Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
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Angiotensin converting enzyme inhibitors (ACE-I) are widely used in patients with severe heart failure on the basis of the significant improvement in mortality in the CONSENSUS-I trial in patients with Class IV heart failure. Recent data from the 5-year clinical trial Studies of Left Ventricular Dysfunction (SOLVD) suggest a role for ACE-I in patients with mild to moderate heart failure as well as in those with asymptomatic left ventricular dysfunction. The SOLVD treatment trial in patients with a left ventricular ejection fraction (LVEF) less than or equal to 35% and treated for heart failure with conventional therapy including digitalis, diuretics, or vasodilators demonstrated that the addition of enalapril resulted in a significant reduction in mortality from heart failure as well as in the combined end point of death plus hospitalization from heart failure. These data suggest that ACE-I should be the base of therapy for patients with mild to moderate heart failure, as well as for those with severe heart failure.
Clin Cardiol 1992 Sep
PMID:Congestive heart failure: new therapeutic strategies. 139 11

Congestive heart failure is a syndrome common in the United States, especially in elderly patients. The most common etiology is coronary artery disease. A number of general factors contribute to the heart failure syndrome, including loss of muscle, decreased myocardial contractility, pressure or volume overload, or restricted filling. All of these factors may play a role in a given patient as, for example, with coronary artery disease. Although systolic dysfunction with a reduced ejection fraction is the most common heart failure syndrome, up to 40% of patients may have a relatively preserved ejection fraction with diastolic dysfunction. As the heart begins to fail, a number of compensatory mechanisms are activated. These include increased heart rate, the Frank-Starling mechanism, increased catecholamines, activation of the renin-angiotensin system, and release of atrial natriuretic peptides. Although these mechanisms are initially helpful to the cardiovascular system, they frequently overshoot, initiating a vicious cycle. For example, with a decrease in cardiac output, there is a reflex increase in systemic vascular resistance in order to maintain perfusion pressure. This increase in resistance, however, acts as a load on the left ventricle and further reduces cardiac output. The best evidence for the existence of this vicious cycle is the beneficial change in hemodynamics produced by vasodilator drugs and the ACE inhibitors. Thus, an understanding of pathophysiology allows for the selection of rational therapy. An unresolved problem in heart failure patients is how best to reduce the high incidence of sudden death, which is one of the major challenges for the future.
Clin Cardiol 1992 Sep
PMID:Pathophysiology of congestive heart failure. 139 15

Recent concepts about post-infarction left ventricular remodeling, which is the basis for heart failure in these patients, as well as its prevention by ACE inhibitors are briefly summarized. Those data were the rationale for the SAVE trial. The most important initial aspects of this trial (general objective, pre-specified endpoints, inclusion and exclusion criteria, etc.) are then described as well as the basal characteristics of the respective cohort. The most important results of the SAVE trial, now in press, are subsequently presented. Several clinical guidelines, derived from these results, are then suggested. Finally, some new questions, both clinical and pathophysiological, and originated by the results from the SAVE results, are commented.
Rev Port Cardiol 1992 Sep
PMID:[The SAVE trial: rational basis, results, and reflections]. 147 63

In a retrospective study we analyse two populations of aged patients in congestive heart failure, one treated with ACE inhibitors other not and the other with conventional therapy. Both populations received the same medication (diuretics and digitalis) and are equivalent in age, sex distribution, NYHA functional class and echocardiographic left ventricular parameters. Comparing the mortality of the two populations at the first, second and third year of follow-up, a statistically significant reduction in mortality was found on the ACE inhibitors treated population, at the first year. However, this reduction did not reach statistical significance at second and third years. The results are similar to trials in which the effects of ACE inhibitors are studied on general populations in heart failure.
Rev Port Cardiol 1992 Jun
PMID:[Effect of converting enzyme inhibitors in cardiac insufficiency mortality in the elderly]. 150 88

Age-related changes (e.g., decrease in plasma renin activity and total body potassium, increase in plasma catecholamines, volume depletion) need to be taken into account when selecting an antihypertensive agent for the elderly patient. A number of large scale clinical trials (e.g., Systolic Hypertension in the Elderly Program, Veterans Administration Cooperative Study, European Working Party on High Blood Pressure in the Elderly) have demonstrated that antihypertensive therapy with diuretics substantially reduced cardiovascular mortality and stroke incidence. However, since diuretics, even potassium-sparing agents, may induce hypokalemia, newer antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors and calcium antagonists) may also be appropriate as first-line monotherapy for this patient population. ACE inhibitors are effective antihypertensive agents and are associated with a lower rate of adverse effects than diuretics, beta blockers, and centrally acting agents. Nevertheless, periodic monitoring of serum potassium, creatinine levels, and renal function is advisable. An important feature of calcium antagonists is that they lower blood pressure with no negative effect on serum lipids or glucose metabolism. Typically, they have few side effects, peripheral edema being the most commonly reported. A recent double-blind randomized study comparing a new sustained release nifedipine formulation and the ACE inhibitor lisinopril found the 2 drugs equivalent in efficacy with no differences in the rate of adverse events.
Am J Cardiol 1992 Apr 30
PMID:Hypertension in the elderly with a special focus on treatment with angiotensin-converting enzyme inhibitors and calcium antagonists. 157 76

Early in the acute phase of myocardial infarction the phenomenon of expansion may occur, with regional thinning and dilatation of necrotic region. This complication may be detected by echocardiography since the first hours of infarction. During the two subsequent weeks, an additional increase of left ventricular volume may occur, due to an increase of length of the infarcted segments and, as well, of the contractile segments which suffer a "volume overload hypertrophy". This is the phenomenon of remodeling. Finally during the first year post infarction, a progressive left ventricular dilatation may develop. This late dilatation seems to be due to an increase of perimeter of the contractile regions only. By the time this topographic changes have occurred, the left ventricle assumes a more spheric configuration. Left ventricular dilatation affects adversely cardiac function, with higher incidences of heart failure and death. Experimental and clinical studies show that, in selected patients, remodeling and ventricular dilatation may be attenuated by the administration of angiotensin-converting-enzyme inhibitors, with better indices of left ventricular function. Final results of several on-going multicenter studies are awaited for; they will allow a better definition of the role of ACE inhibitors on prevention and treatment of left ventricular dysfunction after myocardial infarction.
Rev Port Cardiol 1992 Mar
PMID:[Expansion of infarction, dilatation and ventricular remodelling. Therapeutic potential of angiotensin-converting enzyme inhibitors]. 161 Jun 13

Therapeutic approaches to the management of heart failure have traditionally focused on shortterm hemodynamic and symptomatic goals, but present evidence suggests that most therapeutic decisions have long-term consequences. Treatment may change the rate of disease progression, modify the need for additional therapy, influence the number of hospitalizations, and alter the risk of death. However, there may be little relation between a drug's short-term effect on cardiac function or cardiovascular symptoms and its long-term effect on survival. Some therapeutic interventions favorably influence the outcome of patients with heart failure, even though they exert negative inotropic effects; others adversely affect the outcome of patients, even though they markedly improve cardiac performance. This discordance might be explained if the most important predictor of response to a therapeutic intervention in heart failure were the effect of the pharmacologic agent on neurohormonal systems rather than on hemodynamic variables. In general, drugs that decrease the effects of the sympathetic nervous system (digitalis glycosides) and the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitors) reduce the risk of worsening heart failure. Conversely, drugs that potentiate the effects, or increase the activity, of the sympathetic nervous system (phosphodiesterase inhibitors) or the renin-angiotensin system (calcium antagonists) increase cardiovascular morbidity and mortality. These observations suggest that physicians should no longer focus on short-term hemodynamic or symptomatic goals in the treatment of heart failure but, instead, should manage patients to improve both the quality and quantity of life.
Am J Cardiol 1992 Jun 04
PMID:Long-term strategies in the management of heart failure: looking beyond ventricular function and symptoms. 162 88

Although digitalis glycosides were introduced in the treatment of cardiac maladies greater than 200 years ago, controversy persists regarding the precise role of digoxin in any multidrug approach to the treatment of congestive heart failure (CHF). Despite its widespread use for more than 2 centuries, only recently have double-blind, randomized, placebo-controlled trials of digoxin therapy been conducted in patients with moderate CHF and sinus rhythm. These trials demonstrate that digoxin is superior to placebo in improving left ventricular (LV) ejection fraction, increasing exercise capacity, and preventing CHF worsening. Digoxin produces benefits similar to those seen with angiotensin converting enzyme (ACE) inhibitors with regard to clinical compensation and improvement in LV function. However, improved survival is demonstrated only in response to ACE inhibitors. The recently completed RADIANCE study addresses the value of combining digoxin with ACE inhibitor therapy in patients with mild-to-moderate CHF. Because increased mortality has been reported with the newer oral inotropic agents, it currently appears that digoxin is the only oral inotropic agent useful in clinical practice in the treatment of CHF. However, the effects of digoxin on mortality in patients with CHF remain unknown. In the large, double-blind, randomized trial conducted by the National Heart, Lung, and Blood Institute, the effects of digoxin on mortality in patients with CHF and already being treated with ACE inhibitors are currently being evaluated. Presently, based on the results of placebo-controlled studies, it appears that digoxin, alone or in combination with ACE inhibitors, is beneficial in patients with any signs or symptoms of CHF due to systolic LV dysfunction.
Am J Cardiol 1992 Jun 04
PMID:Review of randomized trials of digoxin therapy in patients with chronic heart failure. 162 92

We evaluated effects of inhibitors of angiotensin converting enzyme (ACE) on growth responses in isolated rat carotid arteries (CA) during continuous exposure to exogenous growth factors in vitro. In freshly isolated CA of adult Wistar-Kyoto rats (WKY) that had been denuded of endothelium, angiotensin-I (AT-I) and angiotensin-II (AT-II) induced concentration dependent contractions (1 nM to 1 microM). Captopril (100 microM) and lisinopril (10 microM) did not affect responses to AT-II, but increased the ED50 for AT-I 50-fold. To study the effects of ACE inhibition on arterial growth responses in vitro, we measured nuclear incorporation of the thymidine analogue, 5-bromo-2'-deoxyuridine (BrdUrd), during organoid culture of isolated CA segments in continuous presence of 20% calf serum. During 4 days of organoid culture 7-10% of the medial smooth muscle nuclei incorporated BrdUrd. During long-term culture (15 days) a new layer of cells developed at the adventitial border of the arterial segments. Continuous presence of captopril (10 microM to 100 microM) or lisinopril (1 microM to 10 microM) did not affect the extent of DNA synthesis in the media or in the newly formed cell layer. Unlike endothelin-1 (ET-1), exogenous AT-II did not stimulate DNA synthesis in isolated renal artery segments. These observations indicate the presence of ACE accessible to exogenous AT-I in arterial compartments other than the endothelium. Interference with this enzyme did not alter growth responses of the isolated arterial wall to serum. Since, in addition, exogenous AT-II did not stimulate intra-arterial DNA synthesis, effects of ACE-inhibitors on arterial growth responses in vivo are most likely due to an indirect effect.
Basic Res Cardiol 1991
PMID:Effects of angiotensin II and angiotensin converting enzyme inhibitors on contractile and growth responses in isolated carotid arteries of the rat. 164 65

We treated 48 patients with intravenous enalaprilat within 24 hours from the onset of acute myocardial infarction. Concomitant therapy included thrombolytic treatment (29), intravenous metoprolol (34), intravenous nitroglycerin (16) and intravenous furosemide (15). The first 40 patients included had systolic blood pressure at baseline greater than or equal to 110 mmHg. Intravenous bolus injections of 0.2-1.2 mg (mean 1.0 mg) enalaprilat in one hour were given to 20 patients and an intravenous infusion of 1 mg over two hours was administered to another 20 patients, as well as to a separate group of 8 patients with systolic blood pressure between 100-109 mmHg at baseline. The infusion was stopped in five cases when the systolic blood pressure fell below 100 and 90 mmHg, respectively, in the two infusion groups. No hypotensive reactions were symptomatic. Blood pressure decreased from a mean of 134/82, 131/79 and 106/72 mmHg to a minimum of 117/71, 118/73 and 97/63 mmHg, respectively, in the three groups. Almost complete suppression of plasma angiotensin converting enzyme activity was achieved within 30 minutes. No significant changes were found in plasma levels of angiotensin II, renin activity or atrial natriuretic peptide between baseline and 24 hours. Treatment was continued with oral enalapril 2.5-10 mg/day, which was generally well tolerated. We conclude that intravenous and oral enalapril added to conventional therapy in the early phase of acute myocardial infarction is well tolerated in selected patients, but should be carefully titrated.
Int J Cardiol 1991 Oct
PMID:Enalaprilat in acute myocardial infarction: tolerability and effects on the renin-angiotensin system. 165 99


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