Characterization of P2-purinoceptor subtypes has facilitated understanding of the many diverse effects produced by purine nucleotides. P2X-Purinoceptors are located on vascular smooth muscle where they mediate vasoconstriction resulting from ATP released as a cotransmitter with noradrenaline from sympathetic nerves. P2Y-Purinoceptors are usually located on the vascular endothelium where they have a role as mediators of vascular relaxation by locally produced ATP. In some vessels, P2Y-purinoceptors are also located on the smooth muscle, perhaps in association with purinergic or sensory nerves, where they can elicit direct relaxation to neuronally released ATP. The net effect of ATP and its analogues on isolated vessels or on vascular beds will be the results of actions mediated by P2X- and P2Y-purinoceptor subtypes, although changes in vascular tone and in integrity of nerves and endothelial cells may alter the balance of the response. Such changes have been observed in diseased states (e.g., atherosclerosis) and may have important implications for the involvement of P2-purinoceptors in, for example, vasospasm. The development of selective and potent antagonists to P2X- and P2Y-purinoceptors has so far remained elusive, and their therapeutic potential can only be guessed.

With normal and von Willebrand disease (vWD) pigs, we studied the role of von Willebrand factor (vWF) in platelet-vessel wall interactions and occlusive arterial thrombosis. Two methods of arterial injury have been used to determine the thrombotic response of flowing blood in vivo. The first involves balloon catheter injury. After superficial denudation of endothelium from coronary intima, platelets adhere to the subendothelium in a monolayer. Similar numbers of adherent platelets are found in both phenotypes, but platelets in vWD pigs have impaired pseudopod formation and are less well spread morphological indexes of limited platelet activation. Deeper injury, which involves the media, produces nonocclusive platelet-fibrin microthrombi. The second injury method involves pinching the artery at a site of superimposed stenosis, a procedure that almost always exposes media. This procedure induces platelet-fibrin microthrombi in normal and vWD pigs, but only normal pigs develop occlusive thrombosis. Both methods of arterial injury have also been performed in normal and vWD pigs with diet-induced hypercholesterolemia and atherosclerosis. Atherosclerosis promotes platelet spread in vWD pigs but does not abolish the protection from stenosis and injury-induced occlusive thrombosis. In addition, neutralization of vWF activity in normal pigs by a monoclonal antibody prevents the induction of occlusive thrombosis by the stenosis and pinch-injury procedure. This monoclonal antibody also causes performed platelet aggregates to break up. These experimental models of inducing arterial thrombosis have been used in normal and vWD pigs to demonstrate interactions between normal and atherosclerotic vessel wall constituents, circulating platelets and vWF that are fundamental in the process of arterial thrombosis.

The baboon offers many advantages as an experimental animal to study vascular disease, thrombus formation and dissolution, effects of mediating variables, and the relative efficacy of therapeutic interventions. Each specific application for testing therapeutic agents may require testing in somewhat different model systems. For example, although the arteriovenous vascular graft model is efficient, cost effective, and well adapted to study of interventions for acute arterial thrombosis, surgical endarterectomy extends the evaluation to include interactions with the injured vascular wall. As the antithrombotic products of genetic engineering and molecular biology emerge, it will be increasingly important to have relevant, reproducible, and quantitative approaches to evaluate their effects in vivo.

Coronary artery bypass grafts, angioplasty, and thrombolysis are beneficial procedures for patients with coronary artery disease. However, these procedures can fail by mechanisms related to interactions between platelets and the damaged arterial wall. An experimental model for studying some of the mechanisms of platelet interaction with endothelial- and medial-damaged stenosed arteries is described. Dogs or pigs are anesthetized, and the chest opened. The heart is exposed, the circumflex or left anterior descending coronary artery is dissected out, and an EMF or Doppler flow probe is placed on it. Distal to the flow probe, the artery is clamped with a vascular clamp to produce endothelial and/or medial injury. Then, an encircling plastic cylinder is placed around the outside of the injured artery, producing a "critical stenosis." Acute platelet thrombus formation begins to occur in the stenosed lumen, gradually increasing the amount of stenosis. This causes the coronary flow to decline and reach zero flow when the artery is completely occluded. Then, the thrombus is embolized into the distal circulation, and flow is restored to normal levels. This occurs repeatedly causing cyclic flow reductions (CFRs). These CFRs can be made larger and to occur more frequently by increasing in vivo platelet activity, by raising the plasma catecholamine levels, or by increasing the collagen exposed in the stenosed lumen by increased medial damage. If an effective dose of an antiplatelet agent is given, the CFRs will be decreased in size and frequency or abolished entirely. Aspirin and other agents abolish the CFRs in this model; however, CFRs can be renewed by infusions of catecholamines or platelet activating factor. Thus, the model may be useful for studying mechanisms that enhance or inhibit arterial thrombosis in stenosed arteries with endothelial and medial injury.

Catheter ablative techniques have assumed an increasingly important role in the treatment of patients with drug-refractory cardiac arrhythmias. Catheter ablation of the AV junction is considered the procedure of choice for management of patients without bypass tracts with drug-resistant supraventricular arrhythmias. Catheter techniques have been used with increasing frequency in attempts to ablate accessory AV tracts. These techniques currently appear to be less effective than surgical techniques but involve less morbidity and expense. In some centers, accessory pathway ablation using catheter techniques is the procedure of first choice in selected patients with drug-refractory tachycardia mediated by an accessory pathway. Catheter ablation of ventricular tachycardia should be reserved for patients with mappable ventricular tachycardia who are not candidates for cardiac electrosurgery or insertion of an automatic defibrillator. The development of more flexible catheters and more manageable energy delivery systems holds promise for more effective catheter techniques.

Left ventricular hypertrophy (LVH) is the major risk factor associated with myocardial failure. An explanation for why a presumptive adaptation such as LVH would prove pathological has been elusive. Insights into the impairment in contractility of the hypertrophied myocardium have been sought in the biochemistry of cardiac myocyte contraction. Equally compelling is a consideration of abnormalities in myocardial structure that impair organ contractile function while preserving myocyte contractility. For example, in the LVH that accompanies hypertension, the extracellular space is frequently the site of an abnormal accumulation of fibrillar collagen. This reactive and progressive interstitial and perivascular fibrosis accounts for abnormal myocardial stiffness and ultimately ventricular dysfunction and is likely a result of cardiac fibroblast growth and enhanced collagen synthesis. The disproportionate involvement of this nonmyocyte cell, however, is not a uniform accompaniment to myocyte hypertrophy and LVH, suggesting that the growth of myocyte and nonmyocyte cells is independent of each other. This has now been demonstrated in in vivo studies of experimental hypertension in which the abnormal fibrous tissue response was found in the hypertensive, hypertrophied left ventricle as well as in the normotensive, nonhypertrophied right ventricle. These findings further suggest that a circulating substance that gained access to the common coronary circulation of the ventricles was involved. This hypothesis has been tested in various animal models in which plasma concentrations of angiotensin II and aldosterone were varied. Based on morphometric and morphological findings, it can be concluded that arterial hypertension (i.e., an elevation in coronary perfusion pressure) together with elevated circulating aldosterone are associated with cardiac fibroblast involvement and the resultant heterogeneity in tissue structure. Nonmyocyte cells of the cardiac interstitium represent an important determinant of pathological LVH. The mechanisms that invoke short- (e.g., collagen metabolism) and long-term (e.g., mitosis) responses of cardiac fibroblasts require further investigation and integration of in vitro with in vivo studies. The stage is set, however, to prevent pathological LVH resulting from myocardial fibrosis as well as to reverse it.

Experimental models of vascular injury have enhanced our understanding of the pathophysiological process leading to vascular obstruction in both spontaneous and accelerated atherosclerosis. Based on experimental findings, we present and discuss a pathological classification of vascular injury or damage and its role in the pathogenesis of various vascular diseases. In addition, these animal models have provided insights into the roles of platelets and lipid metabolism in the evolution and progression of atherosclerosis and have suggested potential therapeutic applications. Thus, based on studies in the pig models, antiplatelet agents have been shown for the first time to have a beneficial effect in preventing the formation and progression of coronary atherosclerotic lesions in humans. Similarly, our findings in high density lipoprotein plasma fractions regarding inhibition and even reversal of the process of atherosclerosis in a hypercholesterolemic rabbit model have added new insights to an explosive field of lipoprotein research and provided new avenues of therapeutic strategies. our in vivo and ex vivo pig models of an extracorporeal perfusion chamber mimicking the various coronary conditions have aided in the understanding of the pathophysiology of the acute coronary syndromes and intensified our search for the ideal antithrombotic regimen in these high-risk patients. Finally, a carotid pig model of balloon angioplasty, a dog model of saphenous vein grafting, and a pig model of heart transplantation not only have provided insights into the pathophysiological process of accelerated atherosclerosis but also are allowing development of new antithrombotic and antiproliferative approaches for the prevention of these accelerated vascular diseases. In summary, we are entering an exciting era in vascular research. Significant advances in our understanding of vascular injury or damage as well as the interactions of blood cells and lipids with the vascular wall have allowed us to formulate new experimental strategies with subsequent clinical application in the prevention and progression of these vascular diseases.

In the last decade, many efforts have been made to study myocardial perfusion by contrast echocardiography. The possibility of differentiating normal from nonperfused myocardium and measuring the extent of the area at risk and myocardial infarction size has already been demonstrated. The aim of this paper is to review the approaches to quantitation of coronary blood flow by contrast echocardiography. In a series of studies, echocardiographic contrast agents have been treated like "deposit tracers." After an upstream contrast injection, myocardial contrast intensity (according to the partition principle) hypothetically reflects the fraction of contrast, and consequently of flow, distributed to the myocardium. A good correlation was found between changes in peak myocardial contrast intensity and corresponding changes in coronary blood flow (r = 0.83). However, this approach is limited by electronic signal distortion and attenuation artifacts. In other studies contrast agents have been treated as intravascular "free-passing" tracers, and (according to the dilution principle) their myocardial transit times hypothetically reflect coronary blood flow. A prolonged myocardial washout halftime with coronary underperfusion has been documented in animal experiments and patients with severe coronary stenosis. However, the majority of contrast agents have intermediate characteristics and do not belong to either category of tracers; furthermore, signal distortion and attenuation phenomena affect the washout phase. The time of myocardial contrast appearance, which is independent of tracer characteristics, permitted the differentiation of baseline conditions from coronary underperfusion but seemed inaccurate in the quantitation of coronary blood flow (r = 0.60).(ABSTRACT TRUNCATED AT 250 WORDS)

Observational data prospectively collected permit the examination of a complex set of decisions, including the decision not to perform any stress testing. Patients with or without previous myocardial infarction admitted for coronary evaluation and not submitted to any stress testing because of clinical reasons are at a higher risk for subsequent death. For prognostication, no test has been better validated than exercise electrocardiography: it can identify patients at low and high risk for future cardiac events among those without symptoms, with typical chest pain, and with previous myocardial infarction. In patients with triple-vessel disease, the results of exercise also allow those at low and high risk to be recognized. Both exercise radionuclide angiography and 201Tl scintigraphy (the latter in larger patient populations) have also demonstrated significant prognostic value on patients with or without previous myocardial infarction. Neither one has shown superiority to the other in prognostication. So far, they have been considered the only viable alternatives to exercise electrocardiography stress testing for diagnosis and prognostication. However, their costs limit their extensive application. Preliminary data suggest that intravenous dipyridamole echocardiography can be used for both diagnosis and prognostication of coronary artery disease; moreover, the prognostic information derived from dipyridamole echocardiography testing seems independent of and additive to that provided by exercise electrocardiography. Further prospective studies on larger patient populations are needed to better define the prognostic value of dipyridamole echocardiography testing.

The human heart in the fasting state extracts free fatty acids (FFA), glucose, lactate, pyruvate, and ketones from circulating blood. The utilization of FFA accounts for most of the oxygen consumed and energy produced at rest. Patients with angiographically demonstrable coronary artery disease and stable angina pectoris have a resting myocardial metabolism similar to that of normal individuals. During atrial pacing in normal persons, there is a significant enhancement of glucose uptake but that of FFA is unchanged, and the oxidation of carbohydrates accounts for more than 60% of the energy produced. In patients with stable angina, myocardial perfusion becomes regionally inadequate during stress. Despite the increase of myocardial glucose utilization, carbohydrate oxidation is negligible. Pyruvate will not be oxidized but in the presence of increased amounts of reduced coenzymes will be reduced to lactate. In addition, a greater amount of alanine will be released by the myocardium through the transamination of pyruvate, with a concomitantly greater uptake of glutamate that serves as the NH2 donor. In addition, glutamate may be used as an anaerobic fuel through conversion to succinate coupled with GTP formation. Although coronary hemodynamics, including myocardial perfusion, return to baseline within a few minutes after stress, a longer time course is needed for myocardial metabolism to become normal. In particular, myocardial utilization of exogenous glucose remains higher well after the normalization of hemodynamic parameters. This is more pronounced in postischemic myocardium, but it also occurs in nonischemic muscle, and glucose is presumably used for rebuilding glycogen stores that were depleted during ischemia.

Dipyridamole echocardiography is gaining popularity as an exercise-independent diagnostic method in patients with suspected or demonstrable coronary artery disease. To assess its safety, feasibility, and diagnostic accuracy in patients recovering from uncomplicated acute myocardial infarction, 131 patients had the test before hospital discharge. The results were compared with those of maximum treadmill testing. We found that dipyridamole-induced transient asynergy remote from the infarct zone was more sensitive (74% versus 53%, p less than 0.05) and specific (97% versus 68%, p less than 0.01) than treadmill testing for detecting multivessel coronary artery disease. In a subgroup of 42 patients treated with thrombolytic therapy, dipyridamole echocardiography was able to detect in 27 the presence of jeopardized but viable myocardium in the infarct zone. An excellent correlation was found between dipyridamole echocardiography responses and infarct vessel patency. Finally, the prognostic impact of dipyridamole echocardiography on patients recovering from acute myocardial infarction was assessed in a consecutive series of 151 patients. Eighteen months of event-free survival was significantly different in patients with positive versus negative dipyridamole echocardiography results (76.1% versus 50.8%, p less than 0.01). The test was also superior to treadmill testing in predicting cardiac events. Thus, dipyridamole echocardiography performed early after acute myocardial infarction is safe, feasible, and accurate for predicting the extent of coronary artery disease and 18-month clinical outcome.

Dipyridamole echocardiography testing is a highly feasible, inexpensive, and safe diagnostic tool, with excellent specificity and good sensitivity--especially in patients with multivessel disease and/or resting dyssynergy--for the diagnosis of coronary artery disease. The test does not offer an "all or none" binary result but rather a complex stratification of the ischemic response along the coordinates of time and space, accurately identifying the degree of physiological impairment of coronary reserve, the severity and extent of coronary disease, the geographic location of the area at risk, and the prognostic outlook. It offers highly competitive diagnostic information versus more sophisticated, time-consuming, and costly radionuclide techniques; in comparison with other stress echocardiography techniques, it is more feasible than exercise and less invasive and better tolerated than pacing. The electrocardiogram usefully integrates the information provided by the mechanical marker of ischemia during dipyridamole testing. The finding of echocardiographically silent ST segment depression represents a clue to the identification of angiographically normal coronary arteries. On the basis of this evidence, dipyridamole testing with two-dimensional echocardiography and 12-lead electrocardiography can be considered a reasonable choice for the exercise-independent diagnosis of coronary artery disease.

The rapid injection into the coronary circulation of solutions containing microbubbles produces an ultrasonic contrast effect in the myocardium. The time-intensity curves generated by sequential videodensitometric analysis of contrast intensity, which is corrected for myocardial background intensity, resembles the curves used in indicator dilution techniques. Studies done in vitro have demonstrated a direct relation between contrast intensity and amount of microbubbles. In animal studies, measurements derived from these curves correlated with changes in myocardial blood flow assessed by microspheres but with varying controversial results. Differences between investigators in technique of injection and size of microbubbles injected are among the list of factors that will alter the time-intensity curve and explain some of the differences in results between investigators. Several factors limit the application of myocardial contrast echocardiography (MCE) to the quantitation of myocardial blood flow. Nevertheless, the results from multiple investigations suggest that the technique is sensitive to changes in perfusion and may be applicable to the evaluation of regional coronary reserve and assessment of the results of revascularization procedures. Peak intensity and area under the time-intensity curve have provided consistent results between investigators; therefore, these measurements have been used to assess regional coronary reserve in experimental studies and patients with coronary artery disease. Although the results are encouraging, they cannot distinguish well between normal and mild impairments in coronary reserve and are subject to larger reproducibility errors.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic and acute hypertension have multiple untoward effects on the coronary circulation, several of which may either mimic or markedly worsen the clinical manifestations of coronary artery disease. Early after the onset of left ventricular hypertrophy secondary to hypertension, coronary vasodilator reserve is significantly impaired. During cardiac hypertrophy secondary to hypertension, the coronary arteries fail to enlarge in concert with ventricular enlargement. This failure results in a relative decrease by approximately 50% in the ratio of epicardial vessel diameter to the mass of myocardium perfused. The lower range of coronary subendocardial autoregulation is altered by chronic renovascular hypertension. A variety of vascular smooth muscle homeostatic mechanisms are abnormal in genetic models of hypertension, as is endothelium-dependent vascular relaxation. Acute hypertension may enhance constriction to serotonin, most likely through the release of potent vasoconstrictor substances from leukocytes and platelets that adhere to the endothelium as a result of endothelial damage. Finally, many of the consequences of myocardial infarction are worsened in the setting of hypertension and left ventricular hypertrophy.

Mature coronary collaterals, which develop during chronic coronary occlusion, are not simply passive conduits but are capable of active vasomotion. Collateral perfusion must traverse not only these vessels but also proximal and distal coronary vessels. This series of resistances significantly modulates perfusion to collateral-dependent and potentially ischemic myocardium. The collateral vessels themselves possess unique vasomotor characteristics, particularly markedly augmented constriction to vasopressin. The recipient coronary microcirculation develops endothelial dysfunction during collateral development, a phenomenon that may markedly alter neurohumoral regulation of perfusion to collateral-dependent myocardium. Finally, the resistances proximal to the origin of the collateral vasculature, which are negligible at rest, become significant when flow to nonischemic regions (non-collateral-dependent) is increased, predisposing to the collateral steal phenomenon. Although collateral vessels play a crucial role in preventing myocardial infarction and often restore both resting and exercise perfusion to normal, the need to use these vessels is associated with important alterations of regulatory mechanisms in the coronary circulation.