Proarrhythmia defined as the exacerbation of existing arrhythmias or the genesis of new arrhythmias de novo may result from any antiarrhythmic agent. The two general clinical syndromes of sustained arrhythmias that result appear to have distinct clinical properties that are consistent with the proposed basic mechanisms of arrhythmogenesis. Torsades de points occurs most commonly in association with administration of type Ia antiarrhythmic agents and has characteristics most consistent with triggered activity mediated by early after depolarization. Conversely, incessant, sustained, monomorphic, wide complex ventricular tachycardia occurs most commonly in association with type Ic antiarrhythmic agents and has characteristics most consistent with incessant reentry. These general subdivisions are probably oversimplified, and in fact, much overlap likely exists. In addition, these proposed mechanisms may not apply to other forms of proarrhythmia such as an increased frequency of isolated ventricular premature couplets or repetitive forms. Furthermore, proarrhythmia may also occur during treatment of supraventricular arrhythmias; although some of these described syndromes are consistent with incessant reentry, the clinical syndromes are not sufficiently defined to better characterize potential mechanisms. Further investigation, therefore, is needed to better define the mechanisms in question, but the mechanisms proposed in this article help to provide a rational approach toward understanding and dealing with clinical proarrhythmia.

Reperfusion injury includes a spectrum of events, such as reperfusion arrhythmias, vascular damage and no-reflow, and myocardial functional stunning. The concept of reperfusion injury remains controversial with many proposed mechanisms when applied to humans, whereas in animal models, there are two main proposed mechanisms: calcium over-load and formation of oxygen free radicals. To prove that reperfusion injury is specifically caused by reperfusion would require evidence that an intervention given at the time of reperfusion can diminish or abolish the injury as in the case of arrhythmias, which are thought to be mediated by excess recycling of cytosolic calcium with delayed afterdepolarizations and ventricular automaticity. In the case of myocardial stunning, the phenomenon may be mediated, at least in part, by a burst of free radicals formed within the first minute of reperfusion and improved by free radical scavengers given at the time of reperfusion. The alternate hypothesis is that cytosolic calcium overload damages mechanisms for normal intracellular calcium regulation so that the stunned myocardium responds to agents that are thought to increase intracellular cytosolic calcium, such as beta-receptor agonists. A further component of reperfusion injury, under active investigation, is microvascular damage with alterations at the level of platelets, leukocytes, and endothelial integrity. From the therapeutic point of view, the divergent results of experimental interventions and the possibility that the abrupt onset of reperfusion in animals differs from the situation in humans with thrombolysis means that the best way currently available to limit reperfusion injury is by minimizing the ischemic period by early reperfusion and by optimizing the metabolic status of the ischemic myocardium at the end of the ischemic period.

Since the first report of the application of Doppler echocardiography in the evaluation of prosthetic heart valves 10 years ago, dozens of studies have reaffirmed the usefulness of this technique in the noninvasive assessment of transvalvular hemodynamics. Most of these studies have established "normal values" for Doppler-determined pressure gradients and valve areas of prosthetic mitral and aortic valves. Although these studies have established the "normal range," they have all emphasized the individual variability in clinically normal functioning valves. Most of these studies have confirmed the extraordinary sensitivity and specificity of Doppler in detecting prosthetic valve dysfunction. The study by Burstow et al further emphasizes the excellent correlation obtained with simultaneous Doppler and catheter transvalvular pressure gradient measurements. The addition of both color flow Doppler techniques and transesophageal echocardiography can only serve to enhance the clinical diagnostic accuracy of this technique. At the present time, Doppler echocardiography is clearly the procedure of choice for the evaluation of the patient with suspected prosthetic heart valve dysfunction.

To evaluate the variability in the reported diagnostic accuracy of the exercise electrocardiogram, we applied meta-analysis to 147 consecutively published reports comparing exercise-induced ST depression with coronary angiography. These reports involved 24,074 patients who underwent both tests. Population characteristics and technical and methodologic factors, including publication year, number of electrocardiographic leads, exercise protocol, use of hyperventilation, definition of an abnormal ST response, exclusion of certain subgroups, and blinding of test interpretation were analyzed. Wide variability in sensitivity and specificity was found (mean sensitivity, 68%; range, 23-100%; SD, 16%; and mean specificity, 77%; range, 17-100%; SD, 17%). The four study characteristics found to be significantly and independently related to sensitivity were the treatment of equivocal test results, comparison with a "better" test such as thallium scintigraphy, exclusion of patients on digitalis, and publication year. The four variables found to be significantly and independently related to specificity were the treatment of upsloping ST depressions, the exclusion of subjects with prior infarction or left bundle branch block, and the use of preexercise hyperventilation. Stepwise linear regression explained less than 35% of the variance in sensitivities and specificities reported in the 147 publications. There is wide variability in the reported accuracy of the exercise electrocardiogram. This variability is not explained by information reported in the medical literature.

The prevention of cardiovascular disease antedates our current preoccupation with risk factors for coronary heart disease and hypertension. Indeed, earlier preventive efforts have in part been so successful that many people have forgotten that they existed. The almost forgotten entity, beriberi heart disease, was first prevented in 1883 by Takaki of Japan. With diphtheria, it was the identification of the causative bacillus by Klebs in 1883, leading finally to the development of diphtheria toxoid by Ramon in 1923, which resulted in the disappearance of diphtheritic heart disease. Success in the attack on syphilitic heart and vascular disease began with Bordet and Gengou in 1901 with the discovery of the phenomenon of complement fixation, and with the formulation of Salvarsan by Ehrlich in 1907. The story of the prevention of rheumatic fever has a large cast of characters, but special recognition must be given to Coburn for his observations confirming the role of the hemolytic streptococcus published in 1931 and showing the prophylactic value of sulfanilamide published in 1939. The important association of maternal rubella with congenital heart malformations was revealed by Gregg in 1941. Alcoholic heart disease was identified particularly by Brigden and Evans in 1957 and 1959, respectively. In relation to coronary and hypertensive heart disease, the names of Anitschkow (1933), Leary (1935), and Keys (1948) in relation to diet, of Freis (1967) in the field of hypertension treatment, of White (1927) in relation to physical exercise, and of English, Willius, and Berkson (1940) and Hammond and Horn (1954) in the role of cigarette smoking, deserve special recognition.

We have speculated previously that the abrupt conversion from chronic stable to unstable angina and the continuum to acute myocardial infarction may result from myocardial ischemia caused by progressive platelet aggregation and dynamic vasoconstriction themselves caused by local increases in thromboxane and serotonin at sites of coronary artery stenosis and endothelial injury. Platelet aggregation and dynamic coronary artery vasoconstriction probably result from the local accumulation of thromboxane and serotonin and also relative decreases in the local concentrations of endothelially derived vasodilators and inhibitors of platelet aggregation, such as endothelium-derived relaxing factor (EDRF) and prostacyclin. With severe reductions in coronary blood flow caused by these mechanisms, platelet aggregates may increase, and an occlusive thrombus composed of platelets and white and red blood cells in a fibrin mesh may develop. When coronary arteries are occluded or narrowed for a sufficient period of time by these mechanisms, myocardial necrosis, electrical instability, or sudden death may occur. We believe that unstable angina and acute myocardial infarction are a continuum in relation to the process of coronary artery thrombosis and vasoconstriction. When the period of platelet aggregation or dynamic vasoconstriction at sites of endothelial injury and coronary artery stenosis is brief, unstable angina or non-Q wave infarction may occur. However, when the coronary artery obstruction by these mechanisms is prolonged for several hours, Q wave myocardial infarction results. Chronic endothelial injury and coronary artery stenosis are probably associated with the accumulation of platelets, white and red blood cells, and a fibrin mesh at the site of stenosis and endothelial injury.