Carlos E. Harrison

Mechanism for the Abnormal Energetics of Pressure-Induced Hypertrophy of Cat Myocardium

Depressed myocardial contractility with paradoxically increased oxygen consumption has been demonstrated in previous studies of pressure overload hypertrophy. To determine whether altered mitochondrial respiration participates in the abnormal energetics of this muscle, right ventricular hypertrophy (RVH) was produced in 12 cats by pulmonary artery banding. A polarographic muscle bath was used to study eight control and eight RVH papillary muscles, and the respiration of mitochondria isolated from these right ventricles was characterized. RVH muscles demonstrated depressed force-velocity and length-tension curves. The myocardial oxygen consumption per gram of peak active tension was increased from 0.65 ± 0.05 nliters/mg beat−1 (control) to 1.10±0.07 nliters/mg beat−1 (RVH) (P<0.001). Abnormal mitochondrial respiration was shown by an increase in the rate of state 4 oxygen consumption from 12.5±0.8 natoms/mg min−1 (control) to 19.9±0.8 natoms/mg min−1 (RVH) (P < 0.001). The altered oxygen cost of active isometric tension in the RVH muscles was linearly correlated with the altered rate of mitochondrial state 4 oxygen consumption (r = 0.91). Ruthenium red, a compound that blocks mitochondrial calcium uptake, reduced the rate of RVH state 4 oxygen consumption to the control level. The present study suggests a mechanism for the abnormal myocardial oxygen consumption in pressure overload hypertrophy and relates it to nonphosphorylating mitochondrial respiration linked to calcium transport.

Lidocaine-induced reduction in size of experimental myocardial infarction☆

In anesthetized open chest dogs, the effects of therapeutic doses of lidocaine on myocardial cell respiration, creatine kinase depletion, left ventricular stroke work and cardiac necrosis were assessed. The dogs were subjected to 40 minutes of occlusion of the left anterior descending coronary artery, followed by 5 hours of reperfusion. Group I (12 dogs) had infusion of saline solution; group II (8 dogs) had infusion of 0.2 mg/kg per min of lidocaine (serum level 16.8 +/- 1.4 microgram/ml); group III (5 dogs) had infusion of 0.04 mg/kg per min or lidocaine (serum level 3.6 micrograms/ml). Ischemic regional myocardial blood flow (measured by 9 micrometer spheres of strontium-85) was 6.34 +/- 1.62 ml/100 mg per min in group I, 1.48 +/- 0.59 in group II (p < 0.05) and 1.32 +/- 0.50 in group III (p < 0.05). Oxygen consumed during conversion of adenosine diphosphate to adenosine triphosphate in mitochondria from control and lidocaine-treated ischemic tissue was depressed (p < 0.05) and correlated (r = 0.63) with creatine kinase depletion. Left ventricular stroke work was not significantly different among the three groups. Infarct size (in percent of left ventricular weight) was 12.6 +/- 2.0 for group I, 4.8 +/- 1.2 for group II (p < 0.01) and 4.8 +/- 2.5 for group III (p < 0.05). The data suggest that the reduction of myocardial infarct size by lidocaine was not dependent on enhanced myocardial blood flow and was independent of left ventricular stroke work.

Five-year experience with temporary pacemaker therapy in the coronary care unit

The clinical course of 1,022 consecutive patients who received a temporary transvenous pacemaker in the coronary care unit during a 5-year period between January 1976 and January 1981 was reviewed. The route of pacemaker insertion was identified in 942 patients (92.2%) and included antecubital vein cutdown in 606 patients (59.3%), subclavian venipuncture in 177 patients (17.3%), right internal jugular venipuncture in 111 patients (10.9%), and femoral venipuncture in 48 patients (4.7%). Pacemaker-related complications occurred in 140 instances (13.7% morbidity), without associated mortality. The most common complication was the development of a new pericardial rub (54 patients, 5.3%). The right internal jugular approach was associated with the lowest complication rate. On the basis of these findings, it is our practice to insert temporary pacemakers via the right internal jugular or subclavian route.

Inhibition of Binding of Tritiated Digoxin to Myocardium by Sodium Depletion in Dogs

Ten intact dogs were subjected to hemodialysis against a solution of low-sodium content to determine the influence of sodium depletion on myocardial binding of digoxin-3H. Serial determinations of serum sodium, potassium, chloride, bicarbonate, pH, and osmolality, of cardiac output, and of cardiac rhythm were obtained in these and in 10 control dogs dialyzed against the standard solution. A dose of digoxin-3H (0.05 mg/kg) was given intravenously after start of the dialysis and the animals were killed 1 hour afterward for measurement of myocardial radioactivity, potassium, and sodium. Significant depletion of serum sodium and chloride and myocardial sodium (P < 0.001) occurred in all animals dialyzed against the low-sodium solution. No significant changes occurred in other serum electrolytes or pH; osmolality was maintained constant by a slow intravenous drip of 25% urea or mannitol. Myocardial radioactivity was reduced in sodium-depleted animals by 50% (P < 0.001). The Na-K ratio was 0.40 in the myocardium of control animals and 0.26 in sodium-depleted animals. It was concluded that depletion of body sodium inhibits binding of digitalis glycosides to the myocardium during the first hour after injection of the dose.

Functional evaluation of cardiac sarcoplasmic reticulum and mitochondria in human pathologic states

Abstract The function of the cardiac sarcoplasmic reticulum (SR) and mitochondria was evaluated in left ventricular papillary muscle obtained from 47 patients with non-ischemic mitral valve disease and chronic heart failure (group I) and in right ventricular crista supraventricularis muscle obtained from 29 patients with congenital subvalvular pulmonic obstruction and right ventricular hypertrophy (group II). Heart muscle was removed approximately 15 min after establishment of cardiopulmonary bypass with hypothermia and about 4 min after first aortic cross-clamping. Cat cardiac tissues were used as a technical control. The SR and mitochondria were isolated by ultracentrifugation. 45 Ca uptake (5 m m sodium oxalate) and binding were quantitated by Swinny Millipore filtration. Oxidative indices were defined polarographically by use of a vibrating platinum electrode. Compared with that of the non-failing patients (group II), the SR of the failing patients (group I) showed a significant depression of Ca uptake and binding at various ATP concentrations in both the absence and the presence of Ca-stabilizing EGTA. Calcium concentration necessary for half-maximal binding ( K M ) to SR approximated 1 × 10 −7 m in each group. There was no significant difference in the Ca-stimulated SR ATPase activity of groups I and II. ADP:O ratios and NADH-linked state 4 respiration were the same in both groups. NADH- and succinate-linked respiratory control and state 3 oxygen consumption rates were significantly lower in the failing group. The addition of ruthenium red, a specific inhibitor of mitochondrial Ca transport, led to a significant reduction of NADH- and succinate-linked state 4 respiration in group I, whereas no significant effect was elicited in group II. State 3 respiration rates were not depressed by ruthenium red. In the failing human papillary muscle, a significant reduction in Ca transfer across the SR membranes is, thus, demonstrated; it seems to be accompanied by a significant increase in Ca recycling across the mitochondrial membranes. No direct correlation among biochemical alterations, hemodynamic parameters, and duration of clinical cardiac failure was found.

The effects of chronic potassium deficiency on myocardial contractility and oxygen consumption

The effects of chronic intracellular cation deficiency on myocardial function and myocardial oxygen consumption were defined by characterizing myocardial contractility and oxygen utilization following dietary-induced potassium depletion. After 25 to 44 days of a low potassium diet, the mechanics of contraction and myocardial oxygen consumption of right ventricular papillary muscles from control and potassium deficient kittens were determined. With severe hypokalemia ([K+] = 2.4 ± 0.2 mequiv./L), myocardial potassium was 68 ± 3 mequiv./kg (control = 85 ± 5, P 0.1). The average forcevelocity curve was shifted downward and to the left with significant depression of preload velocity to 0.49 ± 0.14 muscle length/s (control = 1.24 ± 0.08, P < 0.001). Shortening and thus external work were also depressed in potassium deficient muscles. Although the velocity of contraction and the amount of external work in these after-loaded contractions from potassium deficient muscles were decreased, average myocardial oxygen consumption for any given load was not depressed. Muscles from potassium deficient cats had depressed length-active tension curves with peak developed tension at Lmax of 3.6 ± 0.4 g/mm2 (control = 6.6 ± 0.4; P < 0.001) while the maximum rate of tension development, dPdt, was depressed, (13.9 ± 1.9 g/mm2/s; control = 26.9 ± 2.2; P < 0.001). However, the myocardial oxygen consumption of isometric contractions/g developed tension at Lmax was not depressed, (0.95 ± 0.15 μl/mg/beat × 10−3, control = 0.87 ± 0.12). These data indicate that chronic dietary potassium depletion with depression of both serum and myocardial potassium is associated with marked depression of myocardial contractile state. Although the velocity of contraction was depressed, myocardial oxygen consumption was equivalent to control values in both afterloaded and isometric contractions.

Cardiovascular Hemodynamics of Bicycle and Handgrip Exercise in Normal Subjects Before and After Administration of Propranolol

Radionuclide angiography was used to study the effects of supine and upright bicycle exercise and handgrip exercise in 17 (12 well-trained) normal subjects before (control) and immediately after the administration of propranolol (160 mg/day for 4 days). Cardiac hemodynamic values were related to position in that control left ventricular volumes and the cardiac index were greater in the supine position than in the upright at rest but resting left ventricular ejection fraction was similar in both positions. The pressure volume index was greater in the upright position than in the supine. At maximal exercise before treatment, however, similar cardiovascular hemodynamic measurements were recorded in both positions. Propranolol increased left ventricular end-diastolic volume at rest and at maximal exercise. Left ventricular end-systolic volume, however, was substantially greater only in the upright position both at rest and at maximal exercise when compared with control values. Heart rate, systolic arterial pressure, cardiac index, and pressure volume index were decreased at rest and maximal exercise after treatment with propranolol. Ejection fraction was decreased in the upright position after propranolol administration but was unchanged in the supine position. Handgrip exercise primarily increased heart rate and arterial pressure and did not affect cardiac volume, and this response was unaffected by propranolol.

Preservation of oxidative phosphorylation by lidocaine in ischemic and reperfused myocardium.

The effect of lidocaine (2 mg/kg bolus, 0.04 mg/kg per min infusion) on ischemic and reperfused myocardial respiration was assessed in 32 dogs, using indices of mitochondrial respiration (ADP:O ratio, state 3 and state 4 respiration, and respiratory control index). Heart rate, left ventricular (LV) pressure, LV dp/dt, cardiac index, epicardial ST segment, and regional myocardial blood flow, using 9 +/- 1 micron radiospheres, were measured after 40 min of constriction of the anterior descending coronary artery (N = 16) and after 20 min of reperfusion (N = 16). Results showed that lidocaine increased state 3 respiration and respiratory control in reperfused myocardium (P less than 0.05) with both glutamate and succinate-rotenone as substrate. It is concluded that lidocaine improves postischemic mitochondrial oxidative phosphorylation independent of altered hemodynamics or change in myocardial blood flow.

Epicardial artery-pulmonary artery fistula: Presentation as a continuous precordial murmur

Abstract A patient with a fistula between several small epicardial arteries and the main pulmonary artery presented with a continuous precordial murmur. The clinical findings were similar to those in patent ductus arteriosus. This unique cause for the murmur was discovered at operation, and the fistula was ligated.