Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial.

BACKGROUND: Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. METHODS AND RESULTS: Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. CONCLUSIONS: In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.

Shock in acute myocardial infarction: evolution of physiologic therapy.

In the past 25 years the treatment of shock in myocardial infarction has evolved into a physiologic approach based on on-line measurements of hemodynamic variables. This has aided in the development of new pressor agents so that a family of pharmacologic agents is now available. Appropriate use of vasodilators and recognition and treatment of intravascular volume depletion have increased survival. Recognition and appropriate treatment of the preshock state have decreased the incidence of shock. The criteria for use of mechanical support and surgical intervention are soundly established; the use of thrombolytic therapy and balloon angioplasty for this syndrome is ready to be evaluated.

Regional changes in blood flow, extracellular potassium and conduction during myocardial ischemia and reperfusion.

OBJECTIVES: We postulated that ventricular arrhythmias may arise from the heterogeneous washout of ischemic metabolites. Our objective was to investigate the distribution of extracellular potassium concentration ([K+]o) during myocardial ischemia and reperfusion and to correlate this distribution with regional differences in myocardial blood flow. BACKGROUND: Our previous study showed that reperfusion after a brief period of ischemia resulted in heterogeneous reflow of the ischemic myocardium. METHODS: The changes in regional myocardial blood flow, midmyocardial [K+]o and electrogram duration were quantitated in 14 dogs undergoing 20 min of left anterior descending coronary artery occlusion and 1 min of reperfusion. Regional myocardial blood flow was measured by using 15-microns radioactive microspheres in 1- to 1.5-g full thickness myocardial samples. The [K+]o was measured with intramyocardial K(+)-sensitive electrodes. RESULTS: During coronary occlusion, the ischemic zone exhibited a reduction in regional blood flow to 0.13 +/- 0.06 ml/g per min and increases in [K+]o to 9.3 +/- 2.6 mmol/liter and electrogram duration to 131.8 +/- 38.6% of control. Heterogeneous reduction in regional blood flow at various sites in the ischemic zone had fair correlations with variable increases in [K+]o (r = -0.70) and electrogram duration (r = -0.75). During min 1 of reperfusion, regional blood flow ranged from two to more than seven times baseline, resulting in a disorganized spatial distribution of perfusion with islands of high and low blood flows. Associated with the heterogeneous early reperfusion regional myocardial blood flow, [K+]o and electrogram duration changed at different rates toward normal. Whereas correlation between regional blood flow and [K+]o or standardized electrogram duration was fair during ischemia, this correlation was poor during early reperfusion. CONCLUSIONS: Spatial heterogeneity in regional myocardial blood flow during myocardial ischemia and early reperfusion is associated with heterogeneity in [K+]o and electrophysiologic characteristics, which in turn may play an important role in the genesis of arrhythmias arising from the ischemic and reperfused myocardium.

"Stunning" of the left atrium after spontaneous conversion of atrial fibrillation to sinus rhythm: demonstration by transesophageal Doppler techniques in a canine model.

OBJECTIVES: This study compared left atrial and left atrial appendage contraction velocities in sinus rhythm before and after a brief period of atrial fibrillation in a canine model. BACKGROUND: In patients, left atrial appendage contraction velocities measured during sinus rhythm after cardioversion from atrial fibrillation are depressed relative to left atrial appendage emptying velocities measured during atrial fibrillation, suggesting that the left atrial appendage is mechanically "stunned." METHODS: This phenomenon was studied in a canine model of acute (60 min) pacing-induced atrial fibrillation followed by spontaneous reversion to sinus rhythm using epicardial and transesophageal pulsed wave Doppler. Unique features of the model include: 1) comparison of left atrial function postconversion to baseline sinus rhythm rather than to measurements during atrial fibrillation, 2) control of the duration of atrial fibrillation and 3) elimination of the extraneous influences of direct current shock and antiarrhythmic agents, which may independently depress left atrial function. RESULTS: Hemodynamic conditions (heart rate, mean arterial pressure, cardiac output, mean pulmonary artery pressure, mean right atrial pressure and mean left atrial pressure) at baseline, during 60 min of atrial fibrillation and after reversion to sinus rhythm were constant throughout the study period. Peak left atrial contraction velocities (measured from the transmitral flow velocity profile) were significantly (p < 0.02) reduced to 64+/-22% of baseline values upon spontaneous conversion of atrial fibrillation to sinus rhythm and recovered to basal values by 20 min after resumption of sinus rhythm. Peak left atrial appendage contraction velocities were significantly (p < 0.001) reduced to 49+/-24% of baseline values upon spontaneous conversion of atrial fibrillation to sinus rhythm and recovered to basal values by 40 min after reversion to sinus rhythm. CONCLUSIONS: Even brief (60 min) periods of atrial fibrillation in normal canine hearts result in marked depression of global left atrial systolic function and regional left atrial (left atrial appendage) systolic function upon resumption of sinus rhythm. This "mechanical stunning" of left atrial systolic function appears to be more profound and of longer duration for the left atrial appendage compared with the left atrium as a whole, which may predispose the appendage to blood stasis and thrombus formation. Chronic models of atrial fibrillation need to be developed to examine the impact of longer periods of atrial fibrillation upon the magnitude and duration of postconversion left atrial "stunning."

Progression of native coronary artery disease at 10 years: insights from a randomized study of medical versus surgical therapy for angina.

Repeat coronary angiography was performed in 42 patients 10 years after randomization to medical (n = 21) or surgical (n = 21) therapy for chronic angina. The native coronary arteries were classified into 15 angiographic segments and 3 arterial trunks for analysis of progression of coronary artery disease. The incidence rate of disease progression in coronary segments was 24% and 28% in medically and surgically treated patients, respectively (p = NS). Grafted segments showed a 38% rate of disease progression, which was higher than the 18% rate of for nongrafted segments (p less than 0.001) and the overall rate of 24% for medically treated patients (p less than 0.01). Similarly, 29 (94%) of 31 grafted arteries exhibited disease progression compared with 19 (59%) of 32 nongrafted arteries (p less than 0.01) and 42 (67%) of 63 arteries in medically treated patients (p less than 0.01). In grafted vessels, disease progression occurred more often in arteries proximal (84%) to the anastomosis than in arteries distal (16%) to graft insertion (p less than 0.001). Progression occurred in 46% of proximal segments compared with 23% of distal segments (p less than 0.02). Progression was seen in 23 (55%) of 43 segments with an occluded graft compared with 30 (31%) of 96 segments with a patent graft (p less than 0.02). Ten years after randomization, medically and surgically treated patients showed a comparable rate of disease progression in coronary segments. However, surgical therapy appeared to significantly accelerate atherosclerotic progression in the grafted vessels, especially in the proximal portions. Occluded grafts also correlated with an adverse effect on disease progression.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic interpretation of pericardial effusion.

Echocardiography has proved to be quite useful in the detection of pericardial effusion. As little as 15 ml of fluid within the pericardial space can be detected. Specific signs of pericardial effusion, such as electrical alternans and paradoxical pulse, have become better understood by echocardiographic study. Yet, with all the benefits of echocardiography, the detection of pericardial effusion still may be quite difficult if careful attention is not given to technique. False-positive diagnosis of anterior pericardial effusion can be seen with epicardial fat pad, pericardial cyst, or foramen of Morgagni hernia. False-positive posterior pericardial effusion can be seen in large left pleural effusion, calcified mitral anulus, or excessively medial transducer angulation. New "switched-gain" circuits have helped detection of pericardial effusion by enhancement of pericardial echoes.

Double-blind crossover randomized trial of intravenously administered verapamil. Its use for atrial fibrillation and flutter following open heart surgery.

Fourteen patients with onset of atrial fibrillation (11) or flutter (three) and ventricular rate over 120 beats per minute following cardiac surgery were treated with intravenous (IV) doses of verapamil hydrochloride or placebo in a double-blind crossover protocol. Patients with poor left ventricular function, hypotension, atrioventricular block, and taking beta-blockers and disopyramide were excluded. The dosages were 0.075 mg/kg and 0.15 mg/kg given 15 minutes apart, with termination of study on achieving an end point (conversion to sinus rhythm or slowing of ventricular rate to below 100 beats per minute). None reached the end point with placebo but all with verapamil. Baseline ventricular rate was 144 +/- 20 beats per minute, after placebo 143 +/- 16 beats per minute, and after verapamil 89 +/- 7 beats per minute (mean +/- SD). Thus, IV verapamil briefly slows the ventricular rate of atrial tachyarrhythmias following cardiac surgery.

Left ventricular performance after acute myocardial infarction. Sectrum of functional abnormalities and importance of wall motion disturbances during convalescent phase.

Seventeen patients underwent catheterization of the right and left sides of the heart and left ventricular (LV) angiography three to six weeks after acute myocardial infarction. Fourteen of 17 patients had abnormal LV function. Three patients had altered LV diastolic properties; five patients had abnormalities of diastolic properties and of systolic function; and six patients had abnormal systolic function, but diastolic function could not be assessed. Thirteen of the 14 patients with abnormal LV function had LV wall motion abnormalities, which were quantitatively related to impaired LV systolic function.

Sinus node dysfunction. An overview with emphasis on autonomic and pharmacologic consideration.

Sinus node dysfunction is a disorder of impulse generation and impulse conduction. Previous works have emphasized that the dysfunction occurs not only within the sinus node but also within the escape pacemaker. Adrenergic and cholinergic mechanisms, as well as pulsations and pressure within the sinus node artery, play an important role in normal sinus node activity. Although perinodal fibers act as a buffer zone for sinoatrial conduction, their role in man is yet to be clarified. During normal sinus node activity, pacemaker shifts from the sinus node to the crista terminalis have been shown to occur. Following sinus node destruction, similar shifts do occur. Clinical methods of determining sinus node function, such as the sinus node recovery time and sinus atrial conduction time, are useful but have limitations. Dynamic electrocardiographic monitoring provides the best clinical method available for detecting sinus node dysfunction. Digitalis appears to improve the parameters of sinus node function by increasing the automaticity of latent atrial pacemakers. The atrial arrhythmia of sinus node dysfunction appears to be related to the characteristics of latent atrial pacemaker and "enhanced" cholinergic tone.

Endotoxin, prekallikrein, complement and systemic vascular resistance. Sequential measurements in man.

Eighteen patients were studied prior to and again within 6 hours after transurethral resection or cystoscopy. In addition to hemodynamic measurements, detection of endotoxin by limulus assay and bacteriologic sampling; prekallikrein, C3, C3 proactivator and lysosomal enzyme levels were measured. In five patients limulus assays were positive, and in one, gram-positive bacteremia developed but limulus assay remained negative. All six had significant decreases in prekallikrein, C3 or C3 proactivator. Systemic vascular resistance fell in all six. Four additional patients who had a decrease in systemic vascular resistance were not endotoxemic or bacteremic; one of these had a decrease in prekallikrein only. In the remaining eight patients with neither bacteremia nor endotoxemia, systemic vascular resistance did not change or increase after instrumentation. One had a decrease in C3 proactivator, another in prekallikrein. There was no significant difference in age, disease, antibiotic therapy or bactermia in the two groups of patients. Four of the five resectional procedures were performed in the group that showed decreases in systemic vascular resistance. The data suggest that acute endotoxemia or gram-positive bacteremia in man is associated with depletion of prekallikrein, decreased peripheral resistance and, in some instances, activation of the complement system.

Left atrial transport function in myocardial infarction. Importance of its booster pump function.

After myocardial infarction (MI), left ventricular (LV) end-diastolic pressure (EDP) is higher than mean pulmonary artery wedge pressure because of powerful atrial contraction. To evaluate the significane of atrial contraction to left ventricular function we studied 10 control (C) patients without cardiac disease and 17 patients from three to six weeks after acute myocardial infarction. Cardiac catheterization with simultaneous left ventricular diastolic pressure (DP) and left ventricular cineangiograms were obtained. Left ventricular volumes and pressure were (mean +/- SD): (SEE ARTICLE). Although left ventricular stroke volume was lower in the patients with myocardial infarction than in the control subjects (46 versus 56 ml/m2), atrial contraction contributed more to left ventricular filling during diastole (which is the same as left ventricular stroke volume) in the patients with myocardial infarction than in the controls (16 versus 10 ml/m2). The average atrial contribution to left ventricular end-diastolic volume was 11.9 per cent (C), 15.4 per cent (MI); to left ventricular end-diastolic pressure 20 per cent (C), 38.7 per cent (MI); and to left ventricular stroke volume 21.7 per cent (C), 35.1 per cent (MI). Atrial contribution to left ventricular stroke volume was 56 per cent in patients with a cardiac index less than or equal to 2.0 liters/min/m2 and 31 per cent in those with a cardiac index greater than 2 liters/min/m2 (p less than 0.01). Atrial contraction contributed 35 per cent to left ventricular stroke volume in patients with normal end-diastolic volume and in those with increased end-diastolic volume and 10 per cent to end-diastolic volume in patients with increased end-diastolic volume (p less than 0.001). In patients with myocardial infarction, atrial contraction made a large contribution to left ventricular filling and stroke volume irrespective of the type of left ventricular functional derangement that was present. The "booster pump" function of the atrium cannot be ignored in assessing left ventricular performance.

Treatment of cardiogenic shock in myocardial infarction by intraaortic balloon counterpulsation surgery.

Thirty-seven patients in cardiogenic shock due to acute myocardial infarction were treated with intraaortic balloon counterpulsation and/or surgery. Eighteen of these patients were treated with counterpulsation alone; eight survived and five were in functional class I or II at the time of follow-up; two were in functional class III, and one was in functional class IV. Nineteen patients were treated surgically, eight survived and seven were in functional class I or II at the time of follow-up; one was in functional class III. Good functional recovery with counterpulsation alone is most common with inferior infarction. With surgery, functional recovery depends not only on the extent of the infarction and the coronary anatomy, but also on the ability to perform surgery within 12 hours of infarction or to support the patient with mechanical means for 10 to 14 days after the infarction and then perform surgery.

Effects of indomethacin on coronary hemodynamics, myocardial metabolism and anginal threshold in coronary artery disease.

The effects of orally administered indomethacin or placebo on coronary hemodynamics were studied in 23 patients with coronary artery disease. After indomethacin administration the systemic arterial pressure increased by 12 +/- 4% and the myocardial oxygen consumption by 24 +/- 11%. Coronary sinus flow did not change and coronary vascular resistance increased slightly. Oxygen saturation of the arterial blood did not change, but coronary sinus saturation decreased substantially. Hemodynamic values returned to normal 150 minutes after administration of indomethacin. During rapid atrial pacing, coronary sinus flow increased 79 +/- 14% above the rest value when pacing was done before indomethacin administration; only a 56 +/- 12% increase was seen when pacing was repeated after indomethacin. Peak heart rate achieved during atrial pacing, severity of angina and the degree of ST-segment depression were not altered by indomethacin treatment. Orally administered indomethacin has a mild coronary vasoconstrictive effect that does not interfere substantially with the expected increase in myocardial blood flow during rapid atrial pacing. Anginal threshold is not altered by orally administered indomethacin.

Lack of ouabain effect on pacing-induced myocardial ischemia in patients with coronary artery disease.

Sixteen patients with significant two and three vessel coronary artery disease but without clinical congestive heart failure were studied during rapid atrial pacing before and after infusion of 0.015 mg/kg of ouabain. Seven patients with a decreased (less than 50 percent) ejection fraction and nine patients with a normal ejection fraction had a significant (P less than 0.05) increase in resting arterial systolic pressure after the administration of ouabain. However, resting values for coronary sinus flow, coronary vascular resistance, myocardial oxygen consumption and myocardial lactate extraction did not change significantly in either group. During pacing, patients with a decreased ejection fraction demonstrated more ischemia than patients with a normal ejection fraction; however, the administration of ouabain did not significantly alter pacing-related changes in coronary sinus flow, myocardial oxygen consumption, myocardial lactate extraction, ischemic electrocardiographic changes or onset of chest pain in either group. The administration of ouabain has a negligible effect on coronary hemodynamics, myocardial metabolism or clinical signs of ischemia in patients with coronary artery disease with normal or abnormal left ventricular function.

Ventricular fibrillation during coronary angiography in dogs: the role of calcium-binding additives.

Coronary angiography with Renografin 76 (RG76) occasionally results in ventricular fibrillation (VF). Angiovist 370 (AV370) is a contrast medium similar to RG76 except the calcium-sequestering agents, sodium citrate and EDTA in RG76 have been replaced by calcium EDTA. To determine whether these sequestering agents contribute to contrast medium-induced VF, a comparison was made of the effects of intracoronary injections of RG76, AV370, and saline solutions containing sodium citrate and EDTA (CIT/EDTA) and calcium EDTA (CA EDTA) on myocardial conduction, local QT intervals, and incidence of spontaneous and induced VF in 32 dogs. Four milliliters of RG76 produced a 111 +/- 12-ms increase in local QT intervals, compared with a 73 +/- 8-ms increase with AV370 (p less than 0.001). Spontaneous VF occurred in 12 of 16 six-milliliter injections of RG76, compared with 4 of 16 injections of AV370 (p less than 0.02) An early-cycle premature impulse applied after every fourth beat induced VF in 15 of 16 four-milliliter injections of RG76 compared with 5 of 16 injections of AV370 (p less than 0.01). As the premature beat conducted through the left anterior descending region, conduction slowing and fractionation occurred, which was less with AV370 than with RG76. The CIT/EDTA solution produced a greater increase in QT intervals (77 +/- 5 ms) than the CA EDTA solution (29 +/- 3 ms) or 0.9% saline solution alone (28 +/- 2 ms) (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic improvement following a single dose of oral phentolamine. Administration in patients with chronic low output cardiac failure.

Hemodynamic studies were made in 15 patients with chronic low output cardiac failure before and following a single dose of oral phentolamine (150 mg). After two hours significant (P less than .05) reduction occurred in mean pulmonary, wedge and right atrial pressures and increases in cardiac index and heart rate. In ten patients studied at four hours, wedge pressure remained significantly reduced (-18 percent) and cardiac index significantly increased (+19 percent) from control values. Oral phentolamine results in significant hemodynamic improvement in patients with severe heart failure. Duration of effect for at least four hours after a single dose suggests that intermittent oral therapy may be useful in the management of such patients.

The role of myocardial ischemia in pacing-induced elevation of arterial pressure.

One hundred sixteen patients with suspected or proven coronary arterial disease underwent rapid atrial pacing until the occurrence of pain in the chest or a heart rate of at least 160 beats per minute. Significant elevation of arterial systolic pressure of 25 percent or more above control was observed in 17 patients. Each of these patients had significant coronary arterial disease shown by coronary arteriographic studies. During rapid atrial pacing, each of these 17 patients had pain in the chest and ST-segment changes suggesting ischemia, and 15 had abnormal (less than 10 percent) extraction of myocardial lactate. In the 99 patients who did not have increased arterial systolic pressure during rapid atrial pacing, the frequencies of coronary arterial disease, ischemic ST-segment changes, and abnormal extraction of lactate during rapid atrial pacing were significantly (P less than 0.05) less. Increased arterial systolic pressure during rapid atrial pacing appears to be highly indicative of coronary arterial disease and myocardial ischemia. We suggest that myocardial ischemia may, under certain circumstances, be responsible for short-term increases in arterial pressure.

The effects of rapid volume expansion on the right and left cardiac filling pressures after coronary artery bypass surgery.

Rapid volume expansion is a diagnostic procedure which can reveal typical hemodynamics of pericardial constriction in patients with pericardial disease who have normal hemodynamics in their baseline state. We studied 20 patients with previous coronary artery bypass surgery in order to determine whether this operation results in some degree of pericardial constriction which could be demonstrated by rapid volume expansion. After infusing 1 L of physiologic saline solution over six minutes, the right atrial pressure increased by 5 +/- 2 mm Hg, the right ventricular diastolic pressure by 4 +/- 3 mm Hg, the pulmonary capillary wedge pressure by 7 +/- 3 mm Hg, and the left ventricular diastolic pressure by 7 +/- 4 mm Hg (mean +/- SD). Equalization of the left and right cardiac pressures was not observed, and the normal respiratory variation of the pressures was not altered by rapid volume expansion. Thus, the pericardial manipulation associated with the performance of coronary artery bypass surgery does not commonly result in the development of subclinical pericardial constriction.

Right coronary artery dissection. A complication of cardiac catheterization and coronary angiography.

Four patients are described in whom right coronary artery dissection occurred during retrograde catheterization of the left ventricle or coronary arteries. In two patients, acute myocardial infarction occurred. The possible causes, radiographic features, and clinical implications of this infrequent complication are discussed.

Effects of ouabain on early ventricular relaxation in patients with acute myocardial infarction.

The effects of the administration of ouabain on the peak negative left ventriculat (LV) dP/dt were studied in 14 patients with acute myocardial infarction. Prior to administration of ouabain, negative LV dP/at was lower than previously reported for patients without coronary arterial disease. One hour after administration of ouabain, significant (P less than 0.05) increases in peak positive LV dP/dt and maximal velocity of contractile-element shortening and decreases in LV diastolic pressure were present. These changes were associated with small and insignificant increases in negative LV dP/dt. Early LV relaxation rate is impaired in patients with acute myocardial infarction; however, the reduction in LV diastolic pressures which occurs after administration of ouabain does not appear to be due to an increase in the rate of early LV relaxation but rather is probably related to improved contractility.