Increased renal production of transforming growth factor-beta1 in patients with type II diabetes.

Diabetic nephropathy is a common complication in patients with either type I or type II diabetes. The pathogenesis of diabetic nephropathy is thought to involve both metabolic and vascular factors leading to chronic accumulation of glomerular mesangial matrix. In this context, both transforming growth factor-beta (TGF-beta) and endothelin may contribute to these processes. To determine if diabetic patients demonstrate increased renal production of TGF-beta and endothelin, aortic, renal vein, and urinary levels of these factors were measured in 14 type II diabetic patients and 11 nondiabetic patients who were undergoing elective cardiac catheterization. Renal blood flow was measured in all patients to calculate net mass balance across the kidney. Diabetic patients demonstrated net renal production of immunoreactive TGF-beta1 (830 +/- 429 ng/min [mean +/- SE]), whereas nondiabetic patients demonstrated net renal extraction of circulating TGF-beta1 (-3479 +/- 1010 ng/min, P < 0.001). Urinary levels of bioassayable TGF-beta were also significantly increased in diabetic patients compared with nondiabetic patients (2.435 +/- 0.385 vs. 0.569 +/- 0.190 ng/mg creatinine, respectively; P < 0.001). Renal production of immunoreactive endothelin was not significantly increased in diabetic patients. In summary, type II diabetes is associated with enhanced net renal production of TGF-beta1, whereas nondiabetic patients exhibit net renal extraction of circulating TGF-beta1. Increased renal TGF-beta production may be an important manifestation of diabetic kidney disease.

Sensitivity of isovolumic relaxation to hypothermia during myocardial infarction.

Effects of moderate spontaneous hypothermia on left ventricular systolic and diastolic function during acute myocardial infarction were documented in 17 anesthetized dogs with micromanometric pressure and ventriculographic dimension recordings acquired at baseline and at 1 and 3 h after coronary occlusion. In Group 1 (n = 5), core temperature was allowed to decline spontaneously. In Groups 2 (n = 6) and 3 (n = 6), core temperature was maintained at normothermic levels. Hypothermia impaired isovolumic relaxation markedly despite its lack of effect on ventricular volumes or ejection fraction. At 32.3 degrees C, tau 1/2, defined as the time needed for the left ventricular pressure at the time of peak negative rate of change of left ventricular pressure (dP/dt) to fall by 50%, was increased by 129% 3 h after occlusion. In addition, at this temperature significant changes were found in heart rate, cardiac output, minute work, peak positive and peak negative dP/dt, systolic ejection time, mean velocity of circumferential fiber shortening, mean aortic pressure and end-diastolic pressure. Thus, hypothermia evolving under conditions of general anesthesia profoundly alters left ventricular function in the setting of acute myocardial infarction, a phenomenon that requires consideration and control in studies of myocardial ischemia and left ventricular function in experimental animals.

Diastolic stiffening induced by acute myocardial infarction is reduced by early reperfusion.

Reperfusion early during myocardial infarction improves ejection fraction and this improvement may represent myocardial salvage in the injured segment. Alternatively, reperfusion of injured myocardium may cause intramyocardial hemorrhage with resultant increased stiffness causing a dyskinetic segment to become akinetic, thus improving ejection fraction without concomitant myocardial salvage. To evaluate this possibility, diastolic stiffness was assessed in a closed chest, anesthetized, normothermic dog model immediately after a 1 or 3 h occlusion of the left anterior descending coronary artery and during the 4 weeks after occlusion. Acute myocardial infarction in experimental dogs was accompanied by a fivefold increase in the chamber stiffness constant, a threefold increase in the myocardial stiffness constant and a significant increase in elastic stiffness and end-diastolic pressure. These changes occurred contemporaneously with a marked decline in ejection fraction. Early reperfusion (1 h occlusion) resulted in improvement of the ejection fraction accompanied by simultaneous resolution of the previously increased stiffness. Late reperfusion (3 h occlusion) resulted in permanent depression of ejection fraction with permanent elevation of stiffness. These results indicate that the improved systolic function observed after early reperfusion reflects a process other than increased stiffness, perhaps salvage of jeopardized myocardium.

Antithrombin activity during the period of percutaneous coronary revascularization: relation to heparin use, thrombotic complications and restenosis.

OBJECTIVES: This study evaluated changes in antithrombin (AT) activity around the time of percutaneous transluminal coronary revascularization (PTCR) with unfractionated heparin anticoagulation and the effects these changes had on major thrombotic complications of PTCR. BACKGROUND: Heparin is used during PTCR to prevent thrombosis. However, heparin, a cofactor for AT, causes AT activity to fall. AT activity <70% is associated with thrombosis. There is a prothrombotic state after heparin discontinuation that has not been well explained. METHODS: Antithrombin activity was sampled at the start and end of PTCR and the next two mornings in 250 consecutive patients. We recorded occurrence of major thrombotic events, defined as 1) major thrombotic complications of PTCR; 2) major in-lab thrombus formation; or 3) subacute occlusion. Discriminant analysis was employed to evaluate the relationship of AT activity to these events. Change in AT activity and its relationship to heparin was evaluated. Evidence of restenosis at six months was obtained. RESULTS: There were 14 major thrombotic events. Antithrombin activity <70% was strongly (p = 0.006) associated with these events. The AT activity fell significantly through the morning after PTCR when 21% of patients had AT activity <70%; AT activity did not normalize until >20 h after heparin discontinuation. Pre-PTCR use of heparin led to lower AT activity in proportion to duration of heparin use. There was no relationship between AT activity and restenosis. CONCLUSIONS: Low AT activity may contribute to major thrombotic complications of PTCR. The way heparin is used before and after PTCR is important to development of low AT activity.

Coronary artery ectasia associated with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) is characterized by a variety of cutaneous, mucosal, and visceral vascular anomalies. A patient with classic hereditary hemorrhagic telangiectasia was shown to have three-vessel coronary artery ectasia without evident atherosclerosis, and association not previously demonstrated. The possibility that coronary artery ectasia may be a manifestation of hereditary hemorrhagic telangiectasia is discussed.

Improvement in early diastolic filling dynamics after aortic valve replacement.

With use of ultrafast computed tomography, 13 patients undergoing aortic valve replacement for aortic stenosis were prospectively followed to evaluate the relation between left ventricular mass and diastolic function. Studies were done before intervention, and then at 4 and 8 months later. Mass decreased from 161 +/- 11 g/m2 (+/- standard error of the mean) at baseline to 106 +/- 5 g/m2, and then to 97 +/- 7 g/m2 at 4 and 8 months, respectively, in 12 patients who demonstrated significant (greater than 20%) mass regression after operation. One patient failed to show significant changes in mass. Diastolic function, as defined by the peak filling rate of early diastole, improved (p less than 0.02) in the group with mass regression, from 2.11 +/- 0.17 s-1 at baseline to 2.12 +/- 0.23 s-1, and then to 2.62 +/- 0.26 s-1 at 4 and 8 months, respectively. Improvement in the time to peak filling rate was also noted. Heart rates were unchanged, whereas end-diastolic volumes decreased and ejection fractions increased slightly. Postoperative increase in peak filling rate correlated with regression of ventricular mass to within normal range (+/- 2 standard deviations) and attainment of New York Heart Association class I status by 8 months (p less than 0.02). Thus, improvement in diastolic function can be seen after aortic valve surgery and is associated with improved functional class. Diastolic function improves later than the regression in wall mass and may imply a delayed remodeling of the ventricle.

Expected hemoglobin decrease following percutaneous transluminal coronary angioplasty.

To establish expected changes in hemoglobin during and after percutaneous transluminal coronary angioplasty (PTCA), we measured hemoglobin before, at the end of, and on the 2 mornings after PTCA in 177 consecutive patients without obvious out-of-laboratory blood loss. From these data, we calculated confidence intervals that can be used to compare group data, possibly to identify excessive blood loss with new devices or antithrombotic agents, and prediction intervals to identify unexpected blood loss in an individual patient.

Frequency of low-grade residual coronary stenosis after thrombolysis during acute myocardial infarction.

The clinical, angiographic and demographic characteristics of 42 patients with low-grade (less than 50%) residual stenosis at the infarct lesion after thrombolysis for acute myocardial infarction (MI) were assessed. The study group (group I) represented 21% of 198 consecutive patients receiving thrombolytic therapy over a 59-month period. Data on the 156 remaining patients were pooled for comparison (group II). Group I patients were predominantly men (86%) who were cigarette smokers (81%). Group II patients were predominantly men (75%, p greater than 0.10) but were significantly older (52 +/- 12 vs 56 +/- 10 years, p = 0.02). Prior acute MI or angina was unusual in group I. Sixty percent had no significant (greater than 50%) residual coronary artery disease while 25% had residual single artery disease. Average significant (greater than 50% diameter stenosis) residual vessel disease was 0.6 +/- 1.0 for group I and 1.9 +/- 0.9 for group II (p less than 0.001). In group I, average residual infarct lesion diameter stenosis was 36 +/- 7% in the right anterior oblique and 34 +/- 8% in the left anterior oblique views. Thirty-nine group I patients were discharged with medical therapy and 100% follow-up was obtained over a mean interval of 18 +/- 17 months. Fifteen patients experienced chest pain after acute MI accounting for 17 discrete events. Fifty-nine percent of group I had a benign course on follow-up. Eight events were classified as unstable angina, 4 as acute MI and 5 as atypical angina. Documented coronary vasospasm occurred in 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial infarct artery patency and reocclusion rates after treatment with duteplase at the dose used in the International Study of Infarct Survival-3. Burroughs Wellcome Study Group.

Duteplase, 98% double-chain recombinant tissue-type plasminogen activator, was administered intravenously in 488 patients with acute myocardial infarction in a multicenter, open, safety and patency study. Duteplase dosing was based on body weight. Duteplase was administered as a bolus of 0.04 MIU/kg of thrombolytic activity followed by 0.36 MIU/kg over 1 hour and 0.067 MIU/kg/hour for 3 additional hours. The patency rate of the infarct-related artery at 90 minutes was 69% (330 of 478). The reocclusion rate at 3 to 48 hours was 6% (18 of 301). Reinfarction occurred in 7.6% of patients (37 of 488), but 12 reinfarctions occurred after coronary angioplasty. Serious bleeding occurred in 7.6% of patients (37 of 488), predominantly at the catheterization entry site. There were 3 instances of central nervous system bleeding, 1 fatal. Fibrinogen levels declined to 83% of baseline at 24 hours. Weight-based dosing may explain the low incidence of serious bleeding in this study. The in-hospital mortality was 6.6% (32 of 488). This study documents that the dose of duteplase used in the International Study of Infarct Survival-3 results in a 90-minute coronary artery patency rate and safety profile comparable to those reported in published studies on the approved dose of alteplase.

Peripheral hemodynamic effects of intraventricular and intracoronary contrast media in man.

The effects of intraventricular and intracoronary contrast media on the peripheral arterial and venous beds were directly measured with forearm plethysmography. Standard dose intraventricular radiographic contrast produces a potent peripheral arterial vasodilator effect accompanied by a hypotensive and tachycardic response, followed by peripheral venoconstriction, suggesting that the net hemodynamic response is mediated peripherally. Coronary arteriography is associated with a differing pattern of response, suggesting that the most important hemodynamic effects are mediated via myocardial depression with secondary peripheral vascular responses. Hemodynamic changes occur earlier than those following ventriculography and reflect peripheral arterial and venous constriction. Dose and osmolarity of the contrast are important determinants as well as the site of administration.

Adverse effects of calcium binding contrast agents in diagnostic cardiac angiography. A comparison between formulations with and without calcium binding additives.

RATIONALE AND OBJECTIVES: The authors compared complications and hemodynamic and electrophysiologic effects of two formulations of diatrizoate, one with additives that bind calcium and one without, in diagnostic cardiac angiography. METHODS: Two hundred twenty-three consecutive low-risk patients alternately received Hypaque 76 (group 1, little calcium binding effect), and MD 76 (group 2, significant calcium binding). Electrocardiographic and hemodynamic changes related to coronary angiography and left ventriculography were measured, and complications requiring treatment were recorded. RESULTS: There were more complications in patients in group 2 than in group 1 (18 versus 8, P = 0.04). Arterial pressure fell more, the QT interval increased more, and the heart rate fell more in group 2 after coronary angiography. CONCLUSIONS: Formulations of diatrizoate that minimize calcium binding are advocated for cardiac angiography when using high osmolality contrast media. The more detrimental effects that calcium binding has on myocardial function and cardiac conduction may lead to the higher incidence of complications.

Practical implications of circadian variations in thrombolytic and antithrombotic activities.

It recently has been demonstrated that thrombolytic therapy has circadian pattern of efficacy, as assessed by the ability to rapidly provide coronary patency. A study of 692 patients receiving intravenous tPA and undergoing acute coronary arteriography demonstrated a substantial diurnal pattern in patency with a peak at 8:00 pm. The heightened tendency for a coronary artery to be opened in the evening correlates well with the substantial tendency demonstrated in the same study and in multiple other studies for coronary arteries to thrombose and cause myocardial infarction in the morning hours. Circadian variations have been defined for a number of hemostatic and physiologic factors that would predispose toward clotting in the late morning, and converse circadian patterns have been described for a number of factors associated with thrombolysis that would predispose towards enhanced fibrinolysis in the evening hours. Methods by which efficacy of lytic therapy potentially could be enhanced include development of tPA variants or adjunctive agents that eliminate the circadian nadirs of efficacy, modification of dosage or choice of lytic agent as a function of time of treatment, and selection between pharmacologic lysis and direct angioplasty as a function of time of day.

Mycobacterium gordonae as a human hepato-peritoneal pathogen, with a review of the literature.

Mycobacterium gordonae was cultured from the liver of a 39-year-old woman who presented with ascites, weight loss, and fever. Laparoscopic examination revealed white nodules studding the peritoneum and liver surface, and histopathology revealed caseating granulomas. She was successfully treated with rifampin, ethambutol, and isoniazid. A review of the literature on M. gordonae as a human pathogen in presented. Our patient represents the third reported case of disseminated disease due to this organism and the first to be successfully treated by medical therapy alone.

Dose-ranging study with a new two-chain rt-PA in patients with acute myocardial infarction: a multicenter trial.

Tissue-type plasminogen activator (t-PA) derived from a melanoma cell line was first used in patients with acute myocardial infarction in the early 1980s. Recombinant DNA technology then allowed production of large amounts of t-PA. The TIMI-I trial used a two-chain recombinant (rt-PA) product. A predominantly single-chain rt-PA (alteplase) was used in the majority of the TIMI II trial. The present study used a different form of two-chain rt-PA (duteplase) to determine the effective dose for thrombolysis at 60 min, and to evaluate time to reperfusion, reocclusion at 72-96 h, coagulation profiles, and bleeding events. Duteplase was given intravenously to 75 patients a mean of 3.8 +/- 1 h after the onset of myocardial infarction. Following angiography demonstrating coronary occlusion, 23 patients received a low dose of duteplase [0.16-0.29 million international units per kilogram (MIU/kg)] over 60 min followed by a 5-h infusion in conjunction with heparin, 25 patients received a middle dose (0.30-0.41 MIU/kg) and 23 patients received a high dose (0.43-0.74 MIU/kg). Angiography was then performed every 15 min x 4. Progressive recanalization occurred over 60 min (median 45 min) with an overall success rate of 59% (mean 60-min dose: 0.37 MIU/kg). No dose-response relationship was observed. The reocclusion rate was 9% at 72-96 h. Reductions in fibrinogen and plasminogen correlated with dose, but clinical events did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian variation in the efficacy of tissue-type plasminogen activator.

BACKGROUND: The frequency of onset of acute myocardial infarction follows a circadian pattern, with a peak incidence between 6:00 AM and noon. Circadian variations have been defined for platelet aggregation, plasminogen-activator inhibitor, and a number of hemostatic and physiological factors, all of which might predispose toward clotting in the late morning and thrombolysis in the evening. Thus, the hypothesis for this retrospective analysis was that tissue-type plasminogen activator (TPA) has greater efficacy when administered between noon and midnight, as measured by coronary patency 90 minutes after initiation of treatment. METHODS AND RESULTS: Seven hundred twenty-eight patients were enrolled in either of two studies in which TPA was administered under a uniform protocol for the treatment of acute myocardial infarction. Of these, 692 patients had qualifying arteriograms that allowed standardized assessment by a core angiographic laboratory of the primary end point of 90-minute patency. TPA has a circadian pattern of efficacy, with greater TIMI grade 3 patency when administered between noon and midnight (P < .001). When TPA was given within 2 hours of symptoms (n = 127), the total patency was highest and there was a trend (P = .055) toward the greatest magnitude difference occurring between AM and PM patency. The onset of myocardial infarction was confirmed to have a marked circadian variation with a peak incidence about 10:00 AM. The peak efficacy of TPA was about 8:00 PM, representing a phase difference of about 10 hours after peak infarction incidence. CONCLUSIONS: There is a circadian variation in the ability of TPA to rapidly open coronary arteries, with highest efficacy between noon and midnight. This complements clinical and in vitro knowledge of increased morning thrombosis and is concordant with knowledge of increased morning thrombosis and is concordant with knowledge of a fibrinolytic profile that is more favorable for evening lysis. This finding has implications for understanding the circadian pathophysiology of myocardial infarction and for its chronotherapy.

The dependence of the cardiac effects of nifedipine on the responses of the peripheral vascular system.

To elucidate the mechanisms of reduction of left ventricular end-diastolic pressure by nifedipine in certain individuals, we evaluated cardiac and peripheral hemodynamic responses in 32 patients after they were randomly assigned to nifedipine (20 mg sublingually) or to placebo treatment. Forearm plethysmography was performed during cardiac catheterization with micromanometers. No hemodynamic parameters were changed after placebo. Left ventricular end-diastolic pressure declined by 14% (p less than .02) after nifedipine in patients with impaired left ventricular function, but was unchanged in those with normal function; indexes of peripheral venous hemodynamics (forearm venous tone, forearm volume change) were not affected. In those patients with abnormal left ventricular function, forearm vascular resistance decreased 36% and forearm blood flow increased 31% (p less than .0005 for both), while neither changed in those with normal function. Cardiac output increased by 10% in patients with impaired left ventricular function but was unchanged in the remainder, while calculated total systemic resistance fell by 24% in those with abnormal left ventricular function (p less than .002 for both). Thus, reduction of left ventricular preload by nifedipine is not attributable to venous pooling, but rather this beneficial effect appears to be attributable to improved left ventricular systolic function in response to afterload reduction, particularly in patients with impaired left ventricular function.

Renal and systemic oxygen consumption in patients with normal and abnormal renal function.

Systemic and renal oxygen consumption and hemodynamics were studied in patients with normal renal function (NI; serum creatinine concentration (Screat), 1.0 +/- 0.04 mg/dL) and those with moderate chronic renal failure with diabetes mellitus Screat, 2.7 +/- 0.2 mg/dL) or without diabetes mellitus (Screat, 2.4 +/- 0.1 mg/dL). Patients with chronic renal failure were anemic and had normal systemic oxygen consumption (NI, 10,564 +/- 277; chronic renal failure, 9,669 +/- 362 mumol of O2/min) and elevated systemic oxygen extraction (NI, 22.9 +/- 1; chronic renal failure, 30.9 +/- 1.2%) (P less than 0.02). Cardiac output and index and arterial oxygen saturation were equivalent in normal patients and in patients with chronic renal failure. Patients with chronic renal failure had higher renal oxygen extraction (NI, 7.3 +/- 0.8; chronic renal failure, 13.9 +/- 1%), lower RBF (NI, 572 +/- 146; chronic renal failure, 197 +/- 20 mL/min/kidney), and lower renal oxygen consumption per kidney (NI, 391 +/- 101; chronic renal failure, 177 +/- 20 mumol of O2/min/kidney) than did normal patients (P less than 0.02). There was a linear relationship between hemoglobin and RBF (r = 0.47, P less than 0.02). Patients with chronic renal failure and diabetes had lower RBF (diabetes mellitus, 146 +/- 23; without diabetes, 242 +/- 28 mL/min/kidney) and renal oxygen consumption per kidney (diabetes mellitus, 131 +/- 21; without diabetes, 218 +/- 29 mumol of O2/min/kidney (P less than 0.03) but equivalent renal oxygen extraction when compared with patients without diabetes. Patients with chronic renal failure without diabetes mellitus had higher renal oxygen consumption when expressed per 100 mL of creatinine clearance (diabetes mellitus, 1,016 +/- 150; without diabetes mellitus, 1,453 +/- 175 mumol of O2/min/100 mL of creatinine clearance; P less than 0.03). There was a significant linear relationship (P less than 0.005, r = 0.38) between calculated creatinine clearance and renal oxygen consumption with a y intercept representing basal renal oxygen consumption (115 mumol of O2/min/kidney) and a slope of 2.3 mumol of O2/mL. Patients with moderate chronic renal failure have normal systemic oxygen consumption but reduced RBF and renal oxygen consumption. The latter parameters are even lower in patients with chronic renal failure and diabetes. Renal hypermetabolism is more likely to exist in nondiabetic than diabetic renal disease. Basic human renal physiology and pathophysiology are described by the relationships between renal oxygen consumption, blood flow, oxygen extraction, and creatinine clearance in patients with normal and abnormal renal function of varied cause.