Jens Peder Bagger

Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty

Angiopeptin, a somatostatin analogue, inhibits intimal hyperplasia after percutaneous transluminal coronary artery balloon angioplasty (PTCA) in several animal models. This pilot study sought to determine the effect of subcutaneous infusion of angiopeptin on clinical events and restenosis in patients undergoing successful PTCA. One hundred twelve patients were randomized to receive continuous subcutaneous angiopeptin (750 micrograms/day) or placebo infusion from the day before PTCA and for the following 4 days in a double-blind study. An additional subcutaneous injection of 375 micrograms of angiopeptin or saline was given immediately before PTCA. Eighty patients had a successful PTCA, and 75 of these patients with 94 lesions underwent angiography 6 +/- 2 months after PTCA. All 112 patients underwent a 12-month clinical follow-up examination. Age, sex, smoking, diabetes, hypertension, hyperlipidemia, and morphologic features of stenosis were similar in both groups. The hierarchical 12-month event rate (death, myocardial infarction, coronary artery bypass grafting, and repeated PTCA) was reduced from 34% to 25% (p = 0.30) by angiopeptin by intention-to-treat analysis. Restenosis (> or = 50% diameter stenosis) was significantly reduced in lesions treated with angiopeptin (12% vs 40%; p = 0.003). Late lumen loss also was significantly reduced after angiopeptin treatment (0.12 +/- 0.46 mm vs 0.52 +/- 0.64 mm; p = 0.003). In conclusion, continuous subcutaneous angiopeptin infusion for 5 days tended to decrease clinical events and restenosis after PTCA.

Electrical injury causing ventricular arrhythmias.

Dangerous or long lasting ventricular arrhythmias developed in three patients who had sustained an electrical injury in which current passed through the thorax. In all three cases there was a delay of 8-12 hours between the injury and the onset of symptoms. The ventricular arrhythmias were severe and long lasting. In two of the three patients, ventricular tachycardia or ventricular fibrillation or both occurred and in one patient ventricular parasystole developed. No enzymatic evidence of myocardial necrosis was found but the results of an endomyocardial biopsy carried out in two of the three patients showed focal myocardial fibrosis and increased numbers of Na, K-pumps. The two patients with ventricular tachycardia became symptom free after appropriate antiarrhythmic treatment and in the third patient ventricular parasystole disappeared spontaneously within two years. Patients sustaining electrical injury in which current passes through the thorax should be monitored electrocardiographically for at least 24 hours, and patients with unexpected arrhythmias should be questioned about previous electrical injury.

Atrial natriuretic peptide during pacing in controls and patients with coronary arterial disease

At rest, during cardiac catheterization, aortic plasma levels of immunoreactive atrial natriuretic peptide did not differ between 10 controls with atypical chest pains and normal coronary arteries and 9 patients with stable angina pectoris and coronary arterial disease (55.2 +/- 19.8 vs. 64.8 +/- 19.8 pg/ml, NS). Nor did atrial natriuretic peptide values differ between the two groups during or after atrial pacing (150 beats/minute), which induced electrocardiographic and metabolic signs of acute myocardial ischaemia in the patients with coronary arterial disease but in none of the controls. Pacing, when carried out for more than 300 seconds, induced an increase of plasma atrial natriuretic peptide that correlated with duration of pacing (r = 0.80, P less than 0.001), and similarly in controls and patients with coronary arterial disease. In a second part of the study, which included 2 controls and 2 patients with coronary arterial disease, post-pacing coronary sinus concentrations of atrial natriuretic peptide were 10-20 times higher than peripheral levels (415- greater than 890 pg/ml). The concentration of atrial natriuretic peptide rose as blood from the caval veins (34 +/- 7 pg/ml) entered the right atrium (56 +/- 24 pg/ml), but thereafter was unchanged in the pulmonary artery (51 +/- 3 pg/ml) and the aorta (46 +/- 9 pg/ml). In conclusion, the results gave no evidence for ischaemic heart disease without congestive cardiac failure to be associated with altered levels of atrial natriuretic peptide. It was confirmed that atrial pacing stimulates the secretion of atrial natriuretic peptide which is produced by the heart and released via the coronary sinus into the circulation.

Cardiomyopathy in western Denmark.

A retrospective study was carried out to assess the incidence of cardiomyopathy in western Denmark (Jutland and Funen) (population 2 798 000) during a two year period (1980-81). The WHO/ISCF classification was strictly followed, and rigid criteria for exclusion and inclusion of patients were adopted. Thus cases in which specific heart muscle disorders (myocarditis, alcoholic heart disease, hypertension etc) were merely suspected were excluded. Forty one patients had dilated cardiomyopathy (overall incidence 7.3/10(6) population/year) and 20 hypertrophic cardiomyopathy (overall incidence 3.6/10(6) population/year). In men aged 40-59 years the occurrence of dilated cardiomyopathy was 23.4/10(6) population/year. Only one case of Löfflers endomyocardial disease was diagnosed during the study period. Since the investigation was retrospective and was a study of diseased persons and not a population, and since a specific set of criteria for exclusion and inclusion was rigidly applied, the results represent the minimum frequency of these diseases.

Diagnostic Value of Esophageal Studies in Patients with Angina-like Chest Pain and Normal Coronary Angiograms

The esophagus has been suspected of being the source of angina-like chest pain in symptomatic patients with normal cardiac evaluations. Several studies [1-9] have shown a high incidence (23% to 80%) of esophageal abnormalities in patients with so-called noncardiac chest pain, but the extent to which esophageal abnormalities can be linked in a cause-effect manner to chest pain episodes remains controversial [10]. Patients with angina but normal coronary angiograms have a favorable prognosis for survival [11, 12]. However, the recent cardiologic focus on metabolic abnormalities of the myocardium [13] and impaired left ventricular function [14, 15] has brought into question the homogeneity of the patient samples used in many of the gastroenterologic studies [10, 16, 17]. We studied esophageal dysfunction as a possible source of pain in patients with angina-like chest pain but normal coronary angiograms. The patients were enrolled consecutively and according to strict cardiologic criteria so that only patients in whom the source of chest pain was truly obscure were evaluated. The study patients did not have coronary artery disease, coronary artery spasms, abnormal motion of the cardiac wall, valvular disease, or cardiomyopathy. In addition, coronary sinus lactate release in response to atrial pacing was measured in all patients to determine whether the patients had ischemic myocardial metabolism despite normal macroscopic coronary anatomy. Because the patients with an abnormal response to exercise electrocardiographic testing might have had an independent disease entity (the cardiologic syndrome X) [18, 19], the patients were grouped according to the outcome of such testing. The study design is shown in Figure 1. Figure 1. Diagram of the study design. Methods Participants All patients had chronic angina-like chest pain and normal coronary angiograms and were referred for routine invasive evaluations of myocardial metabolism at Skejby University Hospital, Aarhus, Denmark, between September 1990 and September 1993. The patients were then screened for the esophageal investigation. The study group consisted of 63 patients: 36 women and 27 men (mean age, 51.7 years [range, 18 to 70 years]). Inclusion criteria were the following: 1) chest pain lasting more than 6 months and normal coronary angiogram [less than 50% luminal narrowing] judged independently by the same two experienced cardiologists; 2) left ventricular ejection fraction greater than 50% as determined by ventriculography; 3) valvular and myocardial diseases excluded by echocardiography and angiography; and 4) coronary artery spasm excluded by hyperventilation testing [20]. Myocardial lactate exchange was evaluated by catheterization of the coronary sinus through the antecubital vein and an arterial catheter in the femoral artery. Lactate levels were measured in blood samples obtained simultaneously from the antecubital vein and the femoral artery at baseline (mean, three samples) and during cardiac pacing to 150 beats/min (mean, two samples) for a maximum of 10 minutes or until angina occurred [21]. We excluded patients with spontaneous or exercise-induced bundle-branch block because such patients may be an independent patient group susceptible to developing substantial deterioration of left ventricular function within a span of years [22]. We did not use the results of any previous testing to select study patients. We divided the patients into two groups according to the result of electrocardiographic testing during bicycle exercise [exercise began at 25 W, with a 25-W increase every 2 minutes]: 1) patients with a positive exercise electrocardiogram [more than equals 1 mm horizontal or down-sloping ST-segment depression at 80 ms after the J point] and 2) patients with a normal electrocardiogram. All exercise electrocardiograms were read by the same senior cardiologist, who was blinded to patient history. We selected 22 healthy persons (13 women and 9 men; mean age, 47.6 years [range, 31 to 60 years]) as controls for all esophageal investigations and 24-hour electrocardiographic monitoring. Controls were recruited from hospital staff and blood donors. No control had a history of gastrointestinal, neurologic, endocrinologic, or cardiologic diseases or was taking medication. All participants gave informed consent for the study, which was approved by the local ethics committee. Esophageal Symptom Questionnaire We administered a standard questionnaire to all participants to determine esophageal symptoms. Heartburn was defined as retrosternal burning beginning in the xiphisternal region and ascending to the neck; regurgitation was defined as the passive appearance of gastric or intestinal content, or both, in the mouth; dysphagia was defined as the sticking of a bolus or the subjective sensation of a bolus passing down the esophagus; and odynophagia was defined as the sensation of pain during swallowing. Study Conditions All pharmacologic therapy was discontinued at least 72 hours before the investigation began; treatment with proton pump inhibitors (received by one patient) was stopped 5 days before. All studies were done during an unrestricted hospitalization that was not related to the angiographic procedure. Patients and controls were fully ambulatory. Investigations began between 7:00 a.m. and 7:30 a.m. on the morning after an overnight fast and ended at the same time the following morning. Participants could eat and drink between meals but were told to avoid consuming food or beverages that had a low pH (for example, orange juice, cola-flavored drinks, or citrus fruit). However, we did not directly assess compliance with this point. Participants were allowed to smoke and consume alcohol. Participants recorded all intake by operating an event marker on the portable esophagus monitor and by recording the beginning and end of the intake on a diary time sheet. The same procedure was followed for recording pain periods and periods during which the participants were supine. Esophageal pH and Manometry Monitoring Portable equipment was used for the 24-hour monitoring. The pH probe contained two antimony electrodes (Monocrystant, Synectics Medical, Stockholm, Sweden) that were 5 cm apart. The manometry catheter contained three strain-gauge microtransducers that were 5 cm apart (Konigsberg, Synectics Medical). The probe, the catheter, and an Ag/AgCl skin electrode (which served as a reference for the pH electrodes) were connected to a belt-mounted microprocessor that had a 2-MB memory and a 5-Hz sampling frequency (Microdigitrapper, Synectics Medical). We calibrated the microprocessor at pH values of 7.01 and 1.07 (pH electrodes) and at 0 and 50 mm Hg by immersing the manometry catheter into a water column. The pH probe was attached to the side of the manometry catheter with tape so that one of the two pH electrodes was positioned midway between the proximal and middle transducers and the other was positioned midway between the distal and middle transducers. The combined assembly was inserted into the participants nose and placed in the esophagus. The tip transducers were positioned 2.5, 7.5, and 12.5 cm proximally to the lower-esophageal sphincter; thus, the pH electrodes were positioned 5 and 10 cm above the sphincter. The lower-esophageal sphincter was located by a station pull-through technique in which absolute pressure values are shown in a display on the microprocessor. Positioning was confirmed by ingestion of barium contrast and by video fluoroscopy, a technique previously verified in our center [23]. Analysis of Esophageal Monitoring After the 24-hour esophageal studies ended, data were downloaded to a personal computer-based program (Multigram version 6.01C9, Gastrosoft, Synectics Medical) that has recently been validated in a comparison with manual analysis [24]. The pH data from the two electrodes were analyzed for the percentage of time during which the pH was less than 4.0 (the reflux index). We set an automatic baseline for each pressure channel according to the most frequent level of the smaller pressure variations. The baseline was updated every 20 seconds. A contraction was defined as an increase in the pressure above a 15-mm Hg threshold relative to the baseline that lasted at least 1 second [7, 24-26]. Contractions were temporally classified according to the peaks of the contractions. The analysis program provided values of the median amplitude and duration of the contractions for each pressure channel. The program also reported the percentage of multiple peaked contractions. We defined multiple peaks as secondary peaks in which the amplitude was at least 10% of the amplitude of the main peak, the interval between the local minimum and peak was greater than 0.5 seconds, and the amplitude of the local minimum was at least 15% of the amplitude of the main peak. The analysis report included the percentage distribution of peristaltic, simultaneous, and isolated contractions, the sum of which is 100%. Simultaneous contractions were defined as contraction velocities greater than 15 cm/s. Peristaltic contractions were defined as ranging from 1.3 to 15 cm/s [26]. On the basis of the esophageal recordings, we compared controls with all patients, with patients who had a positive exercise electrocardiogram, and with patients who had a normal exercise electrocardiogram. In the comparison of baseline values with values during pain periods, any abnormal activity could be secondary to the pain rather than the actual cause of the pain. Because of this, the 2-minute prepain interval was introduced [27]. Accordingly, we defined the prepain period as the period that began 2 minutes before and ended after the onset of pain. We defined the pain period as the entire time during which the patient experienced pain. We compared values recorded during prepain and pain periods with those at baseline (the periods during which the participants were upright minus the time

Postoperative infection with meticillin-resistant Staphylococcus aureus and socioeconomic background

Infectious disease can be linked to social deprivation. We investigated whether postoperative infection with meticillin-resistant Staphylococcus aureus (MRSA) is related to socioeconomic background. Patients were stratified by social deprivation according to postcode. In a consecutive series of 1739 UK residents undergoing isolated coronary artery bypass grafting, 23 (1.3%) were infected with MRSA. We noted a graded relation between incidence of infection and social deprivation. Patients from the most deprived areas had a seven-fold higher infection rate (13 of 579 [2.2%]) than those from the least deprived areas (two of 580 [0.3%]; p=0.0040). Patients with MRSA infection had a six-fold higher mortality rate and a longer hospital stay than patients with no such infection. Our findings suggest that patients from deprived areas might be especially susceptible to postoperative infection with MRSA.

Altered global myocardial substrate preference at rest and during pacing in coronary artery disease with stable angina pectoris

In 21 control subjects with atypical chest pains and normal coronary arteries and in 64 patients with stable angina and coronary artery disease (CAD), myocardial exchanges of free fatty acids, glucose, lactate, citrate, glutamate, alanine and oxygen were determined before, during and after pacing. At rest, myocardial uptake of fatty acids was 50% lower in CAD patients than in the control subjects (p less than 0.001), whereas uptakes of glucose and lactate were twice as high (p less than 0.01). CAD patients showed increased myocardial glutamate uptake (p less than 0.001) and alanine release (p less than 0.001). In control subjects, myocardial fatty acid uptake was directly related (r = 0.54, p less than 0.01), whereas uptakes of glucose (r = -0.42, p less than 0.05) and lactate (r = -0.46, p less than 0.05) were inversely related to arterial fatty acid levels. Citrate release was inversely related to glucose uptake (R = 0.44, p less than 0.05). These relations were absent in CAD patients. Glutamate consumption correlated only with glucose uptake in CAD patients (p less than 0.001) but did so with lactate uptake and alanine release in all individuals (p less than 0.001). Pacing caused angina in the CAD patients but not in the control subjects. Pacing induced no metabolic changes among control subjects but provoked myocardial lactate release in 40 CAD patients, including an additional decrease of fatty acid uptake (p less than 0.05) and increase of glucose uptake (p less than 0.05) compared with resting levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intravenous glutamate on substrate availability and utilization across the human heart and leg

To study the effect of monosodium glutamate on hemodynamics and on substrate metabolism in cardiac and skeletal muscle, an intravenous (IV) dose of 1.2, 2.5, or 5.0 mg/kg body weight was administered to 27 patients during arterial-coronary sinus catheterization (15 patients) or arterial-femoral vein catheterization (13 patients). Data were obtained for 25 minutes after the injection. Arterial glutamate concentrations increased 2.5-5 fold in a dose-related manner. Glutamate administration reduced arterial levels of free fatty acids by 25% (P less than .001), of lactate by 13% (P less than .05), and of alanine by 6% (P less than .05). Arterial glucose increased by 10% (P less than .001) and arterial insulin was increased threefold (P less than .01). Myocardial uptake of free fatty acids decreased by 25% (P less than .001), whereas uptakes of glutamate and glucose increased by 60% (P less than .001) and 100% (P less than .001), respectively. Cardiac release of citrate increased transiently (P less than .05), whereas consumption of lactate and releases of alanine were unchanged by the glutamate. Across the leg, the arteriovenous differences of glutamate were elevated threefold to eightfold (dose-related) (P less than .001), and that of glucose was doubled (P less than .01). The release of citrate increased (P less than .01). Arterial-femoral vein gradients of free fatty acids, lactate, and alanine remained unchanged. Heart rate, blood pressure, coronary sinus flow, coronary vascular resistance, and cardiac oxygen uptake were unmodified by glutamate. Six patients complained of short-lasting burning sensations after the highest glutamate doses. In conclusion, glutamate administration stimulates insulin secretion and changes substrate availability and utilization in human cardiac and skeletal muscle from free fatty acids toward glucose and glutamate.

Myocardial insulin resistance in patients with syndrome X.

Insulin resistance is common in patients with angina pectoris, a positive exercise electrocardiogram, and normal coronary angiograms (syndrome X). It is still not known whether insulin resistance affects the cardiac muscle itself and, if so, whether insulin resistance involves myocardial hemodynamics and energy metabolism. We investigated hemodynamics as well as metabolite exchanges across the heart and the forearm in eight patients with syndrome X and eight control subjects during a baseline period after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Myocardial hemodynamics and metabolism were studied at rest, during pace stress, and in the recovery period after pacing. Neither coronary sinus blood flow nor forearm blood flow differed between the groups before and during the clamp. Whole body insulin-stimulated glucose uptake was decreased in the patients (15.6+/-2.1 vs. 23.1+/-2.0 micromol x kg-1 x min-1). Insulin-stimulated glucose uptake in the forearm and the cardiac muscle was equally reduced in the patients (46+/-5 and 48+/-5%). Myocardial glucose uptake correlated with total arterial delivery in the control subjects (r = 0.63, P < 0.01), but not in patients (r = 0.22, P = 0.13). Carbohydrate and lipid oxidation was similar in the two groups at rest, and changes during the clamp were not different in control subjects and patients either at rest, during pacing, or in the recovery period. Patients with syndrome X exhibit myocardial insulin resistance, but cardiac energy metabolism remains unaffected. In patients with syndrome X, insulin-stimulated glucose uptake is independent from myocardial blood flow.

Impact of Impaired Coronary Flow Reserve and Insulin Resistance on Myocardial Energy Metabolism in Patients With Syndrome X

To evaluate the role of a decreased coronary flow reserve in the genesis of angina pectoris in patients with syndrome X, we studied myocardial hemodynamics and metabolism at rest, during pace stress, and in the recovery period after pacing in 18 consecutive patients with syndrome X and in 10 control subjects. By means of positron emission tomography or the intracoronary flow-wire method, patients were subclassified as having microvascular angina (MA, n = 8) when coronary flow reserve was reduced (<2.5) or no microvascular angina (non-MA, n = 10) when coronary flow reserve was preserved (> or =2.5). At rest, coronary sinus blood flow was increased in MA patients. During pace stress, coronary sinus blood flow increased by 39 +/- 6% in MA patients versus 67 +/- 12% in non-MA patients and 69 +/- 7% in controls (p <0.05). Patients with non-MA revealed fasting hyperinsulinemia, increased arterial concentration of free fatty acids, and a similar tendency for beta-hydroxybutyrate. Oxygen extraction and carbon dioxide release did not differ between groups. Net myocardial lactate release was not observed in any patient during pace stress and myocardial energy metabolism was preserved in all patients with syndrome X. During pacing, myocardial uptake of free fatty acids and beta-hydroxybutyrate was increased in non-MA patients. Myocardial uptake of free fatty acids correlated positively and myocardial glucose and lactate uptake correlated inversely with arterial concentrations of free fatty acids in all subjects. Metabolic evidence of myocardial ischemia is uncommon in patients with syndrome X, irrespective of a globally reduced coronary flow reserve. Although patients with syndrome X can be subclassified according to presence of a microvascular or a metabolic disorder, angina pectoris and ST-segment depressions coexist with a preserved global myocardial energy efficiency in all patients.