The Queen's Gambit is an opening move in chess that provides a variety of aggressive options to the player electing it. This report represents a similar gambit (the Sicilian Gambit) on the part of a group of basic and clinical investigators who met in Taormina, Sicily to consider the classification of antiarrhythmic drugs. Paramount to their considerations were 1) dissatisfaction with the options offered by existing classification systems for inspiring and directing research, development, and therapy, 2) the disarray in the field of antiarrhythmic drug development and testing in this post-Cardiac Arrhythmia Suppression Trial (CAST) era, and 3) the desire to provide an operational framework for consideration of antiarrhythmic drugs that will both encourage advancement and have the plasticity to grow as a result of the advances that occur. The multifaceted approach suggested is, like the title of the article, a gambit. It is an opening rather than a compendium and is intended to challenge thought and investigation rather than to resolve issues. The article incorporates first, a discussion of the shortcomings of the present system for drug classification; second, a review of the molecular targets on which drugs act (including channels and receptors); third, a consideration of the mechanisms responsible for arrhythmias, including the identification of "vulnerable parameter" that might be most accessible to drug effect; and finally, clinical considerations with respect to antiarrhythmic drugs. Information relating to the various levels of information is correlated across categories (i.e., clinical arrhythmias, cellular mechanisms, and molecular targets), and a "spread sheet" approach to antiarrhythmic action is presented that considers each drug as a unit, with similarities to and dissimilarities from other drugs being highlighted. A complete reference list for this work would require as many pages as the text itself. For this reason, referencing is selective and incomplete. It is designed, in fact, to provide sufficient background information to give the interested reader a starting frame of reference rather than to recognize the complete body of literature that is the basis for this article.

Rest and exercise radionuclide angiography is frequently employed for the diagnosis of chest pain syndromes. Its value and limitations in this regard have been well studied, but proper utilization of the technique requires an understanding of five critical concepts: 1) Radionuclide angiography is superior to treadmill exercise testing and probably equivalent to thallium scintigraphy, although the published series did not use current methods. 2) The true specificity of radionuclide angiography is about 80%, intermediate between the early optimistic estimates and the later pessimistic ones. 3) The peak exercise ejection fraction is the preferred test parameter for diagnosis, although exercise hemodynamics, symptoms, and electrocardiographic changes should also be considered. 4) Although radionuclide angiography is clearly helpful for noninvasive diagnosis, significant numbers of patients will continue to fall in an uncertain category. 5) The proper application of the technique requires recognition of its limitations and careful attention to technical details. When properly applied, this modality can make an important contribution to clinical decision making.

Recently, considerable effort has been directed toward the application of Doppler methods for detecting diastolic dysfunction. Recordings of transmitral filling velocity as obtained from pulsed-wave Doppler have been extensively investigated as a noninvasive method for determining left ventricular diastolic filling properties. Although Doppler parameters appear to reflect volumetric transmitral flow, close correlations with invasive descriptors of diastolic performance have not been found. Furthermore, Doppler transmitral velocities are sensitive to changes in ventricular preload, afterload, and heart rate. However, at least two distinct Doppler spectral patterns have been identified that are associated with impaired ventricular relaxation and restrictive physiology. Thus, Doppler recordings have proven to be of value in identifying the presence and type of diastolic dysfunction, and in the future they may be helpful in following the response to therapeutic interventions. The purpose of this paper is to review the available information relating Doppler transmitral recordings with catheterization and clinical descriptors of diastolic function. Additionally, the aim is to provide an understanding of the value and limitations of these noninvasive measurements in identifying and treating patients with diastolic abnormalities.

Fab fragments of antibodies specific for cardiac myosin have been labeled with indium-111 and injected intravenously into animals and into patients with heart transplants. The antibodies, developed by Khaw, Haber, and co-workers, localize in cardiac myocytes that have been damaged irreversibly by ischemia, myocarditis, or the rejection process. After clearance of the labeled antibody from the cardiac blood pool, planar imaging or single photon emission computed tomography is performed. Scintigrams reveal the uptake of the labeled antimyosin in areas of myocardium undergoing transplant rejection. In animal studies, the degree of antimyosin uptake appears to correlate significantly with the degree of rejection assessed at necropsy. In patients, the correlation between scans and pathologic findings from endomyocardial biopsy is not as good, possibly because of sampling error in the endomyocardial biopsy technique. The scan results at 1 year correlate with either late complications (positive) or benign course (negative). Current limitations of the method include slow blood clearance, long half-life of indium-111, and hepatic uptake. Overcoming these limitations represents a direction for current research. It is possible that from these efforts a noninvasive approach to the diagnosis and evaluation of cardiac transplantation may evolve that will decrease the number of endomyocardial biopsies required to evaluate rejection. This would be particularly useful in infants and children.

Cardiac positron emission tomography (PET) has evolved rapidly from a relatively esoteric research tool into clinical applications providing unique, quantitative information on myocardial perfusion, metabolism, and cell membrane function and having a potentially significant impact on cardiovascular medicine. Although there are many different positron radionuclides for imaging diverse myocardial behavior, three radionuclides have reached accepted clinical utility. Cardiac PET using nitrogen-13-ammonia, rubidium-82, and fluoro-18-deoxyglucose has proved accurate and definitive in multiple university and private-practice sites for diagnosing and assessing severity and location of coronary artery disease in symptomatic or asymptomatic patients, for identifying injured but viable myocardium potentially salvageable by revascularization, and for ruling out clinically significant coronary artery stenosis with a high specificity in patients who might otherwise undergo coronary arteriography to document the absence of significant disease.

With the introduction of the coronary care unit and more effective therapy for primary life-threatening arrhythmias, cardiogenic shock and the mechanical complications of acute myocardial infarction are now responsible for the majority of in-hospital deaths. These mechanical complications, which include myocardial rupture of the left ventricular free wall, rupture of the ventricular septum, and rupture of the papillary muscle, are estimated to account for 25,000 fatalities yearly in the United States. Although the mechanism of myocardial rupture has not been clearly defined, there is increasing evidence that infarct expansion, which can be readily detected by two-dimensional echocardiography, may be an important pathophysiologic factor. The ready availability of echocardiography in the coronary care unit has made a major impact on the immediate diagnosis of mechanical complications in the hemodynamically compromised patient with acute myocardial infarction. In particular, two-dimensional and Doppler echocardiographic techniques have been extremely useful in the identification and localization of ventricular septal rupture. In addition, papillary muscle rupture can be readily diagnosed by Doppler approaches and is easily distinguished from ventricular septal rupture. In view of increasing evidence that early surgical intervention is indicated in these patients, these echocardiographic approaches offer the surgeon prompt diagnostic and anatomic information. Unfortunately, rupture of the free wall of the left ventricle often results in sudden death within minutes before echocardiographic evaluation can be attempted. Nevertheless, rapid echocardiographic diagnosis provides the patient with the possibility of potential life-saving resuscitative interventions before immediate surgery. Thus, over the past decade, echocardiography has become a vital tool in the diagnosis and evaluation of patients with mechanical complications of acute myocardial infarction. The development of Doppler techniques, color flow Doppler, and esophageal approaches should further enhance our diagnostic abilities and allow careful monitoring of patients before, during, and after surgical repair. It is hoped that with the improvements in echocardiographic evaluation of mechanical rupture and more rapid surgical intervention, future studies will demonstrate better surgical results with good long-term survival in patients with myocardial rupture.

Mortality, left ventricular ejection fraction, and infarct size are important end points in evaluating the efficiency of thrombolytic treatment in clinical trials. Radionuclide assessment of ejection fraction and infarct size is safe, accurate, reproducible, and readily available. Its use in clinical trials supplements mortality data and allows meaningful results in trials with smaller patient numbers. Single photon emission computed tomography improves the detection and quantification of infarct size, and its use with new radiopharmaceuticals will assume an important role in future trials. For an 8-year period, these radionuclide techniques have been used in the Western Washington Thrombolysis Trials and have generally shown smaller infarct size and higher ejection fractions in patients receiving streptokinase and tissue-type plasminogen activator. However, in the most recent trial there was no direct relation between these end points and the time between symptom onset and initiation of treatment. Future trials that direct efforts to treatment in the first hour after symptom onset should further clarify this observation.

The two new 99m (99mTc) labeled myocardial perfusion agents, 99mTc-Sestamibi and 99mTc-Teboroxime, are now available for routine clinical application. Both agents allow assessment of ejection fraction by the first-pass technique at rest or during exercise, thus providing additional information not available with thallium-201. 99mTc-Sestamibi has long myocardial residence time, as well as adequate myocardial extraction, providing images of higher count density and superior quality compared with thallium-201. 99mTc-Teboroxime has excellent myocardial uptake characteristics but is cleared very rapidly from the myocardium. Both tracers have shown results similar to those obtained with thallium-201 for detection of coronary artery disease and the assessment of defect reversibility. 99mTc-Sestamibi studies using the rest/stress imaging sequence can be accomplished in approximately 5 hours; studies using dual-isotope imaging (rest thallium-201 and stress 99mTc-Sestamibi injection) can be completed in 1 to 2 hours. Gated stress images can be performed with 99mTc-Sestamibi, providing simultaneous information of myocardial perfusion at stress and resting wall motion or thickening and allowing rapid differentiation of ischemic from infarcted tissue. Because of its slow myocardial clearance and absence of redistribution, 99mTc-Sestamibi allows uncoupling of the time of injection from the time of imaging and thus can be valuable in the evaluation of acute myocardial infarction and outcome of thrombolytic therapy. With 99mTc-Teboroxime, rapid serial studies are feasible. Pharmacologic stress and rest studies with 99mTc-Teboroxime single photon emission computed tomography potentially can be completed in under 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Numerous highly complex and sensitive noninvasive imaging techniques have enhanced the care of patients with acute myocardial infarction. Optimum use requires specific objectives to be defined in advance, including a review of the potential impact of the test on subsequent decisions. An additional issue that is subject to scrutiny in the current climate of cost containment relates to the incremental value of a specific examination. The imaging modality to be used will partially depend on other issues, including accessibility, cost, and interindividual or institutional expertise with a particular technique. Major applications in noninvasive imaging in the acute coronary syndromes include the following: 1) diagnosis, including identification of associated diseases and contraindications for acute reperfusion; 2) evaluation and management of complications (mechanical and nonmechanical); 3) determination of prognosis (both early and late); 4) estimation of myocardial viability; 5) assessment of therapeutic efficacy; 6) investigational approaches, including 99mTc-sestamibi tomographic imaging, ultrafast cine computed tomographic scanning, and nuclear magnetic resonance imaging. Previous studies in the prethrombolytic era have documented the powerful impact of radionuclide stress testing on prognosis, but this needs to be reevaluated in the light of the changing current population undergoing stress testing. Preliminary data imply that the prognostic accuracy of stress testing after thrombolytic therapy is diminished. Moreover, the role of the open infarct-related artery in traditional estimates of prognosis (e.g., ejection fraction) requires further study. Noninvasive imaging has multiple applications in the diagnosis and management of patients with acute coronary disease, but the decision to use a specific technology in a particular circumstance mandates good clinical judgment and selectivity.

A consistent link appears to exist between predominance of vagal or sympathetic activity and predominance of HF or LF oscillations, respectively: RR variability contains both of these rhythms, and their relative powers appear to subserve a reciprocal relation like that commonly found in sympathovagal balance. In this respect, it is our opinion that rhythms and neural components always interact, just like flexor and extensor tones or excitatory and inhibitory cardiovascular reflexes, and that it is misleading to separately consider vagal and sympathetic modulations of heart rate. In humans and experimental animals, functional states likely to be accompanied by an increased sympathetic activity are characterized by a shift of the LF-HF balance in favor of the LF component; the opposite occurs during presumed increases in vagal activity. In addition, LF oscillation evaluated from SAP variability appears to be a convenient marker of the sympathetic modulation of vasomotor activity. Although based on indirect markers, the exploration in the frequency domain of cardiovascular neural regulation might disclose a unitary vision hard to reach through the assemblage of more specific but fragmented pieces of information.