Edward W. Gertz

Dual carbon-labeled isotope experiments using D-[6-14C] glucose and L-[1,2,3-13C3] lactate: A new approach for investigating human myocardial metabolism during ischemia

Simultaneous lactate production and extraction have been previously demonstrated in the myocardium in patients with coronary artery disease. To quantitate this lactate production and determine its source, dual carbon-labeled isotope experiments were performed. L-[1,2,3-13C3] lactate and D-[6-14C] glucose were infused in 10 patients with significant coronary artery disease. Metabolic samples were obtained at rest and during atrial pacing. Despite net chemical myocardial lactate extraction in the 10 patients at rest and no evidence of clinical ischemia, the L-[1,2,3-13C3] lactate analysis demonstrated that lactate was being released by the myocardium. During atrial pacing, seven patients did not develop clinical symptoms of ischemia, and the chemical lactate analysis showed net lactate extraction. However, tracer analysis demonstrated that there was a significant increase in the lactate released during atrial pacing (from 6.9 +/- 2.3 to 16.2 +/- 10.1 mumol/min) (p less than 0.05). In these seven patients, circulating glucose was the source of 23 +/- 15% of the lactate released at rest, and there was no significant change during pacing. The remaining three patients had mild chest pain and net chemical lactate production during pacing. Lactate release detected by the tracer increased from 5.7 +/- 3.0 mumol/min at rest to 50.9 +/- 16.8 mumol/min during pacing (p less than 0.01). In these patients, the contribution of glucose to lactate production increased significantly during pacing-induced clinical ischemia from 25 +/- 22 to 67 +/- 14% (p less than 0.005). Thus, dual carbon-labeled isotopic experiments are powerful tools for investigating myocardial metabolic pathways.(ABSTRACT TRUNCATED AT 250 WORDS)

A quantitative and qualitative defect in the sarcoplasmic reticulum in the hereditary cardiomyopathy of the syrian hamster

Abstract In the Syrian Hamster with a cardiomyopathy characterized by ventricular dilitation, compensatory hypertrophy and congestive failure, the fragmented sarcoplasmic reticulum (SR) has been isolated.In normal (N) and myopathic (CM) hamsters SR has been studied relative to rate of ATP dependent calcium trapping, calcium capacity per unit SR, and SR quantity per unit of myocardium. The ATP dependent Ca ++ oxalate pumping of the SR was not different from N in CM at 10 days, reduced 22.4% at 200 days, 30.5% at 300 days with moderate failure, and 77.5% at 300 days with severe failure.The quantity of SR in the tissue as judged by the Ca++oxalate capacity of homogenate was unchanged at 10 days but significantly reduced at 200–300 days. Nevertheless the Ca ++ oxalate capacity per unit SR was unchanged at all ages studied, suggesting a dilution of the SR by the resultant hypertrophy.

Mechanisms of heart failure

The question of why the myocardium fails to contact normally and ultimately leads to congestive failure, has occupied the attention of both clinicians and basic scientists for decades. Nevertheless, it is only within recent years that improvements in clinical diagnostic techniques and development of more sophisticated physiological and biochemical methods have permitted a broader understanding of and direct approach to the problem. Our present purpose is to review certain concepts dealing with myocardial failure on both a physiological and biochemical basis with emphasis on some of our most recent experimental work. In the process we would hope to redefine certain ground rules by which the problem may be approached, and review a number of experiments which have been conducted in our laboratories recently as well as over the past several years to explore the underlying bases of the failing heart.

Myocardial metabolism during hypoxia : maintained lactate oxidation during increased glycolysis

In the intact animal, myocardial lactate utilization and oxidation during hypoxia are not well understood. Nine dogs were chronically instrumented with flow probes on the left anterior descending coronary artery and with a coronary sinus sampling catheter. [14C]lactate and [13C]glucose tracers, or [13C]lactate and [14C]glucose were administered to quantitate lactate and glucose oxidation, lactate conversion to glucose, and simultaneous lactate extraction and release. The animals were anesthetized and exposed to 90 minutes of severe hypoxia (PO2 = 25 +/- 4 torr). Hypoxia resulted in significant increases in heart rate, cardiac output and myocardial blood flow, but no significant change in myocardial oxygen consumption. The arterial/coronary sinus differences for glucose and lactate did not change from normoxia to hypoxia; however, the rate of glucose uptake increased significantly due to the increase in myocardial blood flow. Tracer-measured lactate extraction did not decrease with hypoxia, despite a 250% increase in lactate release. During hypoxia, 90% +/- 4% of the extracted 14C-lactate was accounted for by the appearance of 14CO2 in the coronary sinus, compared with 88% +/- 4% during normoxia. Thus, in addition to the expected increase in glucose uptake and lactate production, we observed an increase in lactate oxidation during hypoxia.

Absence of myocardial biochemical toxicity with a nonionic contrast agent (iopamidol)

To evaluate the myocardial metabolic effects of a new nonionic contrast agent, iopamidol, a randomized, double-blind study was performed comparing iopamidol with sodium meglumine diatrizoate (Renografin-76) in 23 patients with ischemic heart disease. Coronary sinus and arterial metabolic samples were obtained prior to and during the 20-minute period following the contrast left ventriculogram. Ten patients received iopamidol and 13 received Renografin-76. The chemical lactate extraction in the iopamidol group was 13 +/- 9% prior to left ventriculography and 17 +/- 12% following the contrast injection (p less than 0.005). In the Renografin-76 group, the lactate extraction was 23 +/- 13% and decreased significantly to 12 +/- 24% following the ventriculogram (p less than 0.01). In a subset of these patients (n = 10), [1-(14)C] lactate was infused as a tracer to quantitate the amount of lactate released by the myocardium. [1-(14)C] lactate analysis demonstrated that the fall in lactate extraction ratio following Renografin-76 was due to an increase in myocardial lactate release. In the Renografin-76 group there was a 53 +/- 37% increase in lactate release at 10 minutes after contrast agent injection (p less than 0.005), while in the iopamidol patients there was no significant change in lactate release following contrast ventriculography. The increase in lactate release in the Renografin-76 group suggests that myocardial ischemia is induced with this ionic contrast agent. In comparison, the nonionic contrast agent is less toxic to the myocardium and is not associated with the biochemical changes of cellular ischemia.

A calcium-stimulated, ouabain-inhibited ATPase in a myocardial fraction enriched with sarcolemma.

Abstract An active intracellular to extracellular Ca2+ efflux has been proposed in heart muscle. A myocardial sarcolemmal ATPase stimulated by an intracellular pCa and serving as a Ca2+ pump has been postulated. A recently developed myocardial sarcolemmal preparation has not permitter a search for such an enzymatic activity. In these studies, an ATPase has been demonstrated in the sarcolemma which is activated by Mg2+, stimulated as the Ca2+ is raised to a pCa of 6, and is inhibited by ouabain. These findings suggest a mechanism by which Ca2+ within the myocardium may be modulated and thus how the force of contraction may be altered by cardiac glycosides.

Quantitative analysis of seven-pinhole tomographic thallium-201 scintigrams: Improved sensitivity and estimation of the extent of coronary involvement by evaluation of radiotracer uptake and clearance

Recent studies have shown that the sensitivity of conventional thallium-201 scintigraphy can be increased by the quantitative assessment of myocardial radiotracer clearance rates in conjunction with the evaluation of radionuclide uptake. In this study, a similar analysis of tomographic scintigrams was performed to determine the feasibility and value of this approach, particularly in estimating the extent of disease and detecting three vessel coronary involvement. Seventy patients undergoing cardiac catheterization for chest pain were studied by exercise and 3 hour delayed thallium-201 scintigrams using the seven-pinhole tomographic technique. Each study was evaluated by visual inspection of the tomographic sections and quantitative analysis. The latter approach consisted of comparing circumferential profiles of the initial post-exercise radionuclide uptake and the 3 hour clearance rates generated from each of three left ventricular slices with similar profiles representing the lower 95% confidence limits derived from 15 middle-aged volunteers. An abnormality was considered present when a patients profile fell below these limits for a 30 degrees arc, and was ascribed to disease in a particular artery when it involved that vessels usual distribution. Among the 61 patients without apparent primary myocardial or valvular disease, the diagnostic sensitivity of thallium scintigraphy was increased from 86% (43 of 50) to 96% (48 of 50) without a change in specificity (both 9 of 11 or 82%). More importantly, the quantitative approach permitted detection of 85% (107 of 126) of significantly obstructed coronary vessels compared with 47% (59 of 126) by visual analysis (p less than 0.001), again without sacrificing specificity (85 versus 87%).(ABSTRACT TRUNCATED AT 250 WORDS)