ACE Inhibitors in Heart Failure: Prospects and Limitations

ACE inhibitors have been shown to be effective in reducing the morbidity and mortality of patients with left ventricular systolic dysfunction, but their application to clinical practice in this situation is still limited. In part, the failure to prescribe an ACE inhibitor to a patient with left ventricular systolic dysfunction is due to perceptions regarding their side effects, such as cough and renal dysfunction. Relatively few patients with left ventricular systolic dysfunction and a serum creatinine ≥2 mg/dl receive an ACE inhibitor in clinical practice. In this situation one should consider an agent such as fosinopril, which is metabolized by the liver as well as secreted by the kidney. In patients with moderate renal dysfunction, fosinopril has been well tolerated without an increase in serum creatinine. In patients who develope cough due to an ACE inhibitor, consideration should be given to an angiotensin II type 1 receptor blocking agent, such as losartan. The relative safety and efficacy of an ACE inhibitor compared with an angiotensin II type 1 receptor blocking agent is being explored in a prospective randomized trial (Evaluation of Losartan In The Elderly [ELITE]), as well as the safety and pharmacological effectiveness of adding an angiotensin II receptor antagonist to an ACE inhibitor (Randomized Angiotensin receptor antagonists–ACE-inhibitor Study [RAAS]). There may also be a role for the combination of an aldosterone receptor antagonists and an ACE inhibitor in patients with left ventricular systolic dysfunction. Once an ACE inhibitor is administered to a patient with left ventricular systolic dysfunction it should be continued indefinitely. ACE inhibitors may be of value not only in preventing the progression of heart failure but also in reversing endothelial dysfunction and preventing the development of atherosclerosis and its consequences, such as myocardial infarction.     

Comparison of supine and erect bicycle exercise electrocardiography in coronary heart disease: Accentuation of exercise-induced ischemic ST depression by supine posture

Exercise-induced electrocardiographic ST depression was compared during supine and erect graded bicycle exercise in 43 patients with chest pain but no prior myocardial infarct; all had ≥1 mm of ST depression during either erect or supine exercise; 16 had multivessel, 24 had 1-vessel and 3 had no coronary artery disease. Supine exercise used 4 minutes/stage and erect exercise used either 4 minutes or 3 minutes/stage with identical graded work loads for both postures. Chest pain occurred in 31 patients during erect and in 29 during supine exercise. ST depression was ≥1 mm in 28 patients during erect exercise and in all 43 during supine exercise (p <0.001); mean maximal ST depression was 1.3 ± 0.2 mm during erect and 2.6 ± 0.2 mm during supine exercise (p <0.001). Maximal work load was higher during erect than supine exercise (745 ± 32 versus 678 ± 32 kpm/min; p <0.001). The accentuation of ST depression by supine posture was not attributable to the changes in heart rate, rate-pressure product or mean blood pressure during supine versus erect exercise. In the 10 patients who had 2 erect bicycle tests using work load durations of 3 and 4 minutes, the maximal ST depression was not significantly different (erect 3 minutes 1.3 ± 0.5 mm and erect 4 minutes 1.4 ± 0.4 mm). In 7 patients who also had a maximal treadmill exercise test, the maximal ST depression was significantly greater during supine exercise (2.3 ± 0.4 mm) than during either an erect bicycle test (0.6 ± 0.4 mm) or treadmill exercise (0.7 ± 0.4 mm) (p <0.05). Supine posture should be considered as an important potentiator of exercise-induced myocardial ischemia whem comparing indicators such as electrocardiography, radionuclide ventriculography and thallium-201 myocardial perfusion imaging during exercise.     

Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet. QUIET Investigators. QUinapril Ischemic Event Trial

Angiotensin-converting enzyme inhibitors have proven to be of clinical benefit in congestive heart failure. Whether they also provide benefit to patients with coronary artery disease in the absence of congestive heart failure via an antiatherosclerotic mechanism is a question the QUinapril Ischemic Event Trial quantitative coronary angiography (QCA) study attempted to answer: 1,750 patients with normal left ventricular function who were undergoing coronary angiography and angioplasty were randomized to 20 mg/day of quinapril versus placebo and followed for 3 years for cardiac end points. A randomly selected subgroup of the total cohort underwent follow-up angiography. The primary QCA end point was the categorical designation of progression versus nonprogression, defined either by QCA or by a cardiac event in patients selected for the QCA trial who had no usable follow-up x-ray film. Secondary end points in patients with 2 angiograms were: new stenosis development, change in minimum lumen diameter index, and change in percent diameter stenosis index. There were 119 progressors among 243 placebo-treated patients (49%) and 111 progressors among 234 quinapril-treated patients (47%) (p = NS). There were 44 patients with new stenosis development in the placebo group (19%) and 50 (22%) in the quinapril group (p = NS). Change in minimum lumen diameter index was -0.21+/-0.03 mm in the placebo group and -0.18+/-0.03 mm in the quinapril group (p = NS). Finally, change in percent diameter stenosis index was +5.1+/-1.0 in the placebo group and +3.5+/-1.0 in the quinapril group (p = NS). Potential confounders of this trial are presented and discussed.     

Drosophila homolog of the murine Int-1 protooncogene.

We have isolated phage clones from Drosophila melanogaster genomic and cDNA libraries containing a sequence homologous to the murine Int-1 protooncogene. The Drosophila gene is represented by a single locus at position 28A1-2 on chromosome 2. The gene is expressed as a 2.9-kilobase-long polyadenylylated mRNA in embryo, larval, and pupal stages. It is hardly detectable in adult flies. The longest open reading frame of the cDNA clone corresponds to a protein 469 amino acids long. Alignment of the predicted amino acid sequences shows that the Drosophila protein is 86 amino acids longer than its murine counterpart. In spite of the difference in length, the two proteins are highly conserved with an overall sequence homology of 54%. Both Drosophila and murine Int-1 proteins begin with a hydrophobic leader sequence and contain cysteine residues and sites for glycosylation (four in the murine protein and one in the Drosophila protein) in conserved positions, suggesting that they play important functional roles.     

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.     

Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease

Acetylcholine causes endothelium-dependent dilation of normal arteries in most animal species. The effect of acetylcholine on normal human coronary arteries is controversial. Pathologic studies and epicardial echocardiography have shown that diffuse atherosclerosis is often present despite angiographic evidence of discrete coronary artery disease (CAD). Therefore, we postulated that acetylcholine would cause vasoconstriction of coronary arteries that are angiographically normal in patients with CAD. Coronary artery diameter, measured by automated quantification of digitized cineangiograms, was determined before and after the intracoronary infusion of 0.2 mM acetylcholine at 0.8-1.6 ml/min. The diameter of stenotic or irregular segments of six atherosclerotic coronary arteries decreased from 1.80 +/- 0.42 mm before acetylcholine to 1.26 +/- 0.46 mm after acetylcholine (p = 0.0025). Acetylcholine had a significantly different effect on the diameter of two groups of coronary arteries that are angiographically normal. Acetylcholine caused a 0.16 +/- 0.09-mm increase in the diameter of 14 normal coronary arteries in patients without CAD, whereas it caused a 0.26 +/- 0.12-mm decrease in the diameter of 14 normal coronary arteries in patients with CAD (p less than 0.01). Thus, the normal response to intracoronary acetylcholine is vasodilation, suggesting that endothelium-derived relaxing factor is released from normal human coronary endothelium. The vasoconstrictive effect of acetylcholine in the angiographically normal coronary arteries of patients with CAD suggests the presence of a diffuse abnormality of endothelial function.