Douglas E. Vaughan

Effect of Captopril on Progressive Ventricular Dilatation after Anterior Myocardial Infarction

We conducted a double-blind, placebo-controlled trial to determine whether ventricular dilatation continues during the late convalescent phase after myocardial infarction and whether therapy with captopril alters this process. Fifty-nine patients with a first anterior myocardial infarction and a radionuclide ejection fraction of 45 percent or less underwent cardiac catheterization 11 to 31 days after infarction, when they were not in overt congestive heart failure. They were randomly assigned to placebo or captopril and were followed for one year. A repeat catheterization was performed to evaluate interval changes in hemodynamic function and left ventricular volume. Thirty-eight male patients were evaluated with maximal-exercise treadmill tests every three months. No differences were detected at base line in clinical, hemodynamic, or quantitative ventriculographic variables. During one year of follow-up, the end-diastolic volume of the left ventricle increased by a mean [+/- SEM] of 21 +/- 8 ml (P less than 0.02) in the placebo group, but by only 10 +/- 6 ml (P not significant) in the captopril group. The left ventricular filling pressure remained elevated with placebo but decreased (P less than 0.01) with captopril. In a subset of 36 patients who were at high risk for ventricular enlargement because they had persistent occlusion of the left anterior descending coronary artery, captopril prevented further ventricular dilatation (P less than 0.05). Patients given captopril also had increased exercise capacity (P less than 0.05). This preliminary study indicates that after anterior myocardial infarction, ventricular enlargement is progressive and that captopril may attenuate this process, reduce filling pressures, and improve exercise tolerance.

Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 receptor antagonists.

Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis.

Plasminogen activator-inhibitor C-1 (PAI-1) plays a critical role in the regulation of fibrinolysis, serving as the primary inhibitor of tissue-type plasminogen activator. Elevated levels of PAI-1 are a risk factor for recurrent myocardial infarction, and locally increased PAI-1 expression has been described in atherosclerotic human arteries. Recent studies have shown that the administration of angiotensin converting enzyme inhibitors reduces the risk of recurrent myocardial infarction in selected patients. Since angiotensin II (Ang II) has been reported to induce PAI-1 production in cultured astrocytes, we have hypothesized that one mechanism that may contribute to the beneficial effect of angiotensin converting enzyme inhibitors is an effect on fibrinolytic balance. In the present study, we examined the interaction of Ang II with cultured bovine aortic endothelial cells (BAECs) and the effects of this peptide on the production of PAI-1. 125I-Ang II was found to bind to BAECs in a saturable and specific manner, with an apparent Kd of 1.4 nM and Bmax of 74 fmol per mg of protein. Exposure of BAECs to Ang II induced dose-dependent increases in PAI-1 antigen in the media and in PAI-1 mRNA levels. Induction of PAI-1 mRNA expression by Ang II was not inhibited by pretreating BAECs with either Dup 753 or [Sar1, Ile8]-Ang II, agents that are known to compete effectively for binding to the two major angiotensin receptor subtypes. These data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.

Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function.

BackgroundRecent clinical trial data indicate that the use of angiotensin converting enzyme (ACE) inhibitors among patients with left ventricular dysfunction results in reduced rates of coronary thrombosis, a provocative finding that suggests a potential interaction between the renin-angiotensin system and fibrinolytic function Methods and ResultsIn four normotensive subjects and six hypertensive patients, we investigated whether infusion of angiotensin II (Ang II) affected circulating levels of plasminogen activator inhibitor-i (PAI-1), the most important physiological inhibitor of tissue-type plasminogen activator (t-PA). Overall, mean levels of PAI-1 antigen increased significantly from 20.1 ng/mL before Ang H infusion to 36.0 ng/mL at the end of Ang II infusion (p=0.008), whereas no change in PAI-1 was observed for control subjects infused with 5% dextrose (p=0.46). Among the normotensive subjects for whom graded doses of Ang II were infused at 0, 1, 3, and 10 ng · kg-1 · min-1, mean PAI-1 levels increased sequentially from 14.7 ng/mL to 23.0, 26.8, and 33.5 ng/mL, a dose-response relation that, compared with controls, was highly significant (p<0.001). Among the hypertensive patients for whom a single 45-minute infusion of Ang II was given at a dose of 3 ng · kg-1 · min-1, PAI-1 levels increased from 23.7 to 37.7 ng/mL, whereas PAI-1 levels among control subjects infused with 5% dextrose decreased from 16.9 to 10.8 ng/mL (p=0.04). Finally, when compared with infusion of 5% dextrose solution, infusion of Ang II appeared to have little effect on circulating levels of t-PA antigen. ConclusionThese in vivo data suggest that infusion of Ang H results in a rapid increase in circulating levels of PAI-1, a finding that may help to explain clinical observations linking the renin-angiotensin system and thrombotic risk. (Circulation 1993;87:1969-1973)

RANDOMISED CONTROLLED TRIAL OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR VERSUS UROKINASE IN THE TREATMENT OF ACUTE PULMONARY EMBOLISM

The effect of intravenous recombinant human tissue-type plasminogen activator (rt-PA) was compared with that of urokinase in 45 patients with angiographically documented pulmonary embolism (PE) in a randomised controlled trial. The two principal end-points were clot lysis at 2 h, as assessed by angiography, and pulmonary reperfusion at 24 h, as assessed by perfusion lung scanning. All patients received the full dose of rt-PA but urokinase infusions were terminated prematurely (on average after 18 h) in 9 patients because of allergy in 1 and uncontrollable bleeding in 8. By 2 h, 82% of rt-PA-treated patients showed clot lysis, compared with 48% of urokinase-treated patients (p = 0.008; 95% CI for the difference = 10-58%). Improvement in lung scan reperfusion at 24 h was identical in the two treatment groups. The reduction in fibrinogen did not differ significantly between the rt-PA and urokinase groups (45% vs 39% at 2 h and 34% vs 40% at 24 h). The results indicate that in the dose regimens employed, rt-PA acts more rapidly and is safer than urokinase in the treatment of acute PE.

Left ventricular remodeling in the year after first anterior myocardial infarction: A quantitative analysis of contractile segment lengths and ventricular shape

Infarct expansion after myocardial infarction results in early ventricular enlargement and distortion of ventricular geometry. To characterize the components of late volume enlargement, biplane left ventriculography was performed in 52 patients 3 weeks and 1 year after a first anterior myocardial infarction. Biplane diastolic circumference and contractile and noncontractile segment lengths were measured. Global geometry was evaluated by using a sphericity index (angiographic volume of the ventricle divided by the volume of a sphere with the same circumference). Regional geometry was assessed by measurement of endocardial curvature, an important determinant of wall tension. End-diastolic volume was enlarged at baseline and increased at 1 year (230 +/- 42 to 244 +/- 55 ml, p = 0.01) as a result of increases in contractile segment length (34 +/- 5 to 37 +/- 5 cm, p less than 0.001) and sphericity index (0.74 +/- 0.07 to 0.76 +/- 0.08, p less than 0.001), whereas the noncontractile segment length decreased (15 +/- 6 to 12 +/- 6 cm, p less than 0.005). Curvature analysis revealed a flattening of presumably high tension concavity at the anterobasal (-6.0 +/- 4.0 to -4.5 +/- 3.7, p less than 0.01) and inferior (-4.5 +/- 2.0 to -3.6 +/- 2.1, p less than 0.005) margins of the infarct and less bulging of the anterior wall (9.4 +/- 2.5 to 8.2 +/- 2.3, p less than 0.001). Patients selected for late enlargement (diastolic volume increase greater than 20 ml, n = 19) had an increase in sphericity (0.75 +/- 0.05 to 0.80 +/- 0.08, p less than 0.005) and in diastolic circumference (54 +/- 3 to 56 +/- 4 cm, p less than 0.001) secondary to elongation of the contractile segment (32 +/- 4 to 36 +/- 4 cm, p = 0.001) at 1 year. Thus, late ventricular enlargement after anterior infarction results from an increase in contractile segment length and a change in ventricular geometry and is not a result of progressive infarct expansion. In the group of patients at high risk for late ventricular enlargement because of persistent occlusion of the infarct-related vessel, captopril therapy attenuated late volume enlargement by preventing these changes in contractile segment length and chamber geometry.

Effects of left ventricular shape and captopril therapy on exercise capacity after anterior wall acute myocardial infarction

The importance of left ventricular (LV) shape in determining exercise capacity was assessed in 40 male patients with LV dysfunction after anterior acute myocardial infarction (AMI). Because captopril therapy is known to improve exercise capacity in this patient population, the potential interaction between LV shape and captopril therapy was also evaluated. Patients underwent cardiac catheterization 2 to 4 weeks after AMI followed by randomization to receive placebo or captopril. LV shape was defined from biplane ventriculography by a sphericity index (volume observed/volume of sphere using long axis as diameter). Quarterly clinical assessments and maximal exercise testing were performed. A cumulative heart failure score, specific activity scale and average exercise time for the year were calculated. A greater shape distortion (increasing sphericity index) was associated with increased LV volumes, decreased ejection fraction and a larger abnormally contracting segment. Sphericity index was the only independent predictor of average exercise duration in the placebo group. Placebo-treated patients in the tercile with the most spherical ventricles had not only the lowest exercise capacity (p less than 0.01), but also accumulated the highest heart failure (p less than 0.05) and specific activity scale (p less than 0.05) scores. Captopril-treated patients with the same baseline distortion of LV shape did not manifest these shape-dependent objective and subjective measures of reduced functional capacity.

ACUTE PULMONARY EMBOLISM TREATED WITH TISSUE PLASMINOGEN ACTIVATOR

Recombinant human tissue-type plasminogen activator (rt-PA) was given via a peripheral vein to 36 patients with angiographically documented pulmonary embolism. The regimen was 50 mg/2 h followed by repeat angiography and, if necessary, an additional 40 mg/4 h. By 6 h, 34 of 36 patients had angiographic evidence of clot lysis, slight in 4, moderate in 6, and marked in 24. The quantitative score improved 21% by 2 h and 49% by 6 h. Fibrinogen decreased 30% from baseline at 2 h and 38% from baseline at 6 h. 2 patients had major complications: in one, bleeding from a pelvic tumour required surgery; in the other, who had had coronary artery bypass surgery eight days earlier, pericardial tamponade developed. These initial results in selected patients make a case for expanded investigational use of peripheral intravenous rt-PA in pulmonary embolism.

Frequency of hypercholesterolemia after cardiac transplantation

Cardiac transplant patients are prone to accelerated coronary atherosclerosis. The mechanism by which this process occurs is not yet known, although immunologically mediated arterial injury is thought to play a primary role in its pathogenesis. Despite immunosuppressive potency, patients treated with cyclosporin A remain at significant risk for the development of accelerated atherosclerosis. It is hypothesized that cyclosporin As hepatotoxic effects might contribute to the atherosclerotic process by impairing low density lipoprotein hepatic clearance in transplant patients, which would be reflected in a more atherogenic lipoprotein profile. To test this hypothesis, serum cholesterol levels were analyzed after transplantation. Significant and progressive increases in total cholesterol and in the total-to-high density lipoprotein cholesterol ratio were found. This atherogenic lipoprotein profile may contribute to accelerated atherosclerosis in cardiac transplant patients treated with cyclosporin A.

Synergistic disaggregation of platelets by tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin.

Endothelial cells produce at least three substances that can attenuate the platelet aggregation response: tissue-type plasminogen activator; the platelet inhibitory prostaglandins I2 and E,; and endothelium-derived relaxing factor, one form of which exhibits properties of nitric oxide. Since platelet aggregates formed in vivo are involved in the initiation of many clinically important occlusive vascular syndromes, we tested the hypothesis that these endothelial products act synergistically to disperse platelet aggregates. Our data reveal that tissue-type plasminogen activator, prostaglandin E, and nitroglycerin (an organic nitrate activator of guanylate cyclase analogous to endothelium-derived relaxing factor) act synergistically to disaggregate platelets and do so in part by modulation of platelet cyclic nucleotides. These data suggest a potential mechanism by which the endothelium protects against the formation of platelet aggregates in vivo and offer a potential strategy for improving the efficacy of thrombolytic therapy.