P.Jacob Varghese

Cerebral Ischemia and Reperfusion: Prevention of Brain Mitochondrial Injury by Lidoflazine

Mitochondrial degradation is implicated in the irreversible cell damage that can occur during cerebral ischemia and reperfusion. In this study, the effects of 10 min of ventricular fibrillation and 100 min of spontaneous circulation on brain mitochondrial function was studied in dogs in the absence and presence of pretreatment with the Ca2+ antagonist lidoflazine. Twenty-three beagles were separated into four experimental groups: (i) nonischemic controls (ii) those undergoing 10-min ventricular fibrillation, (iii) those undergoing 10-min ventricular fibrillation pretreated with 1 mg/kg lidoflazine i.v., and (iv) those undergoing 10-min ventricular fibrillation followed by spontaneous circulation for 100 min. Brain mitochondria were isolated and tested for their ability to respire and accumulate calcium in a physiological test medium. There was a 35% decrease in the rate of phosphorylating respiration (ATP production) following 10 min of complete cerebral ischemia. Those animals pretreated with lidoflazine showed significantly less decline in phosphorylating respiration (16%) when compared with nontreated dogs. Resting and uncoupled respiration also declined following 10 min of fibrillatory arrest. One hundred minutes of spontaneous circulation following 10 min of ventricular fibrillation and 3 min of open-chest cardiac massage provided complete recovery of normal mitochondrial respiration. Energy-dependent Ca2+ accumulation by isolated brain mitochondria was unimpaired by 10 min of complete cerebral ischemia. However, by 100 min after resuscitation, there was a small, but significant rise in the capacity for mitochondrial Ca2+ sequestration when compared to either control or fibrillated groups. These findings indicate that: (a) 10 min of complete cerebral ischemia causes a substantial decline in the rate at which cortical brain mitochondria can synthesize ATP; (b) pretreatment with lidoflazine significantly protects the ability of brain mitochondria to synthesize ATP following 10-min ventricular fibrillation, (c) mitochondrial damage is completely reversible by 100 min following restoration of circulation, (d) mitochondrial Ca2+ uptake is relatively insensitive to the adverse effects of ischemia.

Efficacy of oral diltiazem to control ventricular response in chronic atrial fibrillation at rest and during exercise

Although digoxin is often the first choice for control of ventricular response in chronic atrial fibrillation, it fails to slow exercise rates. Diltiazem, a calcium channel antagonist that slows atrioventricular conduction, was administered to 16 patients who failed to achieve adequate rate control on low level exercise testing despite digoxin therapy. Therapeutic response to diltiazem was assessed with submaximal and maximal exercise tests and 24 hour ambulatory electrocardiographic monitoring. During the diltiazem treatment phase, ventricular response at rest diminished (96 +/- 17 versus 69 +/- 10 beats/min, p less than 0.001) as did rate during submaximal exercise (155 +/- 28 versus 116 +/- 26, p less than 0.001), maximal exercise (163 +/- 14 versus 133 +/- 26, p less than 0.001) and average ventricular response during 24 hour monitoring (87 +/- 13 versus 69 +/- 10, p less than 0.001). Rate at rest decreased 26 +/- 15% and submaximal exercise rate diminished 24 +/- 12%. Thirteen (81%) of the 16 patients exhibited at least 15% slowing of rate at rest and during submaximal exercise. Eleven patients (69%) reported alleviation of symptoms. There was no change in serum digoxin levels during diltiazem treatment (1.3 +/- 0.5 versus 1.3 +/- 0.6 ng/ml, p = NS). On withdrawal of diltiazem, ventricular response returned to baseline values. Diltiazem is an effective agent for control of ventricular response, both at rest and during exercise, in digoxin-treated patients with chronic atrial fibrillation.

Intravenous digital left ventriculography at rest and with atrial pacing as a screening procedure for coronary artery disease

Digital subtraction left ventriculography using intravenous contrast injection was evaluated as a screening diagnostic method for coronary heart disease. Intravenous ventriculography was performed in 61 patients with 35 cc of contrast medium injected into a central vein (usually the inferior vena cava). Recognition of regional wall motion abnormalities by this technique was shown to be comparable with direct left ventriculography in 40 patients who underwent both imaging modalities at rest. If the rest digital ventriculogram was normal, it was repeated after incremental atrial pacing to the onset of chest pain or to a maximal heart rate of 150 beats/min. Forty-four of the 61 patients had significant coronary artery disease, of whom 10 had a wall motion abnormality at rest on intravenous ventriculography. With pacing, 28 of the 34 remaining patients developed a new wall motion abnormality. Thus, 38 (86%) of 44 patients with coronary heart disease were identified by wall motion abnormalities. One of the 17 patients without coronary artery disease had an abnormal rest study and was incorrectly assigned a diagnosis of coronary disease. Intravenous digital ventriculograms approximate those obtained by direct ventriculography. When combined with atrial pacing they are a sensitive and specific means of detecting coronary artery disease.

Recurrent early ischemic events after thrombolysis for acute myocardial infarction.

Myocardium salvaged by early thrombolysis and then perfused through a residual stenosis may be at risk for ischemic events. To investigate this possibility, the short-term (2-week) clinical course of 81 consecutive patients managed within a randomized intracoronary thrombolysis trial was reviewed. All patients underwent coronary angiography within 5 hours of symptoms of acute myocardial infarction and were stratified into the following 3 outcome groups: patients with initially subtotal occlusion (subtotal group, n = 17), those with initial total occlusion and infarct artery reperfusion (reperfused group, n = 24) and those with continued infarct artery occlusion (occluded group, n = 40). Recurrent ischemic events were defined as spontaneous typical angina, provokable angina on predischarge exercise testing, and reinfarction. Eleven of 17 patients (65%) in the subtotal and 11 of 23 patients (48%) in the reperfused groups had an ischemic event (difference not significant). In contrast, 4 of 37 patients (11%) with occlusion had an ischemic event (p less than 0.01 compared with patients in the subtotal or reperfused groups). Four patients were excluded because of early (within 72 hours) elective coronary bypass surgery or death from pump failure. To eliminate the impact of multivessel coronary artery disease (CAD), 39 patients with 1-vessel CAD were analyzed separately. Five of 9 patients (56%) in the subtotal group, 3 of 10 (30%) in the reperfused group and only 2 of 20 (10%) in the occluded group had an ischemic event. These observations suggest the need for a more definitive revascularization strategy for acute myocardial infarction.

Independent and interactive effects of digoxin and quinidine on the atrial fibrillation threshold in dogs

To assess the effects of digoxin as single therapy and in combination with quinidine in the treatment of atrial fibrillation, the atrial fibrillation threshold was determined from the right atrial appendage and Bachmanns bundle in 11 open chest dogs. In group 1 (six dogs), the atrial fibrillation threshold was determined at baseline, post-quinidine (10 mg/kg intravenously) and then post-digoxin (50 micrograms/kg intravenously). In group 2 (five dogs), the order of drug administration was reversed. The results of this study were: 1) Digoxin had no significant effect on the atrial fibrillation threshold when given alone. 2) Quinidine significantly increased the atrial fibrillation threshold (p less than 0.002) and the addition of digoxin resulted in a further increase in threshold (p less than 0.002). 3) Quinidine produced greater suppression of atrial fibrillation induction at the right atrial site than at the Bachmanns bundle site, suggesting differential effects of quinidine on atrial fibers.

Role of dietary magnesium deficiency in the pressor and arrhythmogenic response to epinephrine in the intact dog

The effect of dietary magnesium deficiency on the pressor and arrhythmogenic responses to epinephrine was investigated in 19 dogs maintained either on a normal diet (11 dogs) or a diet deficient in magnesium (8 dogs). Magnesium-deficient dogs had significantly lower serum magnesium levels than the control dogs on a normal diet. Magnesium-deficient dogs showed an increased pressor sensitivity to epinephrine as determined by the dose of epinephrine required to cause a maximal pressor response (3.4 micrograms/kg/min compared to 13.4 micrograms/kg/min, p < 0.05). Magnesium-deficient dogs also had a significantly lower threshold dose for ventricular premature beats (0.8 microgram/kg/min compared to 2.7 micrograms/kg/min, p < 0.05). Acute administration of magnesium sulfate restored pressor sensitivity and ventricular premature beat threshold to normal levels in the magnesium-deficient dogs. Threshold dose for ventricular tachycardia beat was similar in both normal and magnesium-deficient dogs, and threshold was raised significantly in both groups by acute administration of magnesium.

Time course of ventricular fibrillation threshold in infarcted and non-infarcted myocardium after acute coronary ligation*

The time course of the ventricular fibrillation threshold (VFT) was studied in 10 open-chest mongrel dogs following acute occlusion of the left anterior descanding coronary artery (LAD). The VFT in the infarcted area was compared to a non-infarcted area of the left ventricle supplied by the circumflex coronary artery. Prior to coronary occlusion the mean VFT for the entire group of 10 animals was 14 ma. for the area supplied by the LAD and 17.6 ma. for the area of the left circumflex. Immediately after coronary ligation the VFT decreased in both areas. Within 90 to 120 minutes the VFT in the infarcted area was 27 ma. and after 6 hours of occlusion the VFT was 3 times the pre-ligation value. The VFT in the non-infarcted area remained near the pre-ligation values. The excitability of the infarcted area was markedly decreased after coronary occlusion and this accounted for the increase in the VFT in the infarcted area. In the non-ischemic area the excitability was unchanged during the entire six hour period following occlusion. The study stresses the importance of the location of the electrodes used for fibrillation and the natural course of the VFT in evaluating VFTs within the ischemic myocardium.

Detection of left ventricular wall motion abnormalities for the diagnosis of coronary artery disease: A comparison of exercise radionuclide and pacing intravenous digital ventriculography

Intravenous digital ventriculography before and after pacing was compared with equilibrium gated nuclear ventriculography at rest and after exercise. Specifically, the relative abilities of the 2 techniques to detect resting and stress-related wall motion abnormalities were tested. Twelve normal patients and 28 patients with coronary artery disease (CAD) were tested. Neither technique produced a new wall motion abnormality in a patient with normal coronary arteries. Six patients with CAD had a history of a myocardial infarction (MI); an abnormality at rest was present in all 6 by both techniques. Of the 22 patients with CAD and a normal baseline ventriculogram, a wall motion abnormality developed in 18 during digital ventriculography with pacing; a wall motion abnormality developed in 15 with exercise nuclear ventriculography. Wall motion abnormalities by nuclear ventriculography (performed in the left anterior oblique projection) tended to be apical; digital ventriculography (performed in the right anterior oblique projection) more often produced an abnormality of the anterior or inferior wall, which could be predictive of coronary anatomy. Thus, the 2 techniques are substantially equivalent for the detection of wall motion abnormalities in CAD.

OPTIMIZING ELECTROCARDIOGRAM INTERPRETATION AND CATHETERIZATION LABORATORY ACTIVATION IN ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION: A TEACHING MODULE FOR MEDICAL STUDENTS

To achieve the 90-minute reperfusion goal in ST-segment elevation myocardial infarction (STEMI) care, providers must diagnose STEMIs from electrocardiograms (ECGs) obtained upon emergency room arrival and appropriately activate the catheterization lab. To enhance early STEMI care, we sought to