James J. Kane

Mitochondrial function, oxygen extraction, epicardial S-T segment changes and tritiated digoxin distribution after reperfusion of ischemic myocardium

This study examines the effect of 2 hours of reperfusion on transiently ischemic myocardium in pigs. Indexes of myocardial viability measured were mitochondrial function, oxygen extraction, epicardial S-T segment change and distribution of tritiated digoxin. Results were as follows: (1) Mitochondrial function was markedly impaired in the reperfused area after 60 minutes or more of coronary occlusion. The defect would seem to be a block in electron flow near site I, which can be partially bypassed with succinate. (2) An apparent inability of the reperfused myocardium to extract oxygen did not improve with 2 hours of reperfusion. (3) Epicardial S-T segment mapping suggested that necrosis occurred during reperfusion. (4) There was an altered distribution of tritiated digoxin in the reperfused area. The results show that reperfusion for 2 hours did not improve myocardial viability after 60 minutes or more of ischemia.

Ectopic Ventricular Prematurity and Its Relationship to Ventricular Tachycardia in Acute Myocardial Infarction in Man

In order to determine the role of the coupling interval of a premature ventricular contraction (PVC) in the development of paroxysmal ventricular tachycardia (PVT) during the early phase of acute myocardial infarction in man, 52 male patients with documented acute myocardial infarction had 24-hour Holter monitoring commenced within 24 hours of the onset of prolonged chest pain. Review of the tape recordings revealed that 27 patients had PVT documented, while 25 patients did not. Analysis of the data on the two groups showed that the frequency of PVCs, coupled PVCs, and accelerated idioventricular rhythm (AIVR) were found to be associated with a significantly increased incidence of ventricular tachycardia.The mean coupling interval of the PVCs initiating episodes of ventricular tachycardia was not significantly different from either the mean coupling interval of the isolated PVCs in the patients with PVT or the mean coupling interval of the PVCs in the patients without PVT. This suggests that the coupling interval of a ventricular ectopic is a poor predictor of ventricular tachycardia in the early phases of acute myocardial infarction.

Abnormal mitochondrial oxidative phosphorylation of ischemic myocardium reversed by Ca2+-chelating agents.

Mitochondria isolated from ischemic and ischemic-reperfused myocardium have been shown to have a defect in electron transport and in energy-linked 45 Ca 2+ uptake. In this study, the influence of Ca 2+ on the efficiency of oxidative phosphorylation by mitochondria isolated from ischemic and ischemic-reperfused myocardium was studied by directly measuring ATP production in the presence and absence of Ca 2+ -chelating agent—EDTA and EGTA. Results demonstrate the following. (a) Mitochondria isolated from ischemic myocardium have a low rate of ATP production, reduced ATP/O ratios and lower net ATP production. These functions are improved by EDTA. (2) Mitochondria from ischemic-reperfused myocardium are totally incapable of phosphorylating ADP in the absence of Ca-chelating agents. Addition of EDTA or EGTA either to the isolation medium or to the incubation medium restores the ability of these mitochondria to phosophorylate all added ADP, although the rate of this phosphorylation remained very slow. (3) The Ca 2+ content of mitochondria from ischemic-reperfused myocardium was higher than the Ca 2+ levels of mitochondria from either normal or ischemic myocardium. These results suggest that phosphorylation of ADP by mitochondria from ischemic and ischemic-reperfused myocardium is inhibited by endogeneous ionic Ca 2+ and that this inhibition can be partially reversed by the addition of Ca 2+ -chelating agents.

Improvement of mitochondrial energy production in ischemic myocardium by in vivo infusion of ruthenium red.

Reperfusion of acutely ischemic myocardium results in deficient energy production and abnormal Ca2+ deposition. This study evaluates mitochondrial energy production in ishemic reperfused myocardium following an in vivo infusion of a Ca2+ antagonist, ruthenium red. Results are summarized as follows: (1) In vivo infusion of ruthenium red increases adenosine diphosphate-induced respiration threefold and adenosine triphosphate (ATP) production fivefold compared with those mitochondria derived from myocardium which had been occluded 2 hr and reperfused 2 hr without ruthenium red. (2) Infusion of ruthenium red improves state 3 respiration and ATP production to nearly normal levels by mitochondria isolated from myocardium which had been occluded 30 min and reperfused 2 hr. However, mitochondrial respiration and ATP production from nonischemic myocardium are not altered by in vivo ruthenium red infusion. (3) Ruthenium red infusion decreases both tissue and mitochondrial Ca2+ content in ischemic-reperfused myocardium. (4) The partial improvement in energy production in ischemic-reperfused myocardium by ruthenium red is probably related to a decrease in intracellular Ca2+ concentration.

Digoxin-quinidine interaction: Changes in canine tissue concentration from steady state with quinidine☆

Tissue concentrations of tritiated digoxin inthe dog are altered by simultaneous administration of quinidine. Serum levels rise as tissue concentration decreases significantly in all tissue except brain tissue, where an increase of 51 percent is noted over that of the control digitalized state. The digitalis toxicity associated with digoxin-quinidine interaction appears to be associated with rising brain levels of digoxin and falling levels in the myocardium. These findings suggest a neurally mediated form of toxicity with this interaction related to a change in the space of distribution. The question of possible loss of inotropic effect associated with diminished myocardial digoxin concentration requires further study.

The relationship of paroxysmal ventricular tachycardia complicating the acute phase and ventricular arrhythmia during the late hospital phase of myocardial infarction to long-term survival

The long-term prognosis of paroxysmal ventricular tachycardia (PVT) complicating acute myocardial infarction remains unevaluated. Significant ventricular arrhythmia in the patient after infarction is said to carry a poor prognosis with regard to survival. To evaluate these two important aspects of myocardial infarction in man, 56 patients with documented myocardial infarction had Holter monitoring performed during the initial 24 hours and prior to hospital discharge. In 38 of the 45 survivors, Holter monitoring was repeated an average of 19 months after infarction. There were eight cardiac deaths during follow-up. Data analysis revealed that of 18 patients with PVT during the acute phase, one died during follow-up and 17 survived long-term. Even though the incidence of complex PVCs prior to hospital discharge and at long-term follow-up was higher in patients with PVT during the acute phase than in those without PVT, survival appeared unaffected. Thus, PVT during the acute phase of myocardial infarction and complex PVCs at the time of hospital discharge are not incompatible with long-term survival.

Ventricular performance and biochemical alteration of regional ischemic myocardium after reperfusion in the pig

Reperfusion of acutely ischemic myocardium may cause profound alterations in left ventricular wall performance and metabolism. This study evaluates regional left ventricular wall thickness, analyzes metabolic and biochemical alterations, and examines tissue hemorrhage during 15, 30, and 120 minutes of myocardial ischemia, each followed by 120 minutes of reperfusion. Reperfusion after 15 minutes of ischemia showed nearly normal ventricular wall thickening and motion, intact metabolic and biochemical function, and no tissue hemorrhage. However, reperfusion after 30 and 120 minutes of ischemia was associated with ventricular wall thickening and failure to resume systolic and diastolic wall motion. Furthermore, adverse metabolic and biochemical alterations and reperfusion zone hemorrhaging increased proportionally with the duration of ischemia. These findings suggest critical myocardial damage occurring between 15 and 30 minutes of ischemia in an animal model without preexisting coronary collateral circulation. The observed metabolic and biochemical changes are consistent with irreversible cell membrane defects, allowing calcium ion accumulation and thus adversely affecting diastolic relaxation and systolic thickening.

Echocardiographic detection of right ventricular hypertrophy

M-mode echocardiographic right ventricular wall thickness (RVW) and diastolic right ventricular internal diameter (RVID), when above the accepted normal range (RVW less than or equal to 5 mm, RVID less than or equal to 26 mm), are frequently used clinically to predict the presence of right ventricular hypertrophy. RVID was compared to anatomic right ventricular mass (RVM) in 27 patients and to RVW in 13 patients to determine their accuracy for predicting right ventricular hypertrophy (RVM greater than 65 gm). When increased, both measurements were specific for right ventricular hypertrophy. The specificity for RVW above 5 mm was 100% and for RVID greater than 26 mm was 79%. Neither was a sensitive indicator of hypertrophy. Only 36% of those with anatomic right ventricular hypertrophy had an echocardiographically dilated ventricle, and 67% had a thickened free wall. Neither measurement proved to be an accurate predictor of RVM, with a correlation for RVW of 0.56 and for diastolic RVID of 0.19.

Ventricular Arrhythmia in Chronic Stable Angina Pectoris with Surgical or Medical Treatment

Since both propranolol therapy and saphenous-vein bypass surgery have become accepted treatments for patients with symptomatic coronary-artery disease, it is important to determine if either influences the prevalence of ventricular arrhythmias in these patients. Six-hour dynamic electrocardiography was done on 130 patients with chronic stable angina pectoris at least 1 year after being randomized to surgical or medical therapy. All surgical patients had saphenous-vein grafting; 90% of the medical patients received propranolol. Data analysis showed that even though the overall prevalence of premature ventricular contractions was no different in medical and surgical patients, the prevalence of complex premature ventricular contractions was significantly higher in surgically treated patients not receiving propranolol than in propranolol-treated medical patients (p less than 0.05). However, the survival rate was no different in either group, and the quality of life in the surgical patients remained superior.

Atrioventricular conduction patterns in patients with paroxysmal supraventricular tachycardia

Atrioventricular conduction patterns suggestive of dual A-V nodal pathways have been reported in patients with and without a history of paroxysmal A-V nodal re-entrant tachycardia (PSVT). The purpose of this study was to determine whether significant association exists between this conduction pattern and the occurrence of PSVT in man. The pattern of A-V conduction was evaluated at similar pacing rates in 13 patients with documented PSVT and 135 patients with PSVT. Patients without PSVT were divided into groups with normal PR intervals (106 patients), PR intervals of 120 msec. or less (12 patients), and PR intervals of 200 msec. or greater (17 patients). Evidence of dual A-V nodal pathways was found in seven of 13 patients with PSVT and nine of 135 patients without PSVT, including eight of 106 patients with normal PR intervals, none of 12 patients with short PR intervals, and one of 17 patients with PR intervals of 200 msec. or greater. The incidence of dual A-V nodal pathways was significantly greater (P less than 0.01) in patients with PSVT when compared with all other groups. In two of four patients with PSVT, propranolol was found to unmask evidence of dual pathways; no evidence of dual pathways was produced by propranolol in 23 patients without PSVT. The data show that the pattern of dual A-V nodal pathways is common only in patients with PSVT and is significantly less frequent in patients without PSVT regardless of the presence of short or long PR intervals. The results of this study establish a strong association between this conduction pattern and the occurrence of PSVT in man.