Alvin S. Blaustein

Outcomes in Patients with Acute Non–Q-Wave Myocardial Infarction Randomly Assigned to an Invasive as Compared with a Conservative Management Strategy

Background Non–Q-wave myocardial infarction is usually managed according to an “invasive” strategy (i.e., one of routine coronary angiography followed by myocardial revascularization). Methods We randomly assigned 920 patients to either “invasive” management (462 patients) or “conservative” management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non–Q-wave infarction. Death or nonfatal infarction made up the combined primary end point. Results During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The numb...

Stress-shortening relations and myocardial blood flow in compensated and failing canine hearts with pressure-overload hypertrophy.

Serial changes in left ventricular (LV) size and function during the adaptation to chronic pressure overload and the transition to pump failure were studied in 16 conscious dogs (aortic bands placed at 8 weeks of age). Echocardiographic data at baseline and at 3, 6, 9, and 12 months after banding revealed a progressive increase in LV mass in all dogs. In six dogs with LV pump failure, there was a progressive decline in circumferential fiber shortening (29 +/- 4% at 12 months); this was significantly less than that seen in five littermate controls (38 +/- 3%, p less than 0.05). The average LV to body weight ratio in this group was 9.8 +/- 2.7 g/kg. In 10 dogs without pump failure (compensated LVH group), shortening exceeded that seen in the controls (43 +/- 4%, p less than 0.05); the LV to body weight ratio was 7.7 +/- 1.0 g/kg. At 12 months (cardiac catheterization), the LV end-diastolic pressure was higher in the failure (25 +/- 15 mm Hg) than in the compensated group (8 +/- 5 mm Hg, p less than 0.05); mean systolic stress was also higher in the failure group (313 +/- 67 g/cm2) than in the compensated group (202 +/- 53 g/cm2, p less than 0.05). The transmural distribution of myocardial blood flow was measured (at 12 months) with the radioactive microsphere technique; flow data were then related to an index of demand (a stress-time index). There was preferential blood flow to the subendocardial layers in the control (endo/epi = 1.28) and compensated hearts (endo/epi = 1.10), but in the failure group there was a relative decrease in subendocardial flow (endo/epi = 0.92). However, the absolute values for subendocardial flow in the normal, compensated, and failure groups were 77 +/- 54, 125 +/- 48, and 113 +/- 64 ml/min/100 g; the stress-time indexes in the subendocardial shell were 38 +/- 11, 74 +/- 19, and 93 +/- 34 g sec.10(2)/cm2/min. Despite what appears to be a marginal balance between blood flow and the stress time index in the failure group, the myocardial high energy phosphates were not depleted and the inoptropic state was not depressed. In this model of LV hypertrophy, the observed differences in fiber shortening can be explained on the basis of the inverse afterload-shortening relation; pump failure was due to an inadequate LV hypertrophy with afterload excess.(ABSTRACT TRUNCATED AT 400 WORDS)

Dobutamine Echocardiography and Quantitative Rest-Redistribution 201Tl Tomography in Myocardial Hibernation Relation of Contractile Reserve to 201Tl Uptake and Comparative Prediction of Recovery of Function

BACKGROUND The purposes of this study were to evaluate the comparative accuracy of dobutamine echocardiography and quantitative rest-redistribution 201Tl tomography in the prediction of recovery of function after revascularization and to assess the relation of contractile reserve to thallium uptake. METHODS AND RESULTS Thirty-four patients with stable coronary disease and regional dysfunction underwent dobutamine echocardiography (2.5 up to 40 micrograms.kg-1.min-1) and rest-redistribution 201Tl tomography 1 day before revascularization. Resting echocardiography and scintigraphy were repeated at > or = 6 weeks. Before revascularization, resting 201Tl uptake was similar in segments demonstrating biphasic or sustained improvement and was higher than in those exhibiting no change or worsening function during dobutamine. After revascularization, 201Tl uptake increased only in segments that showed a biphasic response (from 66 +/- 12% to 78 +/- 13%; P < .05). Biphasic response had a sensitivity of 74% and specificity of 89% for prediction of recovery. The use of biphasic or sustained improvement responses increased the sensitivity to 86% with a decrease in specificity to 68%. Qualitative thallium assessment provided a high sensitivity (98%) but poor specificity (27%). Quantification of thallium uptake, however, improved its accuracy: a maximal uptake (at rest or redistribution) of > or = 60% yielded a 90% sensitivity and a 56% specificity. CONCLUSIONS In patients with myocardial hibernation, biphasic response during dobutamine is less sensitive but more specific for recovery of function, whereas indexes of 201Tl scintigraphy are in general more sensitive and less specific, the least accurate being a qualitative assessment of thallium uptake. The sensitivity and specificity of both methods, however, can be altered depending on the quantitative criteria of thallium uptake or combination of responses of the myocardium to dobutamine.

Right ventricular pacing reduces the rate of left ventricular relaxation and filling

Right ventricular pacing alters left ventricular synchrony and loading conditions, each of which may independently influence left ventricular relaxation. Addition of a properly timed atrial contraction by using sequential atrioventricular (AV) pacing minimizes changes in left ventricular loading conditions, but ventricular asynchrony persists. To separate the effects of altered loading from those of asynchrony, the effects of right ventricular pacing and sequential AV pacing on the rate of isovolumic pressure decline (relaxation time constant), myocardial (segment) lengthening rate and chamber (minor axis dimension) filling rate were examined. In 12 open chest anesthetized dogs, left ventricular pressure (micromanometer) and either left ventricular free wall segment length transients (n = 6) or minor axis dimension transients (n = 6) were measured during right atrial, right ventricular and sequential AV pacing; length and dimension were measured using ultrasonic crystals. Compared with right atrial pacing, right ventricular pacing produced a decrease in systolic pressure, a reduction in fractional shortening, a prolongation of the relaxation time constant (23.5 +/- 0.7 to 29.8 +/- 0.8 ms, p less than 0.05), slower peak segment lengthening rate (6.2 +/- 0.6 to 4.6 +/- 0.8 s-1, p less than 0.05) and a slower rate of increase in chamber dimension (3.5 +/- 0.1 to 2.7 +/- 0.1 s-1, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of Hibernating Myocardium: Comparative Accuracy of Myocardial Contrast Echocardiography, Rest-Redistribution Thallium-201 Tomography and Dobutamine Echocardiography

OBJECTIVES We sought to evaluate the comparative accuracy of myocardial contrast echocardiography (MCE), quantitative rest-redistribution thallium-201 (Tl-201) tomography and low and high dose (up to 40 microg/kg body weight per min) dobutamine echocardiography (DE) in identifying myocardial hibernation. BACKGROUND Myocardial contrast echocardiography can assess myocardial perfusion and may therefore be useful in predicting myocardial hibernation. However, its accuracy in comparison to myocardial perfusion scintigraphy and to that of high dose DE remains to be investigated. METHODS Eighteen patients (aged [+/- SD] 57 +/- 10 years) with stable coronary artery disease and ventricular dysfunction underwent the above three modalities before coronary revascularization. Myocardial contrast echocardiography was achieved with intracoronary Albunex. Rest echocardiographic and Tl-201 studies were repeated > or = 6 weeks after revascularization. RESULTS Of 109 revascularized segments with severe dysfunction, 46 (42%) improved. Left ventricular ejection fraction increased from 38 +/- 14% to 45 +/- 13% at follow-up (p = 0.003). Rest Tl-201 uptake and the ratio of peak contrast intensity of dysfunctional to normal segments with MCE were higher (p < 0.01) in segments that recovered function compared with those that did not. Myocardial contrast echocardiography, thallium scintigraphy and any contractile reserve during DE had a similar sensitivity (89% to 91%) with a lower specificity (43% to 66%) for recovery of function. A biphasic response during DE was the most specific (83%) and the least sensitive (68%) (p < 0.01). The best concordance with MCE was Tl-201 (80%, kappa 0.57). Changes in ejection fraction after revascularization related significantly to the number of viable dysfunctional segments by all modalities (r = 0.54 to 0.65). CONCLUSIONS In myocardial hibernation, methods evaluating rest perfusion (MCE, Tl-201) or any contractile reserve have a similar high sensitivity but a low specificity for predicting recovery of function. A limited contractile reserve (biphasic response) increases the specificity of DE. Importantly, the three techniques identified all patients who had significant improvement in global ventricular function.

Left ventricular chamber filling and midwall fiber lengthening in patients with left ventricular hypertrophy: overestimation of fiber velocities by conventional midwall measurements.

Observations that the inner (subendocardial) half of the left ventricular wall contributes more to total left ventricular wall thickening than the outer (subepicardial) half may have important implications in the analysis of myocardial fiber length transients. Accordingly, we measured endocardial and midwall shortening and lengthening rates in normal and hypertrophic heart and compared the results obtained with conventional methods of measurement with those obtained with a modified model that does not depend on use of conventional assumptions about the midwall. This modified (two-shell) cylindrical model) method considers the substantial contribution of inner wall thickening and thus does not require the assumption of a theoretical midwall fiber that remains at the midwall throughout the cardiac cycle. Echocardiographic data from six normal subjects and six patients with concentric left ventricular hypertrophy (LVH) were examined; left ventricular wall thickness ranged from 8 to 10 mm in normal subjects and from 11 to 16 mm in the patients with LVH. By design, the standard measurements of left ventricular size (diastolic and systolic dimensions) and systolic function (fractional shortening and endocardial fiber shortening velocities) were equal in the two groups. Endocardial, conventional midwall, and modified midwall methods all indicate reduced fiber lengthening rates in patients with LVH; peak fiber lengthening rates for normal and LVH groups were 4.5 +/- 0.7 vs 3.1 +/- 0.8 sec-1 (p less than .02) at the endocardium, 2.3 +/- 0.4 vs 1.6 +/- 0.4 sec-1 (p less than .02) at the midwall (conventional method), and 2.1 +/- 0.3 vs 1.4 +/- 0.3 sec-1 (p less than .01) at the midwall (modified method).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial glutathione depletion impairs recovery after short periods of ischemia.

Isolated, isovolumic rat hearts, perfused by Krebs-Henseleit buffer at constant coronary flow rate, were used to explore the hypothesis that endogenous cardiac glutathione provides protection against myocardial dysfunction associated with short periods of ischemia. Experimental animals were depleted of cardiac glutathione to 35% of control levels by intraperitoneal injections of diethylmaleate (DEM). Left ventricular pressure, coronary perfusion pressure, and glutathione levels were measured in control and experimental hearts after 60 minutes of oxygenated perfusion and after 20 minutes of global, no-flow ischemia and 30 minutes of reperfusion. With each protocol, both control and glutathione-depleted hearts received either standard buffer or one supplemented with 2 mM glutathione. Recovery of systolic function after ischemia-reperfusion was impaired in DEM-treated hearts compared with controls. In addition, the rise in perfusion pressure and chamber stiffness was also greater in DEM-treated hearts compared with controls. Recovery in glutathione-depleted hearts was improved when the reperfusate was supplemented with glutathione. In addition, the supplemented reperfusate prevented the decrease in compliance and the increase in coronary perfusion pressure in the glutathione-depleted hearts. Ischemia-reperfusion alone were not associated with a significant alteration in myocardial glutathione levels. Prewashout myocardial levels of glutathione were elevated after reperfusion with glutathione-supplemented buffer but fell to baseline levels after a short washout period. These studies demonstrate that endogenous glutathione is important in protection of myocardium from injury after ischemia-reperfusion, presumably by modifying levels of active oxygen intermediates. The smaller changes in left ventricular pressure and coronary resistance after administration of GSH probably reflects an extracellular mechanism because benefit is seen soon after reperfusion.

Myocardial relaxation: effects of preload on the time course of isovolumetric relaxation.

We studied the effect of an isolated increase in preload on isovolumetric relaxation in the intact dog heart and isometric relaxation in isolated cardiac muscle (dog and rat) preparations. In eight anesthetized dogs, 8 to 12 ml of blood was infused into the left ventricle during a single diastole. The exponential time constant (T) of isovolumetric relaxation was measured in single-beat experiments in which the left ventricular systolic pressure increased (112 +/- 2 to 128 +/- 3 mm Hg; p less than .05, n = 62). In a second series of experiments, left ventricular systolic pressure was held constant (109 +/- 2 to 107 +/- 2 mm Hg; p = NS, n = 23) by simultaneous ventricular infusion and aortic unloading. In the first protocol, T increased from 28.0 +/- 0.4 to 30.7 +/- 0.4 msec (p less than .05), whereas in the second protocol (constant systolic pressure) there was no change in T. The time course of isometric relaxation was also studied in six rat left ventricular papillary muscles and four dog right ventricular trabecular muscles. Preload was varied from 30% to 100% of the peak of the isometric length-tension curve in each muscle. Over this wide range of preload, the isometric force decline recordings were superimposable as long as the comparisons were made at equal levels of total load. Thus an isolated increase in preload does not influence the time course of isovolumetric relaxation.

Intensive Multifactorial Intervention for Stable Coronary Artery Disease Optimal Medical Therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) Trial

OBJECTIVES This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. BACKGROUND Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. METHODS All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. RESULTS The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked >or=150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 +/- 0.13 kg/m(2) to 29.3 +/- 0.23 kg/m(2) (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 +/- 0.49 mm Hg to 123 +/- 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 +/- 0.83 mg/dl to 72 +/- 0.88 mg/dl. CONCLUSIONS Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).

Asynchronous (segmental early) relaxation of the left ventricle.

Segmental early relaxation, a form of left ventricular asynchrony, refers to lengthening of a myocardial segment before mitral valve opening. This phenomenon may occur in normal and diseased hearts; when it is seen in a diseased ventricle it may occur in either the abnormally contracting segment or the normal segment. Experimental data indicate that altered loading conditions, especially nonuniform distribution of load or functional inhomogeneities (as may occur with regional ischemia), or both, may result in asynchronous relaxation of the left ventricle.