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Background: Although inhibitors of the renin–angiotensin–aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)–related factor 2 activators further reduce this risk is unknown. Methods: We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to < 30 ml per minute per 1.73 m2 of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes. Results: The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P < 0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group. Conclusions: Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.)

As an alternative procedure to the exercise stress test used in myocardial scanning, vasoactive drugs were employed to elicit deficits in blood flow to myocardial regions supplied by stenotic arteries which maintain normal resting flow or collateral circulation. The data were collected from 35 dogs, some of which had partial stenosis (70–75%) on either major branch of the left coronary artery, and others which had Ameroid constrictor implants. The effects of lidoflazine, dipyridamole, and nitroglycerin on coronary hemodynamics and myocardial dispersion of potassium 43(43K) in animals with partial stenosis were evaluated in ten acute experiments. In the pilot studies, four rapid serial rectilinear control scans from 43K (750 μCi) were reported; dipyridamole (Persantin), lidoflazine, or nitroglycerin were then administered intravenously. When the selected drug reached a peak vasodilatative effect, a second equal bolus of 43K was given and four additional scans recorded. The last scan from the first set was subtracted from the corresponding regional count rates of all serial scans from the second set, and the resulting images were interpreted to be myocardial perfusion patterns induced by the drug intervention. The later studies were performed by giving only a single isotope injection after administering the drug.

Least-squares regression analysis was computerized to provide functional color images of myocardial perfusion patterns. In 8 of the 9 patients studied, changes in pattern indicated that the revascularization procedure speeded the appearance time and∕or net rate of 43K uptake. The functional images correlated well with coronary arteriograms made before and after surgery. This noninvasive isotope technique may prove to be clinically useful in (a) evaluating coronary artery disease, (b) defining the remaining viable myocardium when an aneurysm is present, and (c) determining the effectiveness of the revascularization procedure.

To improve the sensitivity and accuracy of the detection of coronary artery disease with potassium-43 imaging at rest, a rapid serial scanning technique was developed to detect appearance time and sequence of myocardial isotope accumulation. The group of 85 patients included normal subjects and patients with angina pectoris, myocardial infarction and miscellaneous nonischemic heart diseases. Each patient also underwent coronary angiography and left ventriculography and the results were compared with the results of scanning. An angiographically demonstrable obstruction of 50 percent or greater luminal diameter in a coronary artery was found in 95 percent of the patients whose first serial myocardial scan at rest, accomplished 4.5 minutes after isotope administration, showed delayed regional appearance or abnormal sequence of accumulation of radioactivity by the end of the second scan. Eighty-five percent of individual lesions in a major coronary artery identified by scanning were found at the same site on angiography. Ventricular aneurysms were demonstrated as positive images during the first serial scan, although later scans showed no myocardial activity. Collateral circulation was demonstrable on serial scanning and, when angiographic evidence of such circulation was available, the recipient arterial bed was always correctly identified. In 32 patients who underwent myocardial imaging at rest and after graded exercise testing, the images at rest correlated better with the angiographic data. In conclusion, rapid serial scanning at rest detected coronary arterial lesions of 50 percent or greater, collateral circulation and, often, ventricular aneurysms as positive images.

A retrograde coronary venous injection technique for concentrating diffusible radioisotope in ischemic myocardial regions was evaluated. 85 Krypton in saline solution was injected under pressure into the coronary veins during partial closure of the coronary sinus. In the presence of coronary inflow obstruction, the venous 85 krypton was distributed mainly to the vessels with reduced pressure in ischemic regions. 85 Krypton washout was monitored with a single precordial collimator, and reasonably accurate measurements of flow in the ischemic regions were made. In two dogs, photoscanning techniques, using 133 xenon, were applied to locate and determine the size of the ischemic myocardial regions as radioisotopic hot spots.

Conflicting opinions have been expressed as to the mechanism of pulmonary and peripheral congestion frequently observed in the oliguric stage of acute glomerulonephritis. Hemodynamic studies in 7 patients studied during the oliguric edematous phase of the disease demonstrated that these patients have high ventricular filling pressures associated with an increase in cardiac output and are, therefore, examples of a high output congestive state.

Four dogs underwent direct revascularization of a chronically occluded circumflex artery with an internal mammary artery bypass graft. Preoperative coronary cineangiograms demonstrated well developed intercoronary collateral vessels supplying the circumflex arterial bed. Intraoperative measurements of retrograde circumflex arterial flow and pressure were consistent with the presence of large collateral vessels. Closed chest postoperative estimates of the potential collateral circulation were obtained by advancing a Judkins catheter to the internal mammary wedge position. The graft wedge pressure was equated to the retrograde circumflex pressure. After coronary bypass grafting, the interval coronary angiographic and hemodynamic studies indicated that well developed collateral vessels regressed within the first postoperative month to capacities in the range of those found in normal dogs.

Two diseases of the pericardium have similar effects on the circulation. These are pericardial effusion with cardiac tamponade and constrictive pericarditis. Burwell and Blalock 1 and Lyons and Burwell 2 have defined the pathologic physiology of constrictive pericarditis. Cohnheim 3 and Starling 4 first demonstrated the effects on the circulation of injecting fluid into the pericardial sac. It is our purpse to extend the studies of these latter authors and to show experimentally certain of the similarities in the circulatory dynamics of these two disorders. In addition, our observations suggest a means of recognizing the presence of pericardial effusion in instances where this diagnosis is difficult to establish by the usual methods of examination.

Hemodynamic studies were carried out in 7 patients with arteriovenous fistulas, during rest and exercise, when the fistula was open and closed. A high cardiac output existed in all patients during rest, unless congestive heart failure was present. A uniform decrease in cardiac output was observed upon occlusion of the fistula. Two patients increased their cardiac output supernormally on exercise. Muscular occlusion of the fistula was postulated in 3 patients without heart failure, in whom a decline in cardiac output occurred during exercise. Correlation between the filling pressures of the left ventricle and stroke volume could not be made in the various experimental situations studied.

A previous communication 1 was concerned with the electrical phenomena within the right atrium. Coincidentally with that study, observations were made of the potential variations within the right ventricle. The general technique employed has been described in the earlier publication and will be amplified somewhat in this paper. All studies of the potentials within the normal right ventricle have revealed an R wave as the first deflection of the ventricular complex. Hecht 2 described this as diminutive, but others have noted that it may attain considerable size. The presence of this R wave has been regarded uniformly as corroborative evidence that activation of the left side of the interventricular septum normally precedes activation of the right side. This asynchronism may be regarded as a kind of physiologic, incomplete right bundle branch block of minor grade. In left bundle branch block, 3,4 because septal activation proceeds form the right to the left side of the septum, this initial R wave is lost; and the ventricular complex in the right ventricle begins with an S wave. By the same token, the R wave is unusually prominent in right bundle branch block. Because the electrode has the twofold effect of functioning as both a recording and, by virtue of its mere contact, as a stimulating electrode, two other phenomena have been observed consistently: a tendency to premature ventricular beats or short runs of ventricular tachycardia and the induction of monophasic ventricular action currents. The former, from their appearance in the conventional leads, have been shown to correspond to our present conception of right ventricular premature beats. The latter have been found to disappear when the catheter is withdrawn slightly from its contact with the ventricular wall.

Hemodynamic studies in 13 unselected patients with sickle cell anemia are reported. Twelve of these patients were also studied during mild exercise. The cardiac output at rest was elevated in all and rose significantly with exercise in 9 of the 12 patients. The importance of the increased percentage extraction of oxygen by the tissues in modifying the response of the cardiac output is discussed. The similarity of the response to exercise in the majority of these chronically anemic patients compared with the normal response is described. Included in this series is one case with secondary cor pulmonale and one case of concurrent rheumatic heart disease.

Surveillance of the pulmonary arterial (PA) and capillary wedge (PCW) pressures in coronary care units has been widely accepted as a safe and valuable procedure in the clinical management of acute myocardial infarction.1,2 The PA and PCW pressures provide a reasonable index of the left ventricular performance and serve as a useful guide in the therapeutic management of the patient. Work was undertaken for this report to determine if additional useful information could be derived from these measurements with a pulmonary arterial pressure method for estimating the right ventricular stroke volume.

The phagocytic behavior of the reticuloendothelial system in the rat was assessed by a quantitative technique following fructose-1,6-diphosphate (FDP) administration. In addition, the effect of FDP on the carbohydrate metabolism of human leukocytes was investigated. The rate of colloidal carbon clearance from the blood was increased significantly in the FDP-treated rats as compared to dextrose and saline controls (p less than 0.001). FDP also attenuated the hepatic decrease of ATP (p less than 0.005) and creatine phosphate (p less than 0.005) that has been observed after intravenous administration of colloidal carbon. Carbohydrate metabolism in human leukocytes was enhanced by FDP, with a concomitant increase in ATP content (p less than 0.001). Experimental evidence suggests that FDP intervenes in the Embden-Meyerhof pathway both as a metabolic regulator and as a high energy substrate. These properties of FDP in stimulating the carbohydrate metabolism have recently been described in man.

The hemodynamic, electrocardiographic, and metabolic responses of dogs with acute myocardial ischemia to intravenous administration of fructose-1,6-diphosphate (FDP) were assessed. Analysis of the results (compared to dextrose control) revealed evidence of major improvement of LVEDP and cardiac output, significant decrease of the ST segment, and large increases of ATP and CP in the ischemic district and to a lesser degree in the normally perfused myocardium. These results indicate that FDP intervenes in the Embden-Meyerhof pathway not only as a high energy substrate but also as a metabolic regulator influencing the activity of phosphofructokinase and that of pyruvate kinase. FDP also stimulates glycolysis in dog erythrocytes and increases their ATP and 2–3 DPG content by a factor of 2. The most significant finding in these studies is that this biochemical intervention appears to restore the depressed activity of glycolysis in ischemic myocardium.

A formula has been derived for estimating the left ventricular stroke volume (SV) from measurements of the difference between maximum and minimum cross-sectional area of the ascending aorta (am), ascending aorta pulse wave velocity (c) and systolic period (Ts): SV = 0.54 Ts c am In open chest dogs, this ‘aortometric’ formula for estimating SV compared favorably with measurements by the electromagnetic flowmeter method both with and without aortic regurgitation. This suggests that in the presence of aortic regurgitation, the aortic backflow may be estimated from the difference between the aortometric SV measurement and the systemic blood flow estimated by an independent technique.

The relevance of changes in substrate and ion transport to left ventricular contractility alterations have been examined after insulin, strophanthidin, and their combination, using serial arterial-coronary sinus differences in intact anesthetized dogs. Insulin (0.1 U/kg) was infused into a left coronary artery catheter to minimize systemic changes, producing an accumulated left ventricular uptake of glucose, lactate, and potassium with a rise in respiratory quotient, without affecting pyruvate and free fatty acid extractions. There was no associated change in the d p/d tmax. of left ventricular pressure or in the duration of isometric contraction, used as indices of contractility. Acetyl strophanthidin, .03 mg/kg, produced a 60% increase in d p/d tmax. and significantly shortened isometric duration associated with egress of potassium from the myocardium. Insulin, given 25 min before strophanthidin to reduce K+ egress, failed to do so, but largely interfered with its contractile properties. This effect was also observed with p-chloromercuribenzoate, so that a SH-binding site would seem essential for the inotropic activity of strophanthidin.

The role of the physical state of plasma as a determinant of oxygen availability to the myocardium has been investigated during the course of alimentary lipemia. After the development of substantial plasma lactescence, the coronary blood flow (nitrous oxide method) and myocardial oxygen consumption were assessed in 7 normal human subjects and repeated after heparin-induced lipolysis. The lipemic state was further contrasted with a control fasting group, comparable in age and sex. The mean coronary blood flow for 15 fasting controls was 83 ml. per 100 Gm. of left ventricle per minute with a myocardial oxygen extraction of 11.04 volumes per cent, and a myocardial oxygen consumption of 9.0 ml. per 100 Gm. of left ventricle per minute. By contrast, the mean coronary blood flow during maximal lipemia in the 7 subjects fed cream was 20 per cent below normal, with a value of 67 ml. per 100 Gm. per minute ( p =< 0.01). As the extraction of oxygen was not significantly affected, the calculated myocardial oxygen consumption was proportionately reduced to 7.02 ml. per 100 Gm. per minute ( p =< 0.01). A failure of the anticipated oxygen extraction increment in the face of coronary blood flow reduction suggests an impediment of blood-tissue oxygen transport during lipemia. After the administration of 60 mg. of heparin to the 7 lipemic subjects, a 65 per cent decline in plasma lactescence was observed by 45 minutes, when the coronary blood flow and myocardial oxygen consumption were elevated to 87 ml. per 100 Gm. per minute ( p =< 0.05) respectively. Thus, the reduced coronary flow and myocardial oxygen consumption were restored in each instance to normal levels during the process of plasma clearing. There were no associated systemic hemodynamic changes to account for such increments. These heparin effects appear dependent on the lipemia-clearing property, for no alteration in coronary dynamics was found in 6 additional patients in whom this activity was not manifest after the same heparin dosage. The residual lactescence after post-heparin lipolysis was associated with no significant deviation of coronary dynamics from the normal. That a concentration-dependent phenomenon is operative, was confirmed in a separate group of patients in whom low lactescence values developed in the course of alimentary lipemia without affecting myocardial oxygen consumption. The relevance of the lipemic state, per se, to the pathophysiology of myocardial ischemia appears to depend upon the establishment of an oxygen gradient within the myocardium, presumably through altered pressure-flow relationships produced by lipemic blood within a pathologic vessel.

The myocardial uptake of potassium 42 was compared to the coronary arteriogram in 12 patients to evaluate the use of this method in detecting alterations in myocardial blood flow in patients with ischemic heart disease. Correlation was good in patients with occlusive lesions of the anterior descending artery; in patients with far-advanced coronary artery disease with extensive intercoronary collaterals; and in patients with akinetic or aneurysmal areas of the left ventricular free wall and apex.

The role of red cell mass in the regulation of coronary blood flow and myocardial oxygen consumption has been examined after acute transfusion of sedimented red cells. Patients with substantial blood-loss anemia had a lower than normal left ventricular oxygen uptake, despite a high myocardial blood flow at rest. A 50% rise of hematocrit reduced coronary flow markedly. Although systemic arterial pressure, cardiac output, and left heart work rose, myocardial oxygen consumption was unchanged. Red cell transfusion of normovolemic dogs resulted in a decrease of both myocardial flow and oxygen uptake associated with an elevation of time-tension index and left ventricular work, accelerated isometric contraction and prolonged systole. There was no evidence of ischemia or change of left ventricular hemodynamic parameters that would account for the reduced myocardial blood flow and oxygen uptake. These findings, in the presence of an increased oxygen carrying capacity and extraction, would appear to be related principally to enhanced blood viscosity.

The metabolic response of the left ventricle to a 90 min regional infusion of 1-epinephrine (5 µg/min) was assessed in the intact anesthetized dog for 3 hr. The first hour was characterized by a rise in stroke output at constant filling pressure. Subsequently, contractility fell and there was release of K and PO 4 ions as well as SGOT from the myocardium that was attributed to tissue injury. The myocardial RQ rose for the first hour, presumably due to glycogenolysis, since carbohydrate extraction from blood was unaltered. Production of lactate by the myocardium during the RQ rise occurred without ischemia, since blood flow (Kr 85 method) and O 2 uptake rose 10%. The proportionately greater increase in contractility was not consistent with "O 2 wasting" as a basis for the injury. After 1 hr the RQ fell to levels consistent with predominant lipid utilization. However, FFA extraction declined and the oxidation, extraction and incorporation of palmitate-l-C 14 into tissue lipid were diminished during hormone exhibition. Plasma triglyceride uptake, insignificant in controls, was enhanced during the 3 hr without a rise in arterial concentration. Oxidation of this lipid was insufficient to prevent a threefold triglyceride increment in the myocardium. The authors discuss a possible relationship of these metabolic alterations to the pathophysiologic response induced by epinephrine.

The restriction imposed by mitral stenosis on the cardiac output response to exercise provides a unique opportunity in man to evaluate determinants of coronary flow and myocardial oxygen consumption, since one or several variables may be limited. Coronary and systemic hemodynamic patterns were therefore evaluated in 12 patients with mitral stenosis and compared with normal subjects. While cardiac output and left ventricular work were lower than normal at rest, coronary flow and myocardial oxygen consumption did not differ from normal. During exercise, despite subnormal cardiac output and left ventricular work responses, coronary blood flow and myocardial oxygen consumption increased normally in the group of patients in whom arterial pressure rose. However, coronary flow fell in four patients who experienced exertional hypotension, while myocardial oxygen consumption was reduced or unchanged. In both groups, myocardial oxygen extraction was above normal at rest and rose further during exercise. Changes in myocardial oxygen consumption followed alterations in the pressure-time index, but the excessive heart rate response to exercise resulted in a greater oxygen expenditure per unit of tension developed per beat than that found in normal subjects. It is concluded that the primary determinant of coronary blood flow in mitral stenosis is the arterial perfusion pressure while myocardial oxygen consumption is primarily dependent on the pressure-time index. In addition, heart rates inappropriately high for a given state result in energy expenditures above that required for maintenance of pressure and cardiac output.

Excerpt A method for rapid and repeated determinations of coronary blood flow (CBF) has been devised in dogs using the potentiometric hydrogen electrode. After a brief inhalation of hydrogen gas, t...

Excerpt In view of the ill-defined status of cardiac involvement in chronic alcoholism, a study of the acute effects of ethanol on myocardial metabolism and function has been undertaken in animals ...