effects with each infusion of doxorubicin included a significant increase in heart rate, and no significant change in QRS complex. The cumulative prolonged effects of doxorubicin included slight reduction in QRS amplitude and duration, and marked arrhythmic changes. Four out of seven dogs showed a spectrum of arrhythmic events such as single or groups of premature ventricular complexes (PVCs), bigeminy, ventricular tachycardia (VTAC), ventricular fibrillations (VFIB), and asystole. All dogs did not show each of the events listed above and the same dog did not show all the events all the time. One of these four dogs developed VFIB for 25 min and then asystole leading to sudden death. These studies conclusively showed that fatal arrhythmias develop in some of the dogs receiving doxorubicin treatment accounting for the sporadic incidence of sudden death. Prophylactic treatment with antiarrhythmic agents may prevent such adverse events.

Effects of angiotensin II type 1 receptor antagonist (candesartan) in preventing fatal ventricular arrhythmias in dogs during acute myocardial ischemia and reperfusion.

Fatal arrhythmias may be prevented by long-term oral administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 (AT 1 ) receptor antagonists. However, there have been no studies evaluating the electrophysiologic changes that occur with the acute administration of AT 1 receptor antagonists during acute myocardial ischemia and reperfusion. This study aimed to evaluate the ability of candesartan to prevent fatal arrhythmias during acute myocardial ischemia and reperfusion. The left anterior descending (LAD) coronary artery was ligated for 10 min and then reperfused for 10 min in 45 adult mongrel dogs. Candesartan (1 mg/kg) or saline was administered intravenously 10 min before ligation of the LAD coronary artery (candesartan group [n = 20] and control group [n = 25], respectively). Changes in ventricular effective refractory period (ERP) and intramyocardial conduction time (ICT) in the risk area were compared during LAD occlusion and reperfusion. Ischemia-induced shortening of ERP was inhibited in the candesartan group compared with the control. There was a 4.7 +/- 5.8% increase in ERP in the candesartan group, compared with a 11.5 +/- 6.3% shortening in the control group (p < 0.01). Prolongation of ICT was inhibited in the candesartan group compared with the control group during both ischemia and reperfusion (maximal prolongation of ICT: 0.1 +/- 3.0% vs. 37.7 +/- 9.6%, respectively; p < 0.01). Incidence of ventricular fibrillation was lower in the candesartan group than in the control group (25% [5/20] vs. 72% [18/25], respectively; p < 0.01). Candesartan suppresses changes in ERP and ICT during acute myocardial ischemia and reperfusion, suggesting that candesartan can prevent the development of fatal arrhythmias.

Tuberculous aortitis with coronary ostial and left ventricular outflow obstruction: Unusual cause of sudden unexpected death

Tuberculous aortitis is a distinct, but uncommon, cause of thoracic and abdominal aortic aneurysms. We report an unusual case of tuberculous aortitis in a 12-year-old girl that resulted in her sudden death. The patient suffered from undiagnosed primary pulmonary tuberculosis affecting the apical region of her right lower lobe, with regional hilar lymphadenopathy. The granulomatous inflammatory process spread from the hilar lymph nodes to the aortic root, leading to tuberculous aortitis and the formation of an intraluminal tuberculoma just superior to the aortic valve. The tuberculoma also involved the ostia and proximal portions of both coronary arteries, resulting in obstruction of the coronary arteries in addition to the left ventricular outflow tract. The consequent myocardial fiber hypertrophy and interstitial fibrosis predisposed the patient to the development of fatal arrhythmias that most probably accounted for her sudden death.

Verapamil has antiarrhythmic effects that are mediated in brain through endogenous opioids.

The purpose of this study was to examine the hypothesis that the calcium channel blocker verapamil modulates catecholamine-induced arrhythmias in brain and to explore potential mechanisms of action. Wistar rats with catheters previously inserted in the lateral cerebral ventricle and femoral artery received verapamil 10 or 50 micrograms/kg or the diluent (intracerebroventricularly, i.c.v.) into the lateral cerebral ventricle. Epinephrine was infused to produce arrhythmias. Onset of ventricular arrhythmias, premature ventricular complexes (PVCs), occurred at a significantly (p < 0.05) higher epinephrine dose after the higher dose of verapamil. Development of fatal arrhythmias, mainly ventricular tachyarrhythmias, occurred at significantly (p < 0.05) higher epinephrine concentrations with verapamil 50 micrograms/kg i.c.v. as compared with controls. Comparison of the two enantiomers of verapamil (50 micrograms/kg i.c.v.) showed that S(-)verapamil had the same effect as the racemic mixture whereas R(+)verapamil was intermediate between the control and S(-)verapamil. The antiarrhythmic action of verapamil could not be explained by alteration of the blood pressure (BP) response to epinephrine. Endogenous opioids were implicated in this action of verapamil because the (-)enantiomer of naloxone, which is an opioid antagonist, significantly (p < 0.05) antagonized the antiarrhythmic effects of centrally administered verapamil to suppress epinephrine-induced arrhythmias. In contrast the (+)enantiomer of naloxone did not alter verapamil-induced increase in arrhythmia threshold. Pretreatment with pertussis toxin i.c.v. antagonized the effects of verapamil. Verapamil did not alter the cyclic AMP response to isoproterenol in lymphocytes isolated from Wistar rats not exposed to any other drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine and morphiceptin increase the threshold for epinephrine-induced cardiac arrhythmias in the rat through brain mu opioid receptors.

1. To determine whether morphine modulates the development of cardiac arrhythmias through mu opioid receptors by an action within the central nervous system (CNS). Catecholamine-induced ventricular arrhythmias were produced, in the rat, by continuous infusion of epinephrine at incremental doses until the development of fatal arrhythmias, usually ventricular fibrillation. 2. Morphine, 0.1 mg/kg i.v., significantly suppressed (P < 0.05) the development of epinephrine-induced arrhythmias compared with the control group. This was opposed by the mu opioid antagonist naloxone (1 or 2 mg/kg) in a dose-dependent manner. 3. To determine whether these effects were operative in the brain, rats received an injection of either morphine 50 micrograms/kg or its diluent (control) into the lateral cerebral ventricle intracerebroventricularly (i.c.v.). Morphine significantly increased (P < 0.05) the threshold for the development of arrhythmias. 4. To further explore whether this effect was operative at the mu opioid receptor, a more specific mu opioid receptor agonist morphiceptin (50 micrograms/kg) was administered i.c.v. and produced a significant increase (P < 0.05) in the threshold for cardiac arrhythmias compared with controls. 5. The action of morphine was further established to be operating through mu opioid receptors from experiments with the i.c.v. administration of naloxone (+) and naloxone (-) followed by morphine showing that the action of morphine in the brain was prevented by the opioid antagonist naloxone but not by its stereo-isomer that is not a mu opioid receptor antagonist. 6. These data suggest a role for morphine to modulate cardiac arrhythmias, specifically to increase arrhythmia threshold, through an action within the CNS at mu opioid receptors.

The opioid agonist ethylketocyclazocine accentuates epinephrine-induced cardiac arrhythmias in the rat through an action in the brain

The purpose of this study was to determine whether the opioid receptor agonist ethylketocylazocine (EKC) modulates the development of cardiac arrhythmias by an action within the central nervous system. Catecholamine-induced ventricular arrhythmias were produced in the rat by continuous infusion of epinephrine, at incremental doses, until the development of fatal arrhythmias that were usually ventricular fibrillation. EKC, 1 mg/kg, intravenously (IV) significantly ( p < 0.05) accentuated the manifestations of or reduced the threshold for epinephrineinduced arrhythmias. The effect of EKC was prevented by the kappa opioid antagonist MR 2266 in a dose-dependent manner. To determine whether the central nervous system is a site of this action of EKC, rats received injection of either EKC or the diluent (control) into the lateral cerebral ventricle (ICV). EKC, 100 and 200 μg/kg ICV, significantly ( p < 0.05) altered the doseeffect relationship between epinephrine and arrhythmias so that EKC accentuated the development of cardiac arrhythmias. These data indicate that EKC, through an action in the brain, modulates cardiac arrhythmias and suggests a role for opioid receptor agonists, such as EKC, in cardiac arrhythmias and perhaps sudden cardiac death in man.

Morphine and the endogenous opioid dynorphin in the brain attenuate digoxin-induced arrhythmias in guinea pigs.

The effects of the opioid receptor agonists morphine and dynorphin on digoxin-induced arrhythmias were examined in guinea pigs that had received intravenous digoxin (50 mu/kg bolus plus 500 mu/kg/hr intravenously). Animals received either morphine (50 or 100 micrograms/kg) or dynorphin A(1-13) (50 or 100 micrograms/kg) or saline (the diluent) into the lateral cerebral ventricle (intracerebroventricularly) prior to digoxin. Morphine and dynorphin produced significant (P < 0.05) dose-dependent increases in the threshold of digoxin-induced arrhythmias. The mean digoxin dose at the development of fatal arrhythmias was 775 +/- 42 micrograms/kg in the control group but was significantly higher namely 958 +/- 45 micrograms/kg after 100 micrograms/kg of morphine ICV, and 984 +/- 47 micrograms/kg after 100 micrograms/kg of dynorphin A (1-13) intracerebroventricularly. In the absence of digoxin, the highest doses of each of these opioids did not produce arrhythmias. Changes in blood pressure and heart rate were unlikely explanations for the observed actions of these opioids as morphine accentuated the increase in blood pressure that accompanied digoxin while dynorphin was associated with a lower blood pressure with digoxin, despite similar effects on arrhythmias. In the control group, fatal digoxin-induced arrhythmias were ventricular tachyarrhythmias in two-thirds of cases and complete heart block in the rest. Morphine and dynorphin reduced the development of ventricular tachyarrhythmias. The role of the cholinergic system was explored, with morphine, utilizing atropine sulfate which crosses the blood brain barrier and atropine methylnitrate which does not enter the CNS. Atropine sulfate but not atropine methylnitrate reversed the effects of morphine on digoxin-induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

The calcium antagonist diltiazem has antiarrhythmic effects which are mediated in the brain through endogenous opioids

The purpose of this study was to examine the hypothesis that the calcium channel blocker, diltiazem, modulates catecholamine-induced arrhythmias through CNS mechanisms. Rats, that had catheters previously inserted into the lateral cerebral ventricle and femoral artery, received diltiazem, 10 or 50 μg/kg or the diluent, into the lateral cerebral ventricle (i.c.v.). Epinephrine was infused to produce arrhythmias. The onset of ventricular arrhythmias, premature ventricular complexes, occurred at a significantly ( P < 0.05) greater dose of epinephrine, after diltiazem, compared to the control group and in a dose-dependent manner, with the mean (± 1 SEM) dose of epinephrine being 198 ± 5, 175 ± 13 and 115 ± 15 μg/kg in the groups treated with 50 and 10 μg/kg of diltiazem and the control groups, respectively. The development of fatal arrhythmias, mainly ventricular tachyarrhythmias, occurred at significantly ( P < 0.05) greater concentrations of epinephrine with diltiazem, 50 and 10 μg/kg, 225 ± 5 and 183 ± 13 μg/kg, respectively, compared to controls, 131 ± 15 μg/kg. Endogenous opioids of the mu-type were implicated in this action of diltiazem, because the mu opioid antagonist naloxone, 1 mg/kg (i.V.), significantly ( P < 0.05) antagonized the antiarrhythmic effects of centrally administered diltiazem and the mu opioid agonist DAGO (i.c.v.), did not further enhance the suppression of epinephrine-induced arrhythmias, produced by diltiazem, 50 μg/kg. Atropine sulfate, which crosses the blood-brain barrier and atropine methylnitrate, which does not enter the brain, each at 1 mg/kg (i.V.), produced an equal and significant antagonism of the effect of diltiazem, 50 μg/kg, that was less than that of naloxone. The combination of naloxone plus atropine sulfate completely prevented the effect of diltiazem, 50 μg/kg, on arrhythmias. The antiarrythmic action of diltiazem could not be explained by alteration of the blood pressure or heart rate response to epinephrine. The results suggest that: (a) calcium channels on neurons in the CNS play an important role in the modulation of epinephrine-induced cardiac arrhythmias, (b) diltiazem can suppress arrhythmias through CNS mechanisms, (c) activation of the parasympathetic nervous system mediates some of the effect of diltiazem, but (d) the mechanism of action of diltiazem is modulated through endogenous opioids.

Angiotensin in the brain suppresses epinephrine-induced cardiac arrhythmias through CNS opioid mechanisms

To test the hypothesis that angiotensin II (Ang II) in the central nervous system modulates catecholamine-induced cardiac arrhythmias and to determine whether endogenous opioids are operative in this action, arrhythmias were produced in male Wistar rats, by continuous infusion of epinephrine at incremental doses until the development of fatal arrhythmias that were usually ventricular fibrillation. Rats were instrumented with catheters in the lateral cerebral ventricle, femoral vein and femoral artery. Ang II, 0.5 ug, in the lateral cerebral ventricle (ICV) markedly and significantly (p < 0.05) increased the epinephrine dose, at the occurence of ventricular premature beats compared to the control group 228 ± 11 (SEM) vs 116 ± 7 ug epinephrine/kg and at the onset of fatal arrhythmias 225 ± 13 vs 185 ± 9 ug epinephrine/kg. Ang II, 0.5 ug i.v., did not affect arrhythmia threshold. The angiotensin converting enzyme inhibitor captopril, 1 mg/kg, decreased arrhythmia threshold as ventricular arrhythmias were first noted at 106 ± 4 and fatal arrhythmias occured at 118 ± 4 ug epinephrine/kg. The Ang II receptor antagonist saralasin 150 ug/kg ICV, blunted and 300 ug/kg ICV reversed the effect of Ang II. The mu opioids antagonist naxolone and the kappa opioid antagonist MR 2266, 50 ug/kg ICV, prevented the effect of Ang II on fatal arrhythmias. The action Ang II on arrhythmias could not be explained by the effects of Ang II on blood pressure or heart rate. These data indicate a role for Ang II within the CNS to modulate cardiac arrhythmias and that this is mediated, in part, by endogenous opioids.

Arrhythmias and mortality in congestive heart failure

The extent and severity of myocardial dysfunction and risk of dying are associated with the occurrence of ventricular arrhythmias. However, there is a dissociation between the frequency of ventricular arrhythmias and the prevalence of sudden death among patients with congestive heart failure. Sudden death occurs in 8 to 10% of New York Heart Association functional class I patients and in 20% of class II, III and IV patients, despite increased frequency of malignant arrhythmias and functional deterioration. Yearly mortality rates increase from 12 to 15% in class I and II and is 60% in class IV. Sudden death in class I and II is 50 to 60% of all deaths, whereas in class IV it amounts to only 20 to 30%. The most important cause of death in class IV is progressive congestive heart failure. Ventricular arrhythmia is a trigger event in the development of fatal arrhythmia which depends on a substrate of myocardial scar tissue, hypertrophy and aberrant conducting pathways. However, regional myocardial ischemia, transmembrane electrolyte differences and myocardial stores of catecholamines are important modulators. Depletion of myocardial catecholamines and down-regulation of myocardial β-adrenergic receptors in the myocardium may explain tolerance to ventricular tachyarrhythmias observed in patients with severe congestive heart failure and intolerance to conventional antiarrhythmic drugs. Although angiotensin-converting enzyme (ACE) inhibitors may reduce ventricular arrhythmias, the important role of ACE inhibitors in severe congestive heart failure is to prevent progression of myocardial dysfunction and congestive heart failure. To date, however, ACE inhibitors have not been demonstrated to have a significant effect on the incidence of sudden death. This does not preclude an effect on fatal arrhythmias among patients with milder heart failure and intact stores of myocardial catecholamines.

The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs.

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 micrograms/kg i.v. bolus of digoxin followed by 500 micrograms.kg-1.h-1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p less than 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p less than 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 micrograms/kg bolus and 50 micrograms.kg-1.h-1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg.kg-1.h-1 i.v., was followed by 100 micrograms/kg digoxin i.v. every 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of D-Ala-2-Me-Phe-4-Gly-ol-5 enkephalin on epinephrine-induced arrhythmias in the rat and the interrelationship to the parasympathetic nervous system

The purpose of this study was to evaluate the effects of the mu opioid agonist D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) on catecholamine-induced arrhythmias. Arrhythmias were produced, in the rat, by continuous infusion of epinephrine until the development of fatal arrhythmias that were usually ventricular fibrillation. Intracerebroventricular (ICV) administration of DAGO, 3 nmol, significantly (p < 0.05) shifted to the right the relationship between epinephrine and both the onset of ventricular arrhythmias and the development of fatal arrhythmias. Naloxone, 1 mg/kg i.v., prevented these effects of DAGO. Atropine, 1 mg/kg i.v. or 20 ug/kg ICV, prevented the shift in these dose response relationships. Antagonism of DAGO's effects on arrhythmias could not be explained by an alteration of the blood pressure response to epinephrine. However, DAGO significantly increased blood pressure and decreased heart rate in separate experiments in animals that did not receive epinephrine and atropine prevent the heart rate and blood pressure effects of DAGO. These data show that 1) the mu opioid receptor agonist DAGO suppresses epinephrine-induced arrhythmias, 2) the site of action can be within the CNS, 3) there is a role for the central parasympathetic nervous system to mediate the effect of DAGO and 4) endogenous opioids could modulate catecholamine-induced cardiac arrhythmias.

Protective effect of verapamil upon ouabain-induced cardiac arrhythmias.

Protective influence of verapamil upon ouabain-induced cardiac arrhythmias was investigated in anesthetized (alpha-chloralose 60 mg/kg and urethane 500 mg/kg) open-chest guinea pigs. Verapamil in doses between 100 and 150 micrograms/kg significantly increased (80-90%) the dose of ouabain, necessary to cause ventricular arrhythmias. This was also associated with a larger survival rate. A larger dose of verapamil (225 micrograms/kg) caused a further increase in the dose of ouabain, necessary for the initiation of arrhythmias, but in all the cases second or third degree heart block occurred. Verapamil (150 micrograms/kg) also prevented the development of fatal arrhythmias and death, when it was administered at the onset of ventricular ectopy. However, once the arrhythmias were firmly established, verapamil was ineffective in reversing the toxic response. The data suggests that verapamil exerts a protective effect against the development of digitalis-induced cardiac arrhythmias in doses which are comparable to therapeutic levels in humans. The larger doses of verapamil, however, will be contradicted because of the slowing of AV node and the likelihood of complete heart block.

The effect of D-Ala-2-Me-Phe-4-Met-(O)-OL enkephalin on blood pressure, heart rate and digoxin-induced arrhythmias in the guinea pig

The cardiovascular effects of D-Ala-2-Me-Phe-4-Met-(O)-01 enkephalin were investigated after its administration into the fourth cerebroventricle of the guinea pig. This enkephalin is a synthetic Met-enkephalin analog that is more resistant to degradation and has a high affinity for opioid receptors. It produced a significant increase in blood pressure and decline in heart rate. At high concentrations, 100 ug/kg plus 100 ug/kg/hr in the fourth ventricle, it produced bradyarrhythmias that were sometimes fatal. At doses that did not alter survival or produce arrhythmia, namely 30 ug/kg plus 25 ug/kg/hr in the fourth ventricle, the response to digitalis was assessed. Significant leftward shifts in the relationships between digoxin and arrhythmia occurrence and development of fatal arrhythmias were observed. Thus, D-ala-2-Me-Phe-4-Met-(O)-01 enkephalin has definite cardiovascular effects that include potentiation of digoxin arrhythmias.

Factitious Lowering of the Serum Potassium Level After Cardiopulmonary Resuscitation

Hypokalemia has been suggested as a predisposing factor to the development of fatal arrhythmias in acute myocardial infarction. Evidence cited to support this concept has been derived largely from studies in which the determination of the serum potassium level was made following a cardiac arrhythmia and/or arrest, and often following cardiopulmonary resuscitation (CPR); this postresuscitation potassium level has been considered to be representative of the prearrest value. In the patient described herein, serial determinations of serum potassium obtained fortuitously before and intentionally following sudden unexpected cardiac arrest in a hospitalized patient demonstrate that the prearrest serum potassium level cannot be inferred from electrolyte values obtained after CPR.

Sudden Unexpected Death in Three Generations

Ten instances of sudden unexpected deaths were identified in three generations. Average age at death was 21 years, and in one generation 30% died abruptly at an average age of 13. Syncopal episodes heralded death in 80%, but no other signs or symptoms of cardiovascular disease existed. No abnormalities were found in 22 members of recent generations. Serial study of the conduction systems of two patients revealed minor variances from normal. Perhaps a nonsex-linked gene has produced minor anatomical defects of the conduction system which could predispose to the development of fatal arrhythmias by a variety of environmental factors. The Lev technique for bundle studies of the conduction system should be used in similar instances of unexplained death with grossly normal hearts.