Patricia L. Kozlovskis

Long-term survival after prehospital cardiac arrest: Analysis of outcome during an 8 year study

We analyzed long-term follow-up data accumulated during an 8 year study of survivors of prehospital cardiac arrest. All patients included in this study were primary entrants via community-based rescue systems; patients who were tertiary referrals (survivors of cardiac arrest from other hospitals) were not included in this analysis. In the group of 61 patients entering our study between 1975 and 1980, with a follow-up to 1983, there have been a total of 24 deaths (39%). Sixteen of the 24 deaths were the result of recurrent cardiac arrest; eight were nonsudden cardiac deaths or noncardiac deaths. The mean duration from entry to death in the nonsurvivors was 27.5 +/- 19.7 months, and the time from the index event to last follow-up in the long-term survivors was 59.9 +/- 19.4 months. Life table analysis demonstrated a 10% rate of recurrence of cardiac arrest in the first year, with a 5% per year rate in each of the subsequent 3 years. Left ventricular ejection fractions at entry were not significantly different between survivors (mean = 45.3 +/- 13.6%) and nonsurvivors (mean = 37.6 +/- 12.6%), and the severity of ejection fraction abnormality at entry did not correlate with time to death in the nonsurvivors. However, ejection fraction was significantly lower in patients who died from causes other than recurrent cardiac arrest than in those who died of cardiac arrest (24.5 +/- 9.1% vs 42.7 +/- 9.2%; p less than .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed afterdepolarizations and triggered activity induced in feline Purkinje fibers by alpha-adrenergic stimulation in the presence of elevated calcium levels.

We studied the ability of alpha-adrenergic stimulation to induce delayed afterdepolarizations and triggered activity in Purkinje fibers from cat hearts in the presence of an elevated Ca++ concentration. Delayed afterdepolarizations could not be induced at drive cycle lengths of 200 to 500 msec in the presence of extracellular Ca++ concentrations of 2.7 to 8.1 mM. However, the addition of 10(-5)M phenylephrine in the presence of 5 X 10(-7)M propranolol elicited delayed afterdepolarizations in eight of 10 preparations at a Ca++ concentration of 8.1 mM; nondrive-triggered action potentials were recorded from three of the preparations. These afterpotentials were completely suppressed by 5 X 10(-7)M prazosin or 10(-6)M phentolamine. In the presence of 5 X 10(-7)M propranolol, 10(-5)M phenylephrine prolonged action potential duration and this effect was suppressed by 5 X 10(-7)M prazosin. Methoxamine, at a concentration of 5 X 10(-6)M, was also observed to potentiate delayed afterdepolarizations in all of three preparations studied. These results demonstrate that alpha-adrenergic stimulation can induce afterpotentials in the presence of elevated Ca++ levels in cat hearts. Stimulation of alpha-adrenoceptors may be responsible for arrhythmias under Ca++-loaded conditions such as ischemia and coronary reperfusion.

Automaticity, triggered activity, and responses to adrenergic stimulation in cat subendocardial Purkinje fibers after healing of myocardial infarction.

We studied automaticity, triggered activity, and responses to alpha- and beta-adrenergic stimulation in subendocardial Purkinje fibers overlying healed infarct scars (infarct preparation) and from remote normal zones (noninfarct preparation) of cat left ventricles. The preparations were studied 2 to 4 months after ligation of multiple distal tributaries of the left anterior descending and circumflex arteries. Subendocardial Purkinje fibers from corresponding areas of normal hearts served as control samples (control preparation). Transmembrane action potential characteristics and rates of automaticity (spontaneous phase 4 depolarization) did not differ among control, noninfarct, and infarct preparations. However, overdrive at cycle lengths of less than 400 msec suppressed automaticity to a greater degree in Purkinje fibers of infarct preparations than those of control and noninfarct preparations. Changes in automatic rate during superfusion with isoproterenol (10(-10)M to 10(-6)M) were not different among the three groups of preparations, but exposure to phenylephrine (10(-9)M to 10(-5)M) in the presence of 5 X 10(-7)M propranolol reduced the automatic rate to a greater degree in Purkinje fibers of infarct preparations than those of control or noninfarct preparations. Triggered activity arising from delayed afterdepolarizations was recorded in 10 of 29 infarct preparations (34%), but not in 12 control and 10 noninfarct preparations. These afterpotentials were augmented by increasing extracellular Ca++ concentration, 10(-7)M isoproterenol, and 10(-5)M phenylephrine in the presence of 5 X 10(-7)M propranolol. We conclude that Purkinje fibers overlying healed infarct scars have altered physiology of spontaneous automaticity, enhanced responses to alpha-adrenergic interventions, and a tendency to triggered activity, and that both alpha- and beta-adrenergic effects may result in worsening of arrhythmias by augmentation of afterpotentials in healed myocardial infarction.

Dissimilarities in the electrophysiological abnormalities of lateral border and central infarct zone cells after healing of myocardial infarction in cats

We studied the characteristics of an electrophysiological border zone detected after healing of experimental myocardial infarction in cats. Thirty-two isolated left ventricles were studied in tissue bath 2–7 months after distal left coronary artery ligation. Action potentials were recorded from endocardial ventricular muscle cells in normal, lateral border and central infarct zones. Action potential duration was prolonged in central infarct zone cells, while action potentials of lateral border zone cells had the shortest duration. Ventricular muscle cells in the border zone also had lower resting potential, action potential amplitude and Vmax. Slowly rising action potentials (Vmax ≪ 20 V/ sec) were noted in central infarct zone cells, but more consistently in border zone cells. Functional refractory period of cells in central infarct zone was significantly longer than that recorded from border and normal zone cells. Post-repolarization refractoriness occurred in the majority of border zone cells. Failure of a border zone cell to respond to a premature stimulus during repetitive activity was observed in ten of the 22 preparations in which repetitive activity could be induced. Furthermore, when the coupling interval between driving and premature stimuli was shortened, border zone cells were first to fail to be excited by the premature stimulus. These data indicate that conduction was impaired in the border zone, whereas normal conduction was still possible in central infarct and normal areas. The electrophysiological abnormalities in the endocardial lateral border zone cells of the healed myocardial infarction appear to be the most severe, and the border zone may play an important role in chronic electrophysiological instability observed both in situ and in vitro.

Morphometric mapping of regional myocyte diameters after healing of myocardial infarction in cats.

Myocyte diameters were measured in two models of healed myocardial infarction to test the hypothesis that myocyte hypertrophy is a function of proximity to the infarct. Left ventricular transmural and non-transmural myocardial infarctions were produced in cats by multiple ligatures of the distal tributaries of the left coronary artery system. Thirteen to twenty months after surgery the left ventricular free wall was cut longitudinally, embedded in plastic and stained for reticulum with modified silver stain. Myocardial cell diameters were measured from apex to base through the infarct. No regional differences were found in non-operated control hearts. In the transmural infarct hearts, all cell diameters were significantly increased in comparison to controls (P less than or equal to 0.05). In the hearts with non-transmural infarcts, cell diameters were significantly increased in tissues adjacent to the infarct, but as distance from the infarct increased the cell diameters were not different from controls. Cells from the transmural infarctions had a greater percent increase in diameter, compared to controls, than did cells from the non-transmural infarctions. There is a gradient increase in myocyte diameters in transmural and non-transmural healed myocardial infarctions; this increase is greatest in the tissues adjacent to the infarct. We conclude that cells close to a healed myocardial infarction hypertrophy because they are contracting against a non-compliant scar.

Electrophysiological effects or procainamide in acute and healed experimental ischemic injury of cat myocardium.

We studied the effects of a membrane-active antiarrhythmic agent, procainamide (PA), on cellular electrophysiological consequences of ischemic injury to cat ventricular muscle. The left ventricles of 90- to 120-minute acute myocardial infarctions (AMI) (n = 14), and 2- to 4-month healed myocardial infarctions (HMI) (n = 17), were studied by microelectrode techniques in isolated tissue bath. Control action potential duration at 90% repolarization (APD90) recorded from ventricular muscle cells in AMI areas were short (114 ± 4 msec) compared to recordings from cells in normal areas (136 ± 6 msec) (P < 0.001). In contrast, APD90 of cells surviving ischemia in HMI preparations were longer than normals (159 ± 5 vs. 140 ± 5 msec, P < 0.001). After 60 minutes of exposure to PA, the APD90 of all cells was prolonged, but the absolute and relative magnitudes of prolongation were greater in AMI cells (mean = +40 msec, +35%), than in HMI cells (mean = +19 msec, +13%), P < 0.001. The prolongation of APD90 of normal cells was intermediate. Local refractory period changes paralleled APD90 changes. In seven additional HMI preparations, sustained ventricular activity was induced by premature stimulation. APD90 of HMI cells prolonged less than APD90 of normal cells during exposure to PA in these preparations, and decreased differences of APD90 between normal and HMI cells was associated with loss of inducibility of sustained ventricular activity. The effect of tetrodotoxin (TTX) was compared to the effect of PA in four HMI preparations to determine whether impaired delivery of test substances caused only an apparent decreased responsiveness to PA in HMI zones. TTX caused nearly identical prolongations of conduction times in HMI zones and normal zones, whereas PA caused different effects on APD90 in the two zones. In conclusion, PA alters the time course of repolarization of AMI cells more than that of HMI cells, decreasing the dispersion of repolarization in a given AMI or HMI preparation. The decreased dispersion correlated with loss of ability to induce sustained ventricular activity. Finally, the decreased responsiveness of HMI cells to PA does not appear to be due to impaired delivery to cell membranes, but, rather, appears to be a membrane difference persisting in cells which have survived ischemic injury.

Regional beta-adrenergic receptors and adenylate cyclase activity after healing of myocardial infarction in cats.

Augmented sensitivity to sympathetic mediators occurs in non-infarcted tissues after healing of myocardial infarction. We studied regional beta-adrenergic receptor numbers and adenylate cyclase activity in cat ventricles with healed myocardial infarctions and in the same regions from control hearts. Tissues were obtained from regions remote from and adjacent to the infarct and from the infarct zone itself. Beta-adrenergic receptor numbers were significantly reduced in adjacent and infarcted regions of the healed infarction model. Basal adenylate cyclase activity was increased in tissues remote from and adjacent to the infarct. In remote tissues, total adenylate cyclase activity during maximum isoproterenol stimulation was increased, but the isoproterenol stimulated increment was normal after subtraction of basal activity. In adjacent tissues, total adenylate cyclase activity during isoproterenol stimulation was normal, but the stimulated increment was reduced after subtraction of basal activity. This reduction in activity was reversed when GTP was replaced with Gpp(NH)p. No changes in adenylate cyclase activity, relative to control, were observed in tissues from the infarcted area. These results indicate that chronic changes in the beta-adrenergic receptor/adenylate cyclase system persist after healing of myocardial infarction, and that the nature of the changes are regional depending on proximity to the healed scar.

Regional changes in intracellular potassium and sodium activity after healing of experimental myocardial infarction in cats.

After healing of experimental myocardial infarction in cat hearts, endocardial cells demonstrate persistent regional electrical changes. These include long action potential duration in surviving cells over the infarct scar, and short action potential duration and low membrane potential in border zone cells between the scar and normal tissue. We studied the basis for these electrophysiological changes by measuring intracellular potassium and sodium activity with ionsensitive microelectrodes in normal, border, and infarct zone cells of the cat left ventricle 2–6 months after ligation of multiple distal tributaries of the left anterior descending and circumflex coronary arteries. In normal zone cells, intracellular potassium activity was 89.6 ± 12.3 mM (mean ± SD, n = 9), and sodium activity was 10.8 ± 2.2 mM (n = 5). Neither was significantly different from infarct zone cells (91.2 ± 15.0 and 10.5 ± 3.0 mM, respectively). In contrast, border zone cells had significantly reduced intracellular potassium activity (71.4 ± 5.1 mM, P < 0.01, compared to normal and infarct zone cells) and increased intracellular sodium activity (19.1 ± 5.9 mM, P < 0.05, compared to normal and infarct zone cells). The membrane potential in border zone cells was more positive to calculated potassium equilibrium potential, and less sensitive to the change in the extracellular potassium concentration in the range between 2 and 10 mM, compared to normal and infarct zone cells. Sixty minutes of exposure to 5 × 10−7 M ouabain reduced the membrane potential and intracellular potassium activity to a lesser degree in border zone cells than in normal and infarct zone cells (P < 0.05), but the percent changes from the initial values were not significantly different among the three zone cells. We conclude that action potential changes in infarct zone cells are not accompanied by changes in intracellular potassium and sodium activities, while border zone cell changes are accompanied by reduced intracellular potassium activity and increased intracellular sodium activity. Our data also suggest that border zone cells have altered potassium and/or sodium conductances.

Regional increase in isolated myocyte volume in chronic myocardial infarction in cats

Healing of myocardial infarction is associated with hypertrophy of a region surrounding the scar. In order to characterize the pattern of regional hypertrophy after healing of small myocardial infarctions, we used a Coulter Channelyzer to measure directly regional cell volume and light microscopy to measure cell length of isolated myocytes. Acute left ventricular myocardial infarctions were surgically created in adult cat hearts. After healing for 10.4 +/- 5.0 months, cells were dissociated by collagenase perfusion. Myocardial cells were isolated from three regions of the infarcted ventricle and the same three anatomical regions of unoperated control hearts: (1) remote from the infarct, (2) non-scarred tissues adjacent to the infarct, and (3) from the infarct. The volume of cells from control hearts was correlated significantly with individual body weight resulting in large inter-animal variations, but small intra-animal variations. Inter-animal comparisons were made by normalizing adjacent and infarct regions to percent change from its remote region. Myocyte volumes from hearts with healed infarcts were increased by 31% in the infarct region and by 20% in the adjacent region, relative to the corresponding regions from control hearts (P less than 0.05). Cell lengths were not different from control in any region. Calculated cross-sectional areas followed the same pattern as was observed for cell volumes. We conclude that there is a region of hypertrophy surrounding a small, transmural healed myocardial infarction that is characterized by increased myocyte cross sectional area with no change in cell length. This pattern is typical of the concentric hypertrophy observed with pressure overload rather than eccentric hypertrophy observed with volume overload.

Cellular electrophysiologic changes and "arrhythmias" during experimental ischemia and reperfusion in isolated cat ventricular myocardium.

The cellular electrophysiologic consequences of both regional and global experimental ischemia and reperfusion were studied in the isolated cat myocardium, using conventional microelectrode techniques. Oxygenated Tyrodes solution was perfused through the left anterior descending and circumflex coronary arteries, while the preparation was superfused with Tyrodes solution gassed with 95% nitrogen and 5% carbon dioxide. Electrophysiologic characteristics of endocardial muscle cells were normal during coronary perfusion. When perfusion was discontinued for 30 minutes, resting membrane potential was decreased by 21.6 +/- 4.1%, action potential amplitude was decreased by 29.1 +/- 8.6% and action potential duration was decreased by 54.1 +/- 12.5% (p less than 0.001). Ectopic activity occurred after 5 to 10 minutes of ischemia and was more frequent in regional than in global ischemia (p less than 0.05). Rapid ventricular activity was observed in only 5 (17%) of 29 preparations during ischemia, whereas it occurred in 24 (83%) of 29 preparations during reperfusion. Rapid ventricular activity began 5 to 40 seconds (mean 19) after the start of reperfusion, stopped spontaneously after a mean of 113 +/- 211 seconds and occurred after both regional and global ischemia. The cellular electrophysiologic changes induced by ischemia returned to baseline values within the next 5 minutes. Repeated ischemia and reperfusion runs reproduced the same electrophysiologic changes and rapid ventricular activity. Coronary perfusion with procainamide (20 mg/liter) aggravated the ischemic depressions of action potential amplitude and action potential duration and increased conduction delay during ischemia, but it did not prevent rapid ventricular activity induced by reperfusion. In contrast, verapamil (1 mg/liter) perfusion did not affect the changes in action potential variables during ischemia but prevented reperfusion-induced rapid ventricular activity. Perfusion with calcium ion (Ca2+)-free Tyrodes solution just before ischemia and during reperfusion slowed or prevented reperfusion-induced rapid ventricular activity, without affecting the action potential changes during ischemia. It is concluded that, in these isolated perfused ventricular muscle preparations, different mechanisms may be operative in ischemic and reperfusion arrhythmias and Ca2+ may play an important role in the development of arrhythmias during the reperfusion phase of ischemia/reperfusion sequences.