Judith A. Wisneski

Treadmill score quantifies electrocardiographic response to exercise and improves test accuracy and reproducibility.

SUMMARYWe have developed a sensitive, accurate and highly reproducible treadmill exercise score (TES) that grades the ST-segment (“ischemic”) response to exercise. Instead of using a single value for peak ST depression, our method integrates all ST-amplitude and slope changes that occur during the test, from onset of exercise to the end of recovery. By reflecting not only the depth of ST depression but the manner and time course by which ST changes develop and resolve, TES incorporates data that correlate with severity of coronary artery disease. Exercise ECGs of 70 patients who also had coronary arteriography were analyzed, as well as exercise records of 46 healthy volunteers. Sensitivity, specificity, predictive accuracy and correct classification rate were 85% (50 of 59), 98% (56 of 57), 98% (50 of 51) and 91% (106 of 116), respectively. Use of TES for qualitative interpretation increased sensitivity 10–15% compared with conventional criteria. TES distinguished the group of patients with three-vessel or left main coronary artery disease from those with twovessel (p < 0.002) or one-vessel disease (p < 0.01). These differed from patients with no vessel disease (p < 0.05). TES also varied linearly when compared with angiographically determined coronary scores (p < 0.001, r = 0.71, SEE = 24.2). Thus, the use of TES greatly improves our ability to diagnose and quantify serially the extent of coronary artery disease and improves the accuracy of statistical statements relating to the probability of disease.

Myocardial High-Energy Phosphate and Substrate Metabolism in Swine With Moderate Left Ventricular Hypertrophy

BACKGROUND Although left ventricular hypertrophy (LVH) is frequently associated with impaired coronary vasodilator reserve, it is uncertain whether this leads to myocardial ischemia under physiological conditions. The goal of the present study was to determine whether swine with moderate LVH exhibit metabolic evidence of ischemia when myocardial oxygen requirements are increased. METHODS AND RESULTS Myocardial metabolism was evaluated in an open-chest anesthetized preparation at baseline and during dobutamine infusion in 13 adolescent pigs with moderate LVH induced by supravalvular aortic banding and 12 age-matched control pigs. Transmural myocardial blood flow was quantified with radioactive microspheres; the ratio of phosphocreatine to ATP (PCr/ATP) in the anterior LV free wall was measured by 31P-nuclear magnetic resonance; and anterior wall lactate release was quantified from the arterial-coronary venous difference in 14C- or 13C-labeled lactate. In a subset of 5 animals from each group, the metabolic fate of exogenous glucose was determined from the transmyocardial difference in 6-14C-glucose and its metabolites 14C-lactate and 14CO2. Coronary reserve, as assessed by the ratio of blood flow during adenosine infusion to baseline blood flow, was significantly lower in the LVH pigs compared with controls (3.5 +/- 0.4 versus 5.5 +/- 0.4 mL/g.min, P < .05); however, transmural myocardial blood flow was similar in both groups of pigs, both at baseline and with dobutamine stimulation, probably reflecting the higher coronary perfusion pressure in the LVH pigs. At baseline, PCr/ATP tended to be lower in the LVH pigs (P = .09) but decreased similarly with dobutamine infusion in both groups. Isotopically measured anterior wall lactate release did not differ between the groups at baseline, nor did the increase in lactate release differ during dobutamine stimulation. The uptake of glucose, lactate, and free fatty acids did not differ between the groups in the basal state. However, during dobutamine stimulation, glucose uptake was greater in the LVH group (0.84 +/- 0.09 mumol/g.min versus 0.59 +/- 0.08 mumol/g.min, P < .05). In a subset of animals, 14C-glucose was used to assess glucose oxidation. These data showed that the LVH animals had a greater rate of glucose oxidation (0.6 +/- 0.10 versus 0.28 +/- 0.08 mumol/g.min, P < .05) and a greater rate of glucose conversion to lactate (0.20 +/- 0.04 versus 0.09 +/- 0.02 mumol/g.min, P < .05) compared with the control pigs. CONCLUSIONS These results suggest that despite their reduced coronary vasodilator reserve and the absence of a greater rise in myocardial blood flow to compensate for a substantially higher LV double product, pigs with this model of moderate LVH do not exhibit a greater susceptibility to myocardial ischemia during dobutamine stress. However, LVH pigs exhibit significantly greater use of exogenous glucose during dobutamine stress, as evidenced by increases in both glucose oxidation and anaerobic glycolysis.

Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium

Ischemically injured reperfused myocardium is characterized by increased 18F-fluorodeoxyglucose uptake as demonstrated by positron emission tomography. To elucidate the metabolic fate of exogenous glucose entering reperfused myocardium, D-[6-14C] glucose and L-[U-13C] lactate were used to determine glucose uptake, glucose oxidation and the contribution of exogenous glucose to lactate production. The pathologic model under investigation consisted of a 3 h balloon occlusion of the left anterior descending coronary artery followed by 24 h of reperfusion in canine myocardium. The extent and severity of myocardial injury after the ischemia and reperfusion were assessed by histochemical evaluation (triphenyltetrazolium chloride and periodic acid-Schiff stains). Thirteen intervention and four control dogs were studied. The glucose uptake in the occluded/reperfused area was significantly enhanced compared with that in control dogs (0.40 +/- 0.14 versus 0.15 +/- 0.10 mumol/ml, respectively). In addition, a significantly greater portion of the glucose extracted immediately entered glycolysis in the intervention group (75%) than in the control dogs (33%). The activity of the nonoxidative glycolytic pathway was markedly increased in the ischemically injured reperfused area, as evidenced by the four times greater lactate release in this area compared with the control value. The dual carbon-labeled isotopes showed that 57% of the exogenous glucose entering glycolysis was being converted to lactate. Exogenous glucose contributed to greater than 90% of the observed lactate production. This finding was confirmed by the histochemical finding of sustained glycogen depletion in the occlusion/reperfusion area. The average area of glycogen depletion (37%) significantly exceeded the average area of necrosis (17%). These data demonstrate enhanced and sustained activity of the nonoxidative glycolytic pathway after a prolonged occlusion with reperfusion in canine myocardium. Because glycogen stores remain depleted, exogenous glucose becomes an important myocardial substrate under these pathologic conditions.

Clinical superiority of a new nonionic contrast agent (iopamidol) for cardiac angiography

The hemodynamic and electrophysiologic alterations induced by ionic contrast agents during cardiac angiography are well described. Recently nonionic contrast agents have become available for cardiac angiography. To evaluate the safety of these new agents, a double-blind randomized study was performed comparing a new nonionic agent (iopamidol) with a commonly used ionic contrast agent (Renografin-76). Eighty-one patients undergoing left ventriculography and coronary angiography were included; 41 received iopamidol and 40 received sodium meglumine diatrizoate (Renografin-76). After left ventriculography, there was a decrease in the arterial pressure with both contrast agents. However, the severity and the duration of hypotension were both significantly greater with Renografin-76 compared with the new nonionic agent (p less than 0.001). After selective injections of the coronary arteries, electrocardiographic analysis demonstrated that the increase in the QT interval (p less than 0.0002) and the changes in both the ST segment and T wave amplitude (p less than 0.001) were significantly greater in the Renografin-76 group compared with the iopamidol group. During coronary angiography, 8 of the 40 patients receiving Renografin-76 required temporary pacing for sinus pauses of 2.5 seconds or more, and 2 of the 40 also developed ventricular fibrillation. None of the 41 patients receiving iopamidol had these complications. This report demonstrates that the electrocardiographic changes, the severity and duration of hypotension and the incidence of serious arrhythmias are significantly greater with Renografin-76 than with iopamidol. Thus, this new nonionic agent appears to enhance the safety of cardiac angiography.

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)

Influence of R-wave amplitude on exercise-induced ST depression: Need for a “gain factor” correction when interpreting stress electrocardiograms

Does 2 mm of ST depression induced by exercise have the same clinical significance in a patient with a 30-mm R wave as a patient with a 10-mm R wave in the same monitored lead? To answer this question the exercise responses of 85 patients were compared by 2 quantitative methods of assessing myocardial ischemia. A computer-derived treadmill exercise score, based largely on the characteristics of exercise-induced ST-segment depression, was compared with a thallium exercise score. Both scores correlated well over a wide range of values (r = 0.71, p less than 0.001). Then, the treadmill exercise score was corrected (by adjusting the magnitude of the ST depression to a standardized R-wave amplitude of 12 mm in V5 and 8 mm in aVF) to determine if this would improve its correlation with the thallium exercise score. The patients were separated into 2 groups by R-wave amplitude: 53 had an RV5 of 9 to 17 mm and 32 had an RV5 less than 9 or greater than 17 mm. Correction of the treadmill exercise score for R-wave amplitude did not change the slope and intercepts of the regression line for patients with an RV5 amplitude of 9 to 17 mm, but did for those with an RV5 amplitude less than 9 or greater than 17 mm. In this latter group, R-wave correction changed the regression line from one that differed significantly from that of patients with less extreme RV5 voltage to one that was indistinguishable from it. Correction of the treadmill exercise score also increased the correlation coefficient from 0.54 to 0.68 in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial metabolic alterations after contrast angiography

Contrast media used during angiography are known to produce transient alterations in cardiovascular physiology. However, little information is available concerning what alterations, if any, occur in myocardial metabolism after contrast angiography. Sixteen patients with symptoms of ischemic heart disease undergoing elective left ventriculography were studied. Coronary sinus and arterial blood samples were obtained for free fatty acids, glucose and lactate before and after performing left ventriculography with Renografin-76. Coronary blood flow was determined by the thermodilution technique. Five minutes after ventriculography, the arterial level of free fatty acids had decreased by 18.0 +/- 4.9 percent (mean +/- standard deviation) from the baseline (before angiography) samples (probability [p] less than 0.001). Associated with this decrease in arterial free fatty acids was an increase in the myocardial uptake of this substrate. At 5 minutes after left ventriculography, the free fatty acid uptake had increased 48.5 +/- 33.0 percent compared with the baseline value (p less than 0.001). After the injection of contrast medium, there was no significant change in the arterial levels of glucose or lactate. However, significant decreases in the myocardial uptake of glucose and lactate were demonstrated (-72.5 +/- 44.5 percent [p less than 0.001] and -43.2 +/- 22.9 percent [p less than 0.001], respectively) at 5 minutes. The changes in arterial free fatty acids and in the myocardial uptake of the various substrates persisted throughout the sampling period of 20 minutes after ventriculography. These results demonstrate that contrast medium significantly alters myocardial metabolism. These metabolic alterations persist longer than the hemodynamic changes induced by contrast angiography.

Effects of high arterial oxygen tension on function, blood flow distribution, and metabolism in ischemic myocardium.

BackgroundAlthough oxygen inhalation therapy has long been used in the treatment of acute myocardial ischemia, experimental evidence that increased arterial Po2 has any beneficial effect in the absence of hypoxemia is equivocal. In this study, we used a swine model of subendocardial myocardial ischemia to determine the effects of arterial hyperoxia on regional myocardial contractile function (sonomicrometry), myocardial blood flow distribution (microspheres), and regional myocardial glycolytic metabolism (carbon isotope-labeled substrates). Methods and ResultsIn 10 domestic swine, the left anterior descending coronary artery was cannulated and flow to this artery was strictly controlled via a roller pump in the perfusion circuit. Arterial Po2 was controlled by manipulating inspired oxygen concentration (FIo2). Low-flow myocardial ischemia was induced by reducing pump flow to 50% of the control value, which diminished regional endocardial systolic shortening to 30–50% of normal. After a 15-minute period of flow stability, each animal was exposed in randomized order to two additional 15-minute experimental periods: coronary normoxia (Po2=90-110 mm Hg) and coronary hyperoxia (Po2>400 mmHg). At each level of oxygenation, we measured regional myocardial function, regional myocardial blood flow and metabolism, and hemodynamic indexes of myocardial oxygen demand. Myocardial ischemia during normoxia reduced systolic shortening to 10.9±5.3% in the ischemic zone. Hyperoxia increased ischemic zone systolic shortening substantially to 15.2±4.6%. During myocardial ischemia, endocardial blood flow was decreased to 0.26±0.06 ml· g-1·min-1 in the ischemic zone. During hyperoxia, endocardial blood flow rose to 0.34±0.10 ml· g-1·min-1. The endocardial:epicardial flow ratio was 0.45±t 0.18 in the initial ischemia period and rose to 0.61±0.23 in the hyperoxic period. Myocardial ischemia increased regional uptake of glucose, conversion of glucose to released lactate, and net myocardial lactate release. In the ischemic myocardium, coronary hyperoxia decreased both chemically measured lactate production and isotopically measured lactate release and decreased glucose extraction and the conversion of glucose to lactate. ConclusionsThese data demonstrate for the first time that increasing arterial Po2 to high levels during acute low-flow myocardial ischemia improves both function and flow distribution in the ischemic myocardium and decreases glycolytic metabolism in the ischemic zone. The degree of improvement in contractile function (5% absolute increase in systolic shortening or 25% change normalized to preischemic values) is consistent with the observed increase in subendocardial blood flow.

Myocardial glucose transporters and glycolytic metabolism during ischemia in hyperglycemic diabetic swine

We assessed the effects of 4 weeks of streptozocin-induced diabetes on regional myocardial glycolytic metabolism during ischemia in anesthetized open-chest domestic swine. Diabetic animals were hyperglycemic (12.0 +/- 2.1 v 6.6 +/- .5 mmol/L), and had lower fasting insulin levels (27 +/- 8 v 79 +/- 19 pmol/L). Myocardial glycolytic metabolism was studied with coronary flow controlled by an extracorporeal perfusion circuit. Left anterior descending coronary artery (LAD) flow was decreased by 50% for 45 minutes and left circumflex (CFX) flow was constant. Myocardial glucose uptake and extraction were measured with D-[6-3H]-2-deoxyglucose (DG) and myocardial blood flow was measured with microspheres. The rate of glucose conversion to lactate and lactate uptake and output were assessed with a continuous infusion of [6-14C]glucose and [U-13C]lactate into the coronary perfusion circuit. Both diabetic and nondiabetic animals had sharp decreases in subendocardial blood flow during ischemia (from 1.21 +/- .10 to 0.43 +/- .08 mL.g-1.min-1 in the nondiabetic group, and from 1.30 +/- .15 to 0.55 +/- .11 in the diabetic group). Diabetes had no significant effect on myocardial glucose uptake or glucose conversion to lactate under either well-perfused or ischemic conditions. Forty-five minutes of ischemia resulted in significant glycogen depletion in the subendocardium in both nondiabetic and diabetic animals, with no differences between the two groups. Glycolytic metabolism is not impaired in hyperglycemic diabetic swine after 1 month of the disease when compared with that in normoglycemic nondiabetic animals. The myocardial content of the insulin-regulatable glucose transporter (GLUT 4) was measured in left ventricular biopsies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse reactions of low osmolality contrast media during cardiac angiography : a prospective randomized multicenter study

A multicenter study was performed to determine the incidence of adverse reactions to two contrast media with similar low osmolality during cardiac angiography. The study was of a randomized double-blind design comparing ioxaglate (an ionic dimer) and iopamidol (a nonionic compound) and included 500 patients; 250 patients received ioxaglate and 250 iopamidol. There were 58 adverse reactions attributed to the contrast media in the ioxaglate group and 29 in the iopamidol group (p less than 0.001). Chest pain occurred in 11 patients in the ioxaglate group compared with 5 in the iopamidol group (p = 0.123). Nausea or vomiting was present in 20 and 2 patients, respectively (p less than 0.0003). Allergic adverse reactions, such as bronchospasm, urticaria and itching, occurred in 15 of the ioxaglate group and only 1 of the patients receiving iopamidol (p less than 0.0007). Fifty-two patients in the ioxaglate group had a known allergic history (not to contrast medium) or asthma, whereas 77 receiving iopamidol had a similar history. Seven of the 52 ioxaglate-treated patients developed an allergic adverse reaction compared with none of the 77 in the iopamidol group (p = 0.001). Of 41 patients receiving ioxaglate who were premedicated with diphenhydramine, 4 had an allergic adverse event. In the iopamidol group 45 patients received similar premedication and none had an allergic adverse reaction (p less than 0.03). Thus, this multicenter study shows that adverse reactions occur more often with ioxaglate than with iopamidol and that patients with an allergic history have a greater risk with ioxaglate therapy compared with iopamidol.