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.

Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.

BACKGROUND: The risks and benefits of intensive therapy in non-insulin-dependent diabetes mellitus (NIDDM) need to be defined. In preparation for a long-term trial, a feasibility study of 153 men in 5 medical centers compared standard vs intensive insulin therapy. OBJECTIVE: To assess the rate of development of new cardiovascular events and their correlates. METHODS: Patients with a mean +/- SD age of 60 +/- 6 years and diagnosis of NIDDM for 7.8 +/- 4.0 years were randomly assigned to a standard (1 insulin injection every morning) or to an intensive treatment arm (stepped plan from 1 evening injection of insulin, alone or with glipizide, to multiple daily injections) designed to attain near-normal glycemia levels. A 2.07% separation of glycosylated hemoglobin (HbA1c) was sustained for a mean follow-up of 27 months (P < .001). Predefined cardiovascular events were assessed by a committee unaware of treatment assignment. RESULTS: Mild and moderate hypoglycemic events were more frequent in the intensive than in the standard treatment arm (16.5 vs 1.5 per patient per year, respectively). Mean insulin dose was 23% lower in the standard treatment arm (P < .001). There were 61 new cardiovascular events in 24 patients (32%) in the intensive treatment arm and in 16 patients (20%) in the standard treatment arm (P = .10). There was no difference in total and cardiovascular mortality (n = 5 and n = 3 in the intensive and standard treatment arms, respectively) or in new events in patients with cardiovascular history (n = 10 in each arm). In Cox regression analysis, the only significant correlate for new cardiovascular events was previous cardiovascular disease (P = .04). Entering in the analysis any baseline cardiovascular abnormality, the regression model indicated a lower HbA1c level prior to the event as the only correlate for new cardiovascular events (P = .05). CONCLUSION: A long-term prospective trial is needed to assess the risk-benefit ratio of intensive insulin therapy for NIDDM in patients who require it.

Age-related differences in case-fatality rates among diabetic patients with myocardial infarction. Findings from National Hospital Discharge Survey, 1979-1987.

OBJECTIVE: To determine age-related differences in case-fatality rates among diabetic patients with myocardial infarction (MI). Published studies have demonstrated 60% higher case-fatality rates during acute MI among diabetic patients compared with those without diabetes. However, many previous reports have been of insufficient size to examine the effect of age on mortality and have not been drawn from a representative sample of hospitals. The National Hospital Discharge Survey provides data on discharge diagnosis and vital status from a random sample of approximately 500 short-stay American hospitals. RESEARCH DESIGN AND METHODS: In this analysis, people with acute MI listed as the first diagnosis on the discharge sheet were studied. Any mention of diabetes mellitus on the discharge sheet was used to stratify the patients into those with and without diabetes. RESULTS: Age-adjusted case-fatality rates were identical in patients with and without diabetes for both sexes: 16.1 vs. 16.3 in men and 18 vs. 18.2 in women, respectively. Mortality rates were, however, higher among the younger patients with diabetes. Ratios of the case-fatality percentage by 10-yr age-groups (age 35-75 yr) and greater than or equal to 75 yr old for diabetes versus no diabetes were 1.7, 1.8, 1.2, 0.9, and 0.9 for men and 2.4, 1.2, 1.1, 1, and 0.9 for women. CONCLUSIONS: Diabetes thus appears to increase the in-hospital mortality risk with acute MI disproportionately in the younger age-groups, particularly among men, and does not appear to be a marker of increased risk among the elderly.

Two years of intensive glycemic control and left ventricular function in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.

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.

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.

Absence of differences in platelet dihydroxyphenylalanine (dopa) oxidase polymorphism in health and Duchenne's muscular dystrophy.

Extracts of platelets were subjected to vertical starch gel electrophoresis followed by enzyme staining to further investigate earlier reports of a unique dihydroxyphenylalanine (DOPA) oxidase polymorphism among boys with Duchenne's muscular dystrophy (DMD) and their mothers. This was said to be distinct from those found in healthy controls. Platelets were separated from citrated venous blood by differential centrifugation and checked for purity by phase contrast microscopy. The isolated platelets were disrupted by freeze-thawing in Tris-HC1 buffer (0.02M, pH 8.2), and the resulting platelet extracts were electrophoresed for 15 hours at 130V at 4 degrees C. The starch gels were then sliced and stained with 0.2% DOPA and 0.1% MnCl2. Three electrophoretic patterns of DOPA oxidase activity were found in normal men and women: a single rapidly moving band; a single slowly moving band; and a broad band. These three patterns were also seen in boys with DMD, their mothers, and their fathers. Thus, a unique polymorphism was not found in boys with Duchenne's muscular dystrophy or their carrier mothers.

Chloroplast and Cytoplasmic Enzymes: IV. Pea Leaf Fructose 1,6-Diphosphate Aldolases.

Several peaks of aldolase activity are found in the isoelectric focusing pattern of pea (Pisum sativum) leaf chloroplast extracts. One peak, separated by 0.5 pH unit from the major chloroplast aldolase peak, is found when cytoplasmic extracts are focused. The chloroplast and cytoplasmic enzymes have a pH 7.4 optimum with fructose 1,6-diphosphate. The Michaelis constant for fructose-1,6-diphosphate is 19 muM for the chloroplast, 21 muM for the cytoplasmic enzyme, and for sedoheptulose 1,7-diphosphate, 8 muM for the chloroplast enzyme, 18 muM for the cytoplasmic enzyme. Both enzymes are inhibited by d-glyceraldehyde 3-phosphate and by ribulose 1,5-diphosphate. The similarity in the catalytic properties of the isoenzymes suggests that both enzymes have an amphibolic role in carbon metabolism in the green leaf.

Chloroplast and Cytoplasmic Enzymes: VI. Pea Leaf 3-Phosphoglycerate Kinases.

Pea (Pisum sativum) leaf chloroplastic and cytoplasmic 3-phosphoglycerate kinases (ATP: d-3-phosphoglycerate 1-phosphotransferase, EC 2.7.2.3) have similar Michaelis constants for ATP, 0.7 and 0.55 mm, for ADP, 0.18 and 0.22, and for 3-P-glycerate, 0.59 and 0.54 mm at low substrate concentrations, and 1.6 and 1.25 mm at high substrate concentrations. Both enzymes are inhibited by ADP and AMP in the ATP-utilizing direction and by ATP and AMP in the ATP-generating direction and are controlled by energy charge. Apparently, whether the cytoplasmic and chloroplastic kinases in the plant cell will participate in the reductive pentose phosphate cycle and gluconeogenesis or in glycolysis will be determined by the environment in the cell compartment and not by the differential properties of the enzymes themselves.

Effects of low-dose dobutamine on coronary hemodynamics, myocardial metabolism, and anginal threshold in patients with coronary artery disease.

Fourteen patients with coronary artery disease and normal or near-normal left ventricular function were studied at rest and during atrial pacing until the occurrence of angina (12 patients) before and during infusion of dobutamine (3.80 +/- 0.45 micrograms/kg/min). At rest, during the infusion, three patients developed chest pain, mean ST segment depression increased from 0.02 to 0.08 mV (p less than .001), and myocardial lactate extraction fell from +17.5% to -1.4% (p less than .05). These ischemic changes were associated with significant increases in arterial systolic pressure (134 to 149 mm Hg), heart rate (79 to 91 beats/min), coronary sinus flow (89 to 113 ml/min), and myocardial oxygen consumption (10.8 to 13.5 cc/min). In contrast, during atrial pacing, dobutamine did not reduce the pacing threshold or further increase myocardial oxygen consumption or ST segment changes; however, arterial mean and diastolic pressures were significantly lower with pacing during dobutamine infusion compared with control pacing. In the absence of heart failure, dobutamine in low doses can cause myocardial ischemia in patients with coronary artery disease. The absence of increased ischemia from dobutamine during pacing may reflect reversal of pacing-induced ventricular dysfunction.

Acute anterior myocardial infarction complicated by mural thrombus and peripheral thromboembolism despite anticoagulation.

A 43-year-old man had transmural anterior wall myocardial infarction complicated by hypotension and anterior-apical aneurysmal formation. Despite continuous anticoagulation with heparin sodium (heparin) and warfarin sodium (coumadin), a large pedunculated left ventricular thrombus was formed. Four hours after uneventful left ventriculography, the patient experienced acute superior mesenteric embolism. An emergency mesenteric embolectomy and then left ventricular aneurysmectomy with clot evacuation were performed to save the bowel and to prevent further embolization.

The mechanism and significance of ventricularization of intracoronary pressure during coronary angiography.

Ventricularization of pressure during coronary angiography has been said to identify the presence of left main coronary artery disease, but the hemodynamic features and the mechanism of this process have not been studied. Twenty consecutive patients with ventricularization were identified prospectively in our laboratory. Four patients had a discrete ostial left main stenosis and 16 patients had stenosis of the entire length of the left main coronary artery. The degree of pressure drop upon cannulation of the diseased left main coronary artery was highly variable; the systolic pressure decreased by 9 to 94 mm Hg, and the diastolic pressure decreased by 6 to 60 mm Hg. The morphology of the ventricularized pressure was distinct. It had a presystolic deflection resembling an a wave. The upstroke of this waveform was slower and the downstroke was steeper than that of the aortic pressure. An identical waveform was observed in dogs after partial occlusion of the left main coronary artery with a balloon-tipped catheter. The waveform of the so-called ventricularized pressure is derived from the aortic pressure, which is altered by its transmission across the left main coronary stenosis. The appearance of ventricularization is an important clue to the presence of left main coronary artery disease.

The usefulness of dobutamine in the assessment of the severity of mitral stenosis.

Patients with mitral stenosis often require supine exercise in order to increase their heart rate and cardiac output to assess the severity of their valvular obstruction during cardiac catheterization. We substituted dobutamine for exercise in 14 patients with suspected mitral stenosis. The dobutamine infusion was started at 5 micrograms/kg/min and was increased to 10, 15, and 20 micrograms/kg/min every 3 minutes as tolerated. The heart rate increased from 84 +/- 4 to 123 +/- 7 bpm (p less than 0.001), the cardiac index increased from 2.4 +/- 0.2 to 3.4 +/- 0.2 L/min/m2 (p less than 0.001), and the mean pulmonary artery pressure increased from 27 +/- 3 to 30 +/- 2 mm Hg (p less than 0.02). The pulmonary wedge pressure of 19 +/- 2 mm Hg and the mitral valve index of 0.8 +/- 0.1 cm2/m2 remained unchanged, but the left ventricular end-diastolic pressure decreased from 11 +/- 2 to 6 +/- 2 mm Hg (p less than 0.02). The hemodynamic response during the infusion of dobutamine identified a subgroup of patients with more severe mitral stenosis. Thus, the administration of dobutamine is useful in the evaluation of the severity of mitral valve obstruction during catheterization.

Progression of coronary artery disease after percutaneous transluminal coronary angioplasty.

Thirty-nine patients underwent coronary arteriography 1 to 20 months (mean 7 months) after percutaneous transluminal coronary angioplasty (PTCA). At the time of the repeat study, 35 patients (90%) had recurrent angina or myocardial infarction, and 4 patients (10%) were asymptomatic. Restenosis, defined as greater than 50% loss of PTCA gained diameter, was found in 19 patients (49%). In addition, 20 patients had new lesions or marked progression of existing lesions (defined as greater than 20% or increasing greater than 20% obstruction in coronary diameter) in the previously normal or mildly diseased coronary segments. The new or progressive lesions occurred both in patients with restenosis at the PTCA site (nine of 19) and in patients without restenosis (11 of 20). New or progressive lesions tended to occur more commonly in the artery on which PTCA was performed (13 of 40) than in the artery that did not have PTCA (10 of 77) (p less than 0.02 by chi 2). In arteries that had PTCA, new or progressive lesions occurred more often in the segment proximal to the angioplasty site (seven of 13 or 54%) than in the peri-PTCA segment (two of 13 or 15%) and in the segments distal to it (four of 13 or 31%), but this observation did not reach statistical significance. No other clinical, angiographic, or PTCA procedure variables affected the occurrence of new or progressive lesions. In patients with recurrent angina or myocardial infarction after PTCA, both restenosis and new or progressive lesions are common. New lesions or marked progression of existing lesions tended to occur in the vessel subjected to PTCA.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of acute hypertriglyceridemia and high levels of free fatty acids on left ventricular function.

The effects of acute hypertriglyceridemia and of high levels of free fatty acids on the left ventricular ejection fraction were studied by radionuclide ventriculography in 20 subjects with and without coronary artery disease. An infusion of approximately 125 ml of a 20% fat emulsion over 25 minutes resulted in an increase of plasma triglycerides to the mean of 820 mg/dl and a fall of the left ventricular ejection fraction from the baseline mean of 62% to 58% (p less than 0.05). Ninety minutes after the intravenous administration of 5000 units of heparin, plasma free fatty acids rose to the mean of 4.6 mmol/L and the mean left ventricular ejection fraction increased to 69% (p less than 0.001). The observed changes in blood lipids were not associated with clinical or ECG evidence of myocardial ischemia. We conclude that acute hypertriglyceridemia causes slight depression of left ventricular performance, while high levels of free fatty acids augment it. However, neither hypertriglyceridemia per se nor its rapid conversion to free fatty acids are likely to cause angina in stable patients with coronary artery disease.

Effect of acute postinfusion lipemia and free fatty acids on myocardial contractility: assessment with radionuclide ventriculography.

Equilibrium gated radionuclide ventriculography was used to evaluate the effect of intravenous fat-emulsion overload and excess of free fatty acids (FFA) on left ventricular ejection fraction (LVEF) in 20 patients with and without coronary artery disease (CAD). Fifteen of these patients had normal (greater than 50%) baseline LVEF and 5 had low (less than 50%) baseline LVEF. From 100 to 150 ml of 20% artificial fat emulsion (Liposyn) was infused over 20-25 min. At the end of the infusion, triglyceridemia reached 820 +/- 220 mg% and left ventricular ejection fraction decreased from baseline 62 +/- 19% (mean +/- SD) to 58 +/- 16% (P less than 0.05, paired t-test). After completion of Liposyn infusion, 5,000 U of heparin was administered intravenously and monitoring of LVEF was continued. One and one-half hours following heparin administration, plasma FFA levels reached 3.7 + 2.0 mmol/l and LVEF rose to 69 +/- 19% (P less than 0.001, paired t-test). Our data indicate that acute intravenous fat overload can suppress and high pathophysiologic levels of FFA can increase LVEF. This effect is more uniform and statistically more reliable in patients with normal LVEF. The study failed to demonstrate any significant difference in the effect of this pharmacologic intervention between patients with and without CAD.

The potential risk of thrombosis during coronary angiography using nonionic contrast media.

The influence of contrast media on coagulation has an important association with thromboembolic complication during coronary angiography. In this study, whole blood was methodically mixed with nonionic contrast medium, Iohexol (IOH), conventional ionic contrast medium, Hypaque-76 (H76), and low osmolar ionic dimer Hexabrix (HB) in vitro. The thrombotic propensity of contrast agents can be evaluated by measuring the clot formation of the mixtures. The experiments were repeated with whole blood after systemic heparinization. In the in vitro study, 5 ml of canine (N = 10) and 3 ml of human (N = 11) whole blood was incubated for 30 min in glass tubes with equal volumes of IOH, H76, HB, and 0.9% NaCl before heparinization. Clot formation with IOH and 0.9% NaCl were seen both in dogs (4.0 +/- 0.7 gm and 5.6 +/- 0.8 gm) and in patients (1.4 +/- 0.9 gm and 2.9 +/- 1.3 gm), whereas no clot was seen with H76 or XB. Following heparinization, no clot was visualized in any mixture of whole blood with contrast media or 0.9% NaCl. Similar results were observed in the catheter-syringe system with canine blood (N = 11) mixed with the contrast agents. Blood clots found in 15 min and 30 min of IOH were 0.07 +/- 0.08 gm and 0.44 +/- 0.20 gm (P less than 0.01) and of NaCl were 0.29 +/- 0.37 gm and 0.69 +/- 0.38 gm (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)