Myocardial Demand Research Articles

Which angiographic variable best describes functional status 6 months after successful single-vessel coronary balloon angioplasty?

Objectives. The aim of this study was to determine which quantitative angiographic variable best describes functional status 6 months after coronary balloon angioptasty.Background. Several angiographic restenosis criteria have been developed. These can be divided into those that describe the changein lesion severity and those that merely describe lesion severity at follow-up angiography. The functional significance of these criteria is unknown.Methods. We studied 350 patients with single-vessel coronary artery disease who underwent a single-site balloon dilation. Sensitivity and specificity curves were constructed for the prediction of anginal status and exercise electrocardiography of four quantitative angiographic variables that describe restenosis. The point of highest diagnostic accuracy for the variables was determined at the intersection of the sensitivity and specificity curves. Results of exercise electrocardiography were considered indicative for ischemia 6 months after angioplasty if horizontal or downsloping ST segment depression ≥1 mm occurred.Results. The points of biggest diagsostic accuracy of the angiographic variables were similar for both anginal status and exercise electrocardiegraphy: 1.45 and 1.46 mm for the minimal lumen diameter measurements, 45.5% and 46.5% for the percent dinneter stenosis measurements at follow-up, -0.30 and -0.32 mm for change in minimal lumen diameter and -10% and -10% for the change in percent diameter stenosis at follow-up.Conclusions. Angiographic variables reflecting a change in lesion severity at follow-up angiography were only slightly less accurate than variables that describe lesion severity at follow-up. The large study group and the fact that the same optimal values for diagnostic accuracy of the various quantitative angiographic variables were obtained for the prediction of two different markers of ischemia suggests that these values reflect the lesion severity or increase in lesion severity in major epicardial vessels at which coronary flow reserve is unable to meet myocardial demands.

非観血的な心筋酸素消費・供給の相対的評価法

非観血的な心筋酸素消費・供給の相対的評価法

High-dose intravenous β-blockade in patients early after cardiac operations: Negative inotropism versus myocardial oxygen economy

A high adrenergic strain during reperfusion after ischemia impedes functional recovery. Conversely, adrenergic blockade may be beneficial during reperfusion. Negative inotropic effects may outweigh the expected benefit, however. Against this background hemodynamic and metabolic effects of early postoperative infusion with the beta 1-selective agent metoprolol were studied in 22 patients after coronary operations. During basal postoperative conditions, intravenous metoprolol reduced cardiac index and stroke volume index compared with control patients, while other variables were unaffected. During the higher adrenergic level of a dopamine infusion (7 micrograms/kg per minute), the heart rate, rate pressure product, and myocardial oxygen uptake were attenuated in proportion to the plasma level of metoprolol. Intravenous beta 1-blockade did not affect the cardiac output or stroke volume responses to dopamine (the cardiac output was still, however, 19% lower than in control patients). A release of myocardial creatinine kinase isoenzyme myocardial band was observed during dopamine infusion, suggesting that myocardial ischemia was induced. The release was not influenced by metoprolol, but it correlated with heart rate (r = 0.60; p < 0.01). It is concluded that infusion of metoprolol early after coronary operations depresses myocardial contractility with some 19%, which was without clinical significance in straightforward patients; the increased myocardial metabolic demand during a period of increased adrenergic stress was attenuated by metoprolol. This may be of importance for myocardial recovery.

New insights into the management of myocardial ischemia

Episodes of ST depression are closely related to transient decreases in regional myocardial perfusion during physical or mental stress. At the on-set of these events, there is transient constriction of atherosclerotic stenoses, with an increase in myocardial demand as reflected by increases in heart rate and blood pressure. Recent research has shown that normal epicardial coronary arteries respond to these provocations and to increasing blood flow with progressive vasodilation. In contrast, atherosclerotic vessels lose this ability to dilate and may show paradoxical constriction. This abnormal constriction parallels the response of the arteries to acetylcholine, which can be used to assess the ability of the coronary endothelium to regulate vasodilation. The loss of endothelium-dependent vasodilation appears to be an important functional manifestation of coronary atherosclerosis and a potential triggering mechanism for transient ischemia. Dysfunctional endothelium may also result in a procoagulant surface, with cell adherence and local thrombus formation. Restoration of normal endothelial function is likely to emerge as an important therapeutic objective in the management of myocardial ischemia and coronary atherosclerosis.

Factors involved in left ventricular dysfunction after massive sympathetic activation

We sought to determine whether catecholamines are responsible for the depressed left ventricular (LV) function that follows massive sympathetic nervous system (SNS) activation and whether the additional myocardial energy demands of SNS-induced hypertension contribute to this disorder. An intracisternal injection of veratrine was used to intensely activate the SNS of anesthetized rabbits, and 150 min later, LV function was evaluated in vitro using established techniques. To assess catecholamine involvement, rabbits were pretreated with phentolamine, propranolol, or saline prior to SNS activation. Control animals received veratrine intravenously. In separate experiments, angiotensin II (ANG II) was administered to rabbits to produce hemodynamic and plasma catecholamine profiles comparable to that produced by intense SNS activity. LV function of hearts after either massive SNS activation or ANG II administration was significantly diminished compared with control (P less than 0.01) and could be prevented by pretreatment with the catecholamine antagonists. LV function was also not diminished in another group of animals in which arterial pressure was maintained near baseline throughout the SNS discharge, thus suggesting that the increased myocardial energy demand associated with the development of arterial hypertension contributes to the LV dysfunction. We conclude that toxic concentrations of catecholamines are responsible for SNS-induced LV dysfunction and that hypertension, most likely because of its ability to increase myocardial energy demand, is one of the important events that leads to depressed cardiac function.

Pathophysiology of ischemia in patients with coronary artery disease

C ORONARY atherosclerosis is characterized by subintimal thickening that leads to plaque formation and stenosis.’ During the progression of this pathology in the large epicardial arteries, episodes of transient myocardial ischemia occur and each event is characterized by a reversible decrease in regional myocardial oxygen concentration that characteristically effects a segment of the left ventricle.2 This leads to the failure of systolic and diastolic muscle function, varying degrees of left ventricular failure, and profound metabolic disturbances. This functional expression of coronary artery disease can be induced by provoking disturbances in coronary blood supply and/or increases in myocardial demand for oxygen (ie, during exercise); ischemia also occurs during the activities of everyday life and it can precede damaging clinical events such as acute myocardial infarction, pulmonary edema, and sudden death.?,’ Transient myocardial ischemia in patients with obstructive coronary artery disease occurs in many different clinical syndromes (eg, chronic stable angina, unstable angina, and after myocardial infarction) and its presence always indicates the increased risk of adverse coronary events.2-7 In the majority of patients with ischemia and proven coronary artery disease, there are atherosclerotic stenoses that severely reduce crosssectional area in a segment of at least one epicardial artery. In these circumstances, standardized exercise protocols can provoke and reproduce ischemia and angina at a reproducible level of exercise. These clinical features have nurtured the belief that coronary blood supply is fixed and myocardial demand increases to cause ischemia. Although this concept is useful when considering the benefits of beta-adrenoreceptor blocking drugs, coronary angioplasty and by-pass graft surgery, these therapies probably do not address the disturbed biology of developing atherosclerotic lesions. Clinical studies of transient myocardial ischemia during daily life,8*9 studies of regional myocardial blood flow before and during ischemia”‘-I5 and studies of coronary vasomotion during cardiac catheterization all highlight the active role of the diseased epicardial arteries in causing transient ischemia.16-r9 An enhanced understanding of the biology of atherosclerotic stenoses has clarified pathophysiological mechanisms of myocardial ischemia and has suggested new directions in the development of therapies aimed at physical regression of coronary atherosclerosis and the control of constriction and thrombosis.20.2i This article will focus on transient myocardial ischemia by examining new clinical characteristics and pathogenic mechanisms rather than simply evaluating diagnostic techniques. It will discuss new clinical information about the biology of atherosclerosis and stenoses in relation to the occurrence of ischemia and adverse clinical outcomes. New insights from basic research will only be discussed as they provide fresh directions for clinical research. This paper will focus on transient ischemia rather than myocardial infarction or sudden death and will try to explore the relationship between coronary atherosclerosis, coronary vasoconstriction, and thrombosis as these problems occur in patients.

Cocaine Depresses Myocardial Contractility and Prolongs Isovolumetric Relaxation in Conscious Dogs with Partial Autonomic Nervous System Blockade

The direct effects of cocaine on myocardial contractility and isovolumetric relaxation were investigated in conscious dogs (n = 8) chronically instrumented for measurement of hemodynamics, including left ventricular pressure (LVP) and subendocardial segment length. Experiments were performed in the presence of pharmacologic blockade of beta-adrenergic, cholinergic, and ganglionic receptors because cocaine indirectly produces significant alterations in systemic hemodynamics through central and peripheral sympathomimetic actions. Myocardial contractility was quantitated using the preload recruitable stroke work (PRSW) versus end-diastolic segment length (EDL) relationship. LVP-segment length loops were generated in the unsedated control state and after cocaine administration with use of preload reduction by abrupt inferior vena caval constriction, and PRSW versus EDL slope (Mw) and length intercept (Lw) were calculated. In addition, regional preload recruitable work area (PRWA) and stroke work at constant EDL (SWEDL) were also determined. Ventricular relaxation was assessed using a time constant of isovolumetric relaxation assuming a nonzero asymptote of LVP decay. Systemic hemodynamics, myocardial contractility, and isovolumetric relaxation were recorded and calculated before and 1, 3, 5, and 10 min after cocaine administration (2 mg/kg intravenously, i.v.). Mw was significantly (p less than 0.05) reduced by cocaine (63 +/- 8 during control to 45 +/- 8 mm Hg at 1 min after drug administration). PRWA also reflected significant decreases in myocardial contractility after cocaine administration (1,800 +/- 260 during control to 1,200 +/- 220 mm Hg.mm2 at 1 min after drug administration). Similar results were observed with SWEDL (469 +/- 60 during control to 317 +/- 52 mm Hg.mm at 1 min after cocaine administration). All three indexes of contractile state demonstrated complete recovery of contractile function by 10 min after cocaine administration. The time constant of isovolumetric relaxation was prolonged by cocaine (35 +/- 2 during control to 46 +/- 3 ms at 3 min after drug administration), indicating impairment of diastolic function. Ventricular relaxation returned to control levels within 5 min after cocaine administration. No cocaine-induced alterations in coronary blood flow (CBF) or changes in calculated pressure work index (PWI, an indicator of myocardial O2 consumption) were observed. The present results suggest that cocaine produces direct negative inotropic and lusitropic effects independent of changes in myocardial O2 supply and demand and autonomic nervous system activity in conscious chronically instrumented dogs.

Excluding heart disease in the patient with chest pain

Angina pectoris is chest discomfort associated with myocardial ischemia. When coronary blood flow is inadequate to meet myocardial tissue demand, lactate accumulates, resulting in diastolic and systolic left ventricular dysfunction. This leads to ST-segment abnormalities and eventually to angina pectoris. Angina, most commonly a pressure-type sensation in the midanterior chest precipitated by exercise, stress, or cold, typically lasts 1-5 minutes and is alleviated by rest or nitroglycerin. Diagnostic studies to assess myocardial ischemia include treadmill exercise testing, Holter monitoring, and coronary angiography. Treadmill exercise testing has a relatively low accuracy for diagnosing coronary artery disease. This can be improved by combining exercise with thallium-201 imaging, two-dimensional echocardiography, or positron emission tomography (PET). Thallium-201 scintigraphy and exercise echocardiography have reported sensitivities of 70-85% and specificities of 50-60% when applied to low-risk, asymptomatic populations. PET scanning has a high predictive accuracy (sensitivity 90%, specificity 90-95%) and is more useful as a screening test; it can also assess the functional significance of coronary artery stenoses and differentiate viable myocardium from infarcted tissue. Holter monitoring is too insensitive and nonspecific to be used as a screening test for coronary artery disease; it can, however, assess the total ischemic burden in patients with known coronary artery disease and correlate symptoms and ST-segment abnormalities during episodes of pain at rest. Coronary angiography has been the gold standard for diagnosing coronary artery stenoses. Quantitative angiography has improved the assessment of coronary artery narrowing but is still limited in evaluating coronary blood flow. Doppler flow studies provide useful information regarding coronary flow reserve. Myocardial ischemia as a cause of chest pain is determined by evaluating the clinical characteristics consistent with angina, correlating electrocardiographic abnormalities with perfusion defects or wall motion abnormalities, and determining the extent and functional significance of coronary artery stenoses by coronary angiography.

Effects of inspiratory loading on left ventricular myocardial blood flow and metabolism

With airways obstruction, mean pleural pressure decreases. It has been postulated that associated increases in left ventricular afterload increase myocardial O2 demand (MvO2) and coronary blood flow (CBF). We tested this hypothesis in 12 anesthetized mixed-breed dogs. Through a median sternotomy, dogs were instrumented for the measurement of mean arterial pressure, cardiac output, and left anterior descending CBF. A catheter placed in the coronary sinus allowed sampling of left ventricular venous blood. MvO2 was calculated as CBF x (arteriovenous content difference), and coronary resistance was calculated as (mean arterial pressure)/CBF. After closure of the thoracotomy, animals were studied before and during inspiratory threshold loading (IL) of -20 to -25 cmH2O while breathing 100% O2 before and after bilateral cervical vagotomy. During IL, heart rate fell [approximately 20 beats/min (NS prevagotomy, P less than 0.05 postvagotomy)], arterial PCO2 increased [45 to 66 Torr prevagotomy, 45 to 50 Torr postvagotomy (P less than 0.01)], and arterial O2 content was unchanged. CBF increased with IL:41% prevagotomy (P less than 0.01), 18% postvagotomy (P less than 0.02). However, with IL, MvO2 did not increase significantly either pre- or postvagotomy. Coronary resistance decreased with IL [30% prevagotomy, 24% postvagotomy (P less than 0.01)]. In eight dogs, PCO2 was increased by increasing dead space while the animals were mechanically ventilated and paralyzed. Although there was little change in CBF, heart rate fell by an amount equal to that with IL. We conclude that 1) IL causes coronary vasodilation not related to changes in MvO2, PCO2, or vagal tone; 2) MvO2 does not increase with IL; and 3) decreased heart rate with IL is related to hypercapnia and/or acidosis.

The effect of ergonovine on coronary vasodilatory reserve in patients with angiographically normal coronary arteries

Ergonovine produces physiologic coronary artery narrowing in many patients without focal coronary spasm. The effect of ergonovine-induced coronary vasoconstriction on coronary vasodilatory reserve is unknown. Therefore we studied 10 patients with atypical chest pain and angiographically normal coronary arteries. The heart rate and blood pressure were recorded continuously and coronary Doppler flow velocity was measured continuously with a 20 MHz Doppler-tipped catheter. Ergonovine caused diffuse narrowing of the vessels in all patients, with a 12% ± 5% change in diameter of the left anterior descending coronary artery ( p < 0.001). There was a significant change in systolic (17% ± 12% change; p < 0.05) and mean arterial pressure (13% ± 13% change; p < 0.05), with no significant change in mean coronary flow velocity with ergonovine. Ergonovine also did not attenuate the maximal hyperemic response with papaverine. Thus despite an increase in myocardial demand and a decrease in caliber of conductance coronary vessels, the coronary autoregulatory flow responses were intact after the administration of ergonovine.

Coronary and systemic vascular response to inspiratory resistive breathing.

To evaluate the coronary and systemic cardiovascular response to graded inspiratory resistive breathing, seven dogs were studied 2-4 wk after chronic instrumentation to measure circumflex coronary artery and ascending aortic blood flows as well as aortic and left ventricular (LV) blood pressures. The experiments were performed under chloralose anesthesia (to exclude any confounding emotional effects by dyspnea on cardiovascular variables) and hyperoxic conditions (to prevent chemoreflex activation by hypoxemia). In a randomized fashion, the dogs were subjected to graded inspiratory resistive breathing (spontaneous breathing alone and moderate and severe resistive loading, corresponding to resistances of approximately 0, 40, and 110 cmH2O.s.l-1, respectively). Each run lasted 10 min. Compared with mechanical ventilation with the respiratory muscles at rest, spontaneous breathing alone and moderate and severe inspiratory resistive loading induced pronounced and significant increases in circumflex coronary blood flow (19, 32, and 62%, respectively), which were almost exclusively accounted for by significant decrements in coronary vascular resistance and were paralleled (r = 0.88, P less than 0.0001) by significant increments (18, 31, and 57%) in heart rate transmural-aortic pressure product, an indicator of LV myocardial O2 demand. An increase in myocardial O2 consumption during resistive breathing was confirmed by analysis of coronary sinus blood samples in additional experiments (n = 3). Cardiac output significantly increased (10, 14, and 35%) because of increases in heart rate (15, 24, and 49%), with LV stroke volume and diastolic dimensions remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Deleterious cardiac effects of captopril during acute myocardial ischaemia in the dog.

The aim was to evaluate the effects of the angiotensin converting enzyme inhibitor captopril on acute myocardial ischaemia. Seventeen anaesthetised open chest dogs were randomised to 3 minute angioplasty balloon occlusions of the left circumflex coronary artery before and after intravenous infusion of captopril (n = 8) or placebo (n = 9). There was apparent worsening of ischaemia during balloon inflation after captopril infusion, when compared with control inflation, as suggested by further ST segment elevation of 1.8 (SD 1.8) mm, p less than 0.03, and by further lowering of regional myocardial pH [-0.05(0.05), p = 0.06], and peak positive and peak negative dP/dt [-439(337)mm Hg.s-1, p less than 0.008; -470(316) mm Hg.s-1, p less than 0.004, respectively]. The increase in ischaemia occurred despite reduced double product after captopril administration. Regional myocardial blood flow in the ischaemic artery distribution was lower during post captopril balloon occlusion [-0.1(0.06) ml.min-1.g-1, p less than 0.005] than during control balloon inflation, while coronary vascular resistance increased by 161(172)% (range 45 to 497%, p less than 0.04). There were no significant differences in ST segments, pH, haemodynamic variables, or blood flow during balloon inflations before and after saline infusion. Despite lower myocardial metabolic demands, acute intravenous administration of captopril was associated with increased ischaemia during transient coronary artery occlusion.

Characterization of “Hibernating” and “Stunned” Myocardium with Focus on the Use of Calcium Antagonists in “Stunned” Myocardium

In the initial seconds after a sudden reduction in coronary blood flow, a temporary mismatch between myocardial energy demand and supply exists. The mechanisms underlying the rapidly ensuing reduction in contractile function in the ischemic myocardium are still unknown. In the presence of some residual blood flow, a state of "perfusion-contraction matching" develops. The metabolic status of such hypoperfused myocardium improves, since myocardial lactate production is attenuated and creatine phosphate (CP), after an initial reduction, returns toward control values. The hypoperfused myocardium responds to inotropic stimulation by dobutamine. The recruitment of an inotropic reserve implies increased energy utilization. During inotropic stimulation, after partial normalization, lactate production is again increased, and CP is decreased again. Thus, a supply-demand imbalance that had been at least partially corrected by the ischemia-induced decrease in regional contractile function is precipitated again. A situation of chronic contractile failure in viable myocardium that normalizes upon reperfusion has been termed myocardial "hibernation." Myocardial "stunning" is characterized by a reversible postischemic contractile dysfunction despite full restoration of blood flow. The details of the underlying mechanisms are not clear. An inadequate energy supply and impaired sympathetic neurotransmission have been excluded. Potential mechanisms, which are not mutually exclusive, may include (a) damage of membranes by free radicals, (b) an increase in free cytosolic calcium during ischemia and reperfusion, and (c) a decrease in the calcium sensitivity of the myofibrils. The equally pronounced increases in regional contractility in normal and "stunned" myocardium during postextrasystolic potentiation and the infusion of calcium or the calcium-sensitizing agent AR-L-57, however, suggest an unchanged calcium sensitivity of reperfused myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasotonic myocardial ischemia

The concept that myocardial ischemia can be directly related to enhanced coronary vasomotor tone is now widely accepted. Earlier skepticism has, to a large extent, been neutralized by a steady stream of convincing evidence. Doubts, however, remain as to the real incidence of this phenomenon and its precipitating factors. It is also not clear whether coronary vasoconstriction is a primary event or merely a by-product or secondary factor in a more complex histochemical disturbance afflicting atherosclerotic or nearly normal coronary arteries as a result of yet poorly understood mechanisms. Nevertheless, the simplistic view of ischemia as strictly a result of increased myocardial demand has been swept away by the expanding understanding of the dynamic nature of coronary supply. While primary focal spasm of large epicardial coronary arterial segments is admittedly infrequent, other forms of vasoconstriction are probably not. These include spasm superimposed over fixed obstruction, and that occurring during the “hot war” of unstable ischemia as a result of potent vasoactive by-products. Furthermore, reduced coronary flow as a consequence of constriction of smaller prearteriolar, arteriolar, and collateral beds is believed to play a major role in ischemia in the face of normal epicardial coronary arteries. The so called “syndrome X” is an example of ischemia related to increased coronary resistance. It can result from either reduced responsiveness to vasodilating stimuli or increased sensitivity to vasoconstricting stimuli. The role of stress-related release of catecholamines and its detrimental effect on coronary flow is undergoing serious assessment at present. Potential target sites of such a systemic outpouring can theoretically include the whole extent of the coronary vascular bed. Thus increased coronary vascular tone appears to be quite nonhomogeneous. Its causes, severity,

Hemodynamic and Myocardial Blood Flow: Profiles of Pinacidil and Nitroprusside in Conscious Dogs

Vasodilator antihypertensive agents can induce endocardial underperfusion relative to myocardial metabolic demand in normal hearts. We studied ten conscious normotensive dogs, paced at constant heart rate, to determine the relative probabilities of inducing endocardial ischemia with intravenous sodium nitroprusside or pinacidil, a novel antihypertensive agent. On different days, pinacidil and nitroprusside were infused in each animal to achieve mean aortic pressures (MAP) of 83 +/- 0.2 mm Hg and 62 +/- 1 mm Hg, reduced from control pressures of 106 +/- 3 mm Hg (pinacidil) and 107 +/- 3 mm Hg (nitroprusside). At MAP = 62 mm Hg, pinacidil depressed the left ventricular endocardial:epicardial blood flow (0.81 +/- 0.03) more than did nitroprusside (1.00 +/- 0.06, P less than .01). However, pinacidil increased left ventricular blood flow in all transmural layers at both levels of hypotension (P less than .05); nitroprusside increased only epicardial blood flow at MAP = 62 mm Hg (P less than .05). Neither vasodilator significantly altered myocardial oxygen consumption at either level of hypotension. At MAP = 83 mm Hg, pinacidil depressed the ratio of left ventricular vascular resistance and systemic vascular resistance indices (LVVRI/SVRI) 40 +/- 6 percent (P less than .001) to a level below that existing during nitroprusside infusion (P less than .05). These data indicate that pinacidil has greater selectivity for the coronary circulation over the systemic circulation compared to nitroprusside. Although it is unlikely that either drug caused endocardial ischemia in the present study, the data suggest that pinacidil is less likely to do so than is nitroprusside in normal hearts.

Stunning of the myocardium: An update

When severely ischemic myocardium is reperfused, prolonged myocardial dysfunction--a phenomenon named myocardial stunning--frequently occurs. Stunning also occurs in a variety of other situations. These include myocardium located adjacent to infarcted tissue, transient increase in myocardial O2 demands in the presence of incomplete coronary obstruction, during both systole and diastole, in isolated perfused hearts rendered ischemic or anoxic, and in a variety of clinical situations, such as following ischemic arrest in cardiac surgery, thrombolytic reperfusion, and after episodes of severe ischemia in Prinzmetal's angina or unstable angina. Although the fundamental mechanism(s) responsible for myocardial stunning has not been elucidated, in experimental preparations calcium antagonists, free-radical scavengers, and neutrophil depletion have each been found to be helpful in minimizing it.

Effects of TA-3090, a new calcium channel blocker, on myocardial substrate utilization in ischemic and nonischemic isolated working fatty acid-perfused rat hearts.

Experimental studies have shown that calcium channel blockade has a protective effect on the ischemic myocardium. Although these agents may act by decreasing intracellular Ca2+ accumulation during reperfusion or to reduce oxygen requirements by decreasing myocardial work load, recent evidence suggests that calcium blockers may also favorably alter energy substrate metabolism in ischemic and reperfused myocardium. In this study, TA-3090, a new calcium channel blocker with minimal effect on myocardial work load, was used to study the effect of calcium channel blockade on both myocardial substrate utilization and reperfusion recovery of ischemic hearts. Isolated working rat hearts were perfused at an 11.5 mm Hg preload and an 80 mm Hg afterload with Krebs-Henseleit buffer containing 11 mM glucose, 1.2 mM palmitate, and 500 microunits/ml insulin. In aerobically perfused spontaneously beating hearts, a 0.5 microM dose of TA-3090 had a mild depressant effect on heart rate but no effect on peak systolic pressure development. In paced hearts (250 beats/min), 0.5 microM TA-3090 had no effect on either peak systolic pressure development or contractility. Fatty acid and glucose oxidation was determined by measuring 14CO2 production in hearts perfused with either [14C]palmitate or [14C]glucose, respectively, whereas glycolysis was determined by measuring 3H2O production from [3H]glucose. Under aerobic conditions, fatty acid oxidation was not altered by TA-3090, but a significant decrease in glucose oxidation and glycolytic rates was observed. If hearts were subjected to a 30-minute period of no-flow ischemia, the addition of 0.5 microM TA-3090 to the perfusate before ischemia significantly improved reperfusion recovery of mechanical function. The protective effects of TA-3090 were not observed if TA-3090 was added at the time of reperfusion and were not related to a depression of function before ischemia. TA-3090, added before ischemia, significantly reduced glycogen and ATP depletion during no-flow ischemia and also significantly decreased glycolytic rates in hearts subjected to low-flow ischemia (coronary flow = 0.5 ml/min). Combined, our data suggest that the beneficial effects of calcium channel blockade on the ischemic myocardium are not related solely to a decrease in myocardial work load or metabolic demand before ischemia, but rather may in part be related to a decrease in myocardial energy demand during ischemia itself, resulting in preservation of ATP and a decrease in glycolysis. The decrease in glycolytic rates during ischemia may also result in a reduction of glycolytic product accumulation during ischemia.

Beta-adrenergic blockade in dilated cardiomyopathy, ischemic cardiomyopathy, and other secondary cardiomyopathies

Beta-blockers were initially given to patients with chronic heart failure due to ischemic heart disease and resting tachycardia. The prompt effect on severe backward heart failure was directly associated with an immediate fall in heart rate. This observation led to long-term administration to patients with idiopathic dilated cardiomyopathy and, later, to patients with ischemic cardiomyopathy and secondary cardiomyopathies as well. Due to marked down-regulation of beta receptors, patients with heart failure are extremely sensitive to beta blockade. A test dose of metoprolol 5 mg b.i.d. for 2 days is recommended to select patients for long-term beta-blockade, followed by careful titration with increment in dose over 6 weeks. One important effect of beta-blockade in the early phase of treatment is a reduction in the myocardial energy demand early after the onset of long-term treatment. After 1 month of treatment with beta-blockers, marked improvement of diastolic function is observed. This effect might be attributed to inhibition of calcium overload. After 3 months of treatment, an increase in ejection fraction can be observed, which might be attributed to upregulation of beta receptors. The withdrawal of long-term treatment was followed by a deterioration of heart function in 61% of patients and improvement was seen after reinstitution of beta-blockade. There was an increase in cardiac index and stroke work index at rest as well as during supine exercise. A marked fall in left ventricular filling pressure at rest and unchanged filling pressure during supine exercise was noted, while exercise capacity increased by 25%. A similar pattern was seen in patients with ischemic cardiomyopathies and other secondary cardiomyopathies. However, the increase in ejection fraction in the ischemic cardiomyopathy group was lower (0.06) compared to the groups with dilated cardiomyopathy and other secondary cardiomyopathies (0.18).

Myocardial and Systemic Hemodynamics During Isovolemic Hemodilution Alone and Combined With Nitroprusside-Induced Controlled Hypotension

Myocardial and systemic effects of isovolemic hemodilution alone and combined with controlled hypotension induced with sodium nitroprusside (SNP) were studied in halothane-anesthetized, open-chest dogs. Regional blood flow was measured with radioactive microspheres and used to compute regional oxygen (O2) supply. Values for regional blood flow in myocardium were used to compute myocardial O2 (MVO2) and lactate uptake (MVLAC) using the Fick equation. Hemodilution to hematocrit 50% of baseline increased aortic blood flow and decreased systemic vascular resistance, although other systemic hemodynamic values were not changed. Twofold increases in myocardial blood flow were accompanied by no change in MVO2, MVLAC, or coronary sinus PO2. Hemodilution increased regional blood flow sufficiently in the pancreas, liver, duodenum, skeletal muscle, skin, and brain to preserve O2 supply whereas unchanged blood flow in the spleen and kidney reduced O2 supply. Under hemodilution, 15 min of intravenous SNP sufficient to reduce mean arterial pressure by 50% caused parallel reductions in aortic blood flow, dP/dt max, and left ventricular end-diastolic pressure; systemic vascular resistance was unaffected. Myocardial blood flow and MVO2 decreased proportionally, whereas MVLAC and coronary sinus PO2 did not change. Regional blood flow and O2 supply decreased in the kidney, spleen, liver, and skin. Extending SNP infusion to 60 min increased myocardial blood flow and MVO2, but other hemodynamic values were unchanged. Comparing previous results with adenosine-induced hypotension inferred that coronary vasodilator reserve was greatly reduced at this time. In conclusion, although myocardial O2 supply versus demand balance was well maintained during SNP-induced hypotension under hemodiluted conditions, diminished coronary vasodilator reserve suggests increased vulnerability to ischemia if stresses of augmented cardiac work demand or impaired arterial oxygenation were superimposed. The decrease in O2 supply in the kidney during combined hemodilution and SNP-induced hypotension also warrants concern. These latter findings suggest the need for extensive clinical monitoring when SNP is used for controlled hypotension under hemodiluted conditions.

Patterns of ST-segment change during acute no-flow myocardial ischemia produced by balloon occlusion during angioplasty of the left anterior descending coronary artery

An early manifestation of acute myocardial ischemia is the development of ST-segment and T-wave changes. Clinical decisions for treatment are based on ST-segment shifts on the surface electrocardiogram (ECG). ST-segment depression is believed to represent subendocardial involvement, with less extensive myocardial injury. ST-segment elevation reflects transmural involvement, with greater extent of myocardial injury. 1−3 ST-segment depression is generally induced by factors that increase myocardial demand, such as atrial pacing or exercise stress, whereas ST-segment elevation is induced by near total cessation of coronary blood flow. After acute total occlusion of the vessel, myocardial injury is believed to progress from the endocardium to the epicardial layers. Thus, we would expect to observe ST-segment depression progressing through an isoelectric point to ST-segment elevation. This may explain why some patients have no significant changes on the ECG when presenting with an acute myocardial infarction. To test this hypothesis in humans, we used balloon angioplasty of the coronary arteries as the model for acute noflow ischemia. Intracoronary electrograms were obtained from the center of the ischemic zone by attaching the proximal end of the balloon angioplasty guidewire to the V 1 lead on the surface ECG. Patterns of ST-segment responses on the intracoronary electrogram and surface leads II and V 5 were continuously recorded.