Long-term Angiotensin-converting Enzyme Inhibitor Therapy Research Articles

Effects of combined statin and ACE inhibitor therapy on endothelial function and blood pressure in essential hypertension - a randomised double-blind, placebo controlled crossover study

Background:The aim of this study was to compare the influence of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on endothelial function and blood pressure in patients with essential hypertension on long-term angiotensin-converting enzyme inhibitor therapy.Method:The study was designed as a prospective, double-blind, randomised, placebo controlled, crossover clinical trial. Twenty patients with essential hypertension were treated with an angiotensin-converting enzyme inhibitor; the control group included 10 healthy subjects. Hypertensive patients received in random order 80 mg of fluvastatin daily or placebo for 6 weeks. The following parameters were assessed at baseline and after each treatment period: serum lipids, flow-mediated vasodilation, activity of von Willebrand factor, concentration of vascular endothelial growth factor, C-reactive protein and 24-hour blood pressure profile.Results:Hypertensive patients did not differ from healthy subjects with respect to age, body mass and biochemical parameters, with the exception of C-reactive protein, which was higher in hypertensive patients (P=0.02). After statin therapy, low-density lipoprotein cholesterol (P<0.0001), C-reactive protein (P=0.03), von Willebrand factor (P=0.03) and vascular endothelial growth factor (P<0.01) decreased and flow-mediated vasodilation improved (P<0.001). Statins had no significant effect on blood pressure.Conclusions:Statins added to angiotensin-converting enzyme inhibitors may improve endothelial function and ameliorate inflammation independently of blood pressure.

Prevention of dementia by ACE inhibitors and angiotensin receptor blockers - potential but not proven

Dementia currently exacts a substantial economic burden on societies, health and social care systems and carers in addition to the devastating personal and emotional cost to patients and families (1,2). This burden is predicted to increase substantially in the coming decades and is the major public health issue of this century (1). Currently available therapies are symptomatic only (3), with little or no prospect of disease-modifying treatments entering routine clinical use in the short to medium term. Strategies to prevent or delay the onset of dementia or retard its' progression are, therefore, urgently required and will be of extreme importance to individuals and societies. Currently available medications that could achieve these goals would have many advantages ― potential for immediate use; established safety profile; familiarity to clinicians; relatively low cost giving favourable cost-effectiveness breakdown.

Low-dose spironolactone, added to long-term ACE inhibitor therapy, reduces blood pressure and urinary albumin excretion in obese patients with hypertensive target organ damage

For some hypertensive patients, conventional blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers does not adequately protect against target organ damage. This may be particularly true for hypertensive patients with obesity, a condition often associated with elevated aldosterone levels. We conducted a pre-post study of fixed, low-dose spironolactone (12.5 mg/d), added to chronic ACE inhibitor-based antihypertension regimens, in obese subjects with essential hypertension and preexistent target organ damage. Outcomes of interest were changes in blood pressure (office, 24-h, and nocturnal), urinary albumin excretion, and potassium. 21 subjects with mean age 57.3 +/- 7.1 years, BMI 32.4 +/- 3.4 kg/m2 and 12.0 +/- 7.0 years of antihypertensive therapy were enrolled. The mean aldosterone level before spironolactone treatment was 10.1 +/- 7.3 ng/dl, and over 40% of subjects had baseline levels greater than mean population levels. During 4 weeks of low-dose spironolactone, mean office (110.6 +/- 7.8 to 105.0 +/- 8.1 mmHg, p = 0.004), 24-hour ambulatory (100.6 +/- 9.4 to 95.5 +/- 7.1 mmHg, p = 0.03) and nocturnal (95.3 +/- 11.5 to 87.5 +/- 8.2, p = 0.004) blood pressures all declined significantly. Log urine albumin : creatinine ratios also significantly dropped during spironolactone treatment (p = 0.002); in multivariate analysis, this decline did not appear to be due to changes in blood pressure but was influenced by concomitant changes in estimated glomerular filtration rate. Both the reductions in blood pressure and albumin excretion reversed after withdrawal of spironolactone. Serum potassium levels were essentially unchanged by low-dose spironolactone (p = 0.9). A fixed, low-dose of spironolactone, added to chronic ACE inhibitor therapy, reduced blood pressure and urinary albumin excretion in obese subjects with hypertension and preexistent target organ damage. A relative hyperaldosteronism due to aldosterone escape and/or obesity may explain the beneficial effects of spironolactone therapy in this study.

A Translational Approach to Hypertensive Heart Disease

The spectrum of the cardiac complications of arterial hypertension includes heart failure (HF), sudden death, and cardiac dysrhythmias, as well as the exacerbation of coincidental diseases (ie, atherosclerosis and chronic renal disease).1 However, knowledge of the cardiac impact of chronic elevation of arterial pressure has so evolved that hypertensive heart disease (HHD) may be thought as those consequences derived from left ventricular (LV) responses to fundamental disease mechanisms triggered by mechanical overload and neurohumoral stimuli.2 For instance, the long-held views are that LV hypertrophy (LVH), as the result of cardiomyocyte growth in response to pressure overload, serves to restore heart muscle economy back to normal and to preserve LV function.3 However, a number of alterations of the cardiomyocyte and the noncardiomyocyte components of the myocardium (including apoptosis, fibrosis, and changes in the microcirculation) also develop in HHD that lead to pathological myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle.2 These alterations may explain the overall risk of LVH and its associated cardiac and noncardiac complications in hypertensive patients.4 Although LVH may be detected early and accurately in hypertensive patients by electrocardiography and echocardiography, newer cardiac imaging methods and the monitoring of several circulating biomarkers hold promise as noninvasive tools for the diagnosis of myocardial remodeling. Numerous clinical studies have shown that effective long-term antihypertensive treatment may be associated with a decreased LV mass (LVM), which has been attributed to diminished risk. However, no large study (or meta-analysis) has demonstrated that diminished risk from the contemporary reduction of arterial pressure by virtue of its a priori design. Therefore, because overall risk remains unacceptably high, especially from HF, new therapeutic strategies aimed not only to decrease arterial pressure and LVM but also to repair and even prevent myocardial remodeling …

Aldosterone antagonists: Silver bullet or just sodium excretion and potassium retention?

ACE inhibitors or AT(1) antagonists are powerful therapeutic strategies to slow the progression of renal disease. However, they provide only imperfect protection since they cannot always prevent end-stage renal failure. Innovative approaches are needed to keep patients with chronic kidney disease off dialysis. Blockade of the aldosterone pathway may prove to be such a beneficial therapeutic concept.

Aldosterone Antagonism in Chronic Kidney Disease

Angiotensin-converting enzyme (ACE) inhibitors are potent members of the arsenal to treat chronic kidney disease (CKD). By reducing blood pressure (BP) and disproportionately decreasing intraglomerular pressure, this class of drugs also reduces proteinuria and slows progression of CKD (1,2). Given the high prevalence of cardiovascular disease in this population, it is noteworthy that ACE inhibitors also decrease the incidence of stroke, myocardial infarction (MI), and cardiovascular mortality in patients who are at high cardiovascular risk (3). More recently, data reporting similar benefits of angiotensin receptor blockers (ARB) support their use in the treatment of CKD as well, especially in individuals with type 2 diabetes (4). Furthermore, one sizable study suggested that the combination of an ACE inhibitor and ARB may be more effective than either agent alone (5). Parving and colleagues (6) called attention to the effects of high-dose ARB therapy, up to three times the recommended dose, as an additional means of effectively interrupting the renin-angiotensin-aldosterone system (RAAS). By logical extension, further blockade of the RAAS by direct antagonism of aldosterone also may prove beneficial. Indeed, aldosterone seems to be a potent effector of renal injury (7–9). In the rare cases of primary aldosteronism and its functional analogue, the even more rare Liddle’s syndrome, the observed renal injury probably is independent of the more proximal elements of the RAAS (10,11). Animal models provide an expeditious tool for assessing pathophysiologic change and the efficacy of intervention. The classic model of primary aldosteronism, the mineralocorticoid–nephrectomy–high-salt model of hypertension, develops systemic and glomerular capillary hypertension and sustains renal damage (12). In the remnant kidney model of CKD, ACE inhibitors and ARB attenuate renal injury (13). However, this protection, which is associated with suppression of aldosterone secretion, is abrogated by exogenous aldosterone infusion with return of …

Angiotensin-converting Enzyme Inhibitor-induced Angioedema following Carotid Endarterectomy Misdiagnosed as Cervical Hematoma

Angioedema is a localized swelling of sudden onset, often associated with angiotensin-converting enzyme (ACE) inhibitor use, that most commonly occurs in the face and neck. We present the case of a patient on long-term ACE inhibitor therapy for hypertension, who developed postoperative angioedema after carotid endarterectomy (CEA). The patient was initially misdiagnosed with an expanding cervical hematoma and underwent a surgical wound reexploration. Angioedema is a rare cause of neck swelling and upper airway distress occurring after CEA in patients treated with ACE inhibitors and should be considered in the differential diagnosis.

Long-Term Angiotensin-Converting Enzyme Inhibitor Perindopril Therapy Improves Cerebral Perfusion Reserve in Patients With Previous Minor Stroke

Angiotensin-converting enzyme (ACE) inhibitor-based therapy reduces the recurrence of stroke. The present study assessed the effects of long-term ACE inhibitor therapy on cerebral circulation in patients with previous minor stroke. After a run-in period, 19 patients were randomized to ACE inhibitor therapy (n=9; 4 mg of perindopril daily; mean age, 64+/-8 years; mean systolic/diastolic blood pressure [BP]+/-SD, 133+/-12/77+/-9 mm Hg) or placebo therapy (n=10; mean age, 66+/-9 years; mean BP, 139+/-10/78+/-8 mm Hg). Cerebral blood flow (CBF) was measured during hypercapnia, normocapnia, and hypocapnia using a positron emission tomography with H2(15)O at entry into the study and after 3 to 12 months. Cerebral perfusion reserve (CPR) was defined as percent CBF response to a 1 mm Hg change in arterial partial pressure of CO2 between hypercapnia and hypocapnia. Systolic/diastolic BP and CBF during normocapnia showed no significant changes between entry and completion of the trial in the perindopril and placebo groups. Mean value of CPR showed a significant increase in the perindopril group (from 3.7+/-1.7%/mm Hg to 4.8+/-1.7%/mm Hg; P<0.05) but not in the placebo group (from 4.1+/-0.8%/mm Hg to 4.2+/-0.6%/mm Hg; NS). Statistical parametric mapping analysis also showed global and significant increase (P<0.01, uncorrected) in CPR in the perindopril group alone. Long-term ACE inhibitor-based therapy had a beneficial effect on the cerebral circulation by improving CPR in patients with previous minor stroke.

P2803 NEP inhibition potentiates bradykinin-mediated vasodilatation in patients with heart failure on long-term angiotensin-converting enzyme inhibitor therapy

P2803 NEP inhibition potentiates bradykinin-mediated vasodilatation in patients with heart failure on long-term angiotensin-converting enzyme inhibitor therapy

Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy

ObjectivesThe aim of the present study was to assess the contribution of angiotensin-converting enzyme (ACE) inhibitor therapy to bradykinin-induced tissue-type plasminogen activator (t-PA) release in patients with heart failure (HF) secondary to ischemic heart disease. BackgroundBradykinin is a potent endothelial cell stimulant that causes vasodilatation and t-PA release. In large-scale clinical trials, ACE inhibitor therapy prevents ischemic events. MethodsNine patients with symptomatic HF were evaluated on two occasions: during and following seven-day withdrawal of long-term ACE inhibitor therapy. Forearm blood flow was measured using bilateral venous occlusion plethysmography. Intrabrachial bradykinin (30 to 300 pmol/min), substance P (2 to 8 pmol/min), and sodium nitroprusside (1 to 4 pmol/min) were infused, and venous blood samples were withdrawn from both forearms for estimation of fibrinolytic variables. ResultsOn both study days, bradykinin and substance P caused dose-dependent vasodilatation and release of t-PA from the infused forearm (p < 0.05 by analysis of variance [ANOVA]). Long-term ACE inhibitor therapy caused an increase in forearm vasodilatation (p < 0.05 by ANOVA) and t-PA release (p < 0.001 by ANOVA) during bradykinin, but not substance P, infusion. Maximal local plasma t-PA activity concentrations approached 100 IU/ml, and maximal forearm protein release was ∼4.5 μg/min. ConclusionsLong-term ACE inhibitor therapy augments bradykinin-induced peripheral vasodilatation and local t-PA release in patients with HF due to ischemic heart disease. Local plasma t-PA activity concentrations approached those seen during systemic thrombolytic therapy for acute myocardial infarction. This may contribute to the primary mechanism of the anti-ischemic effects associated with long-term ACE inhibitor therapy.

Effect of long-term therapy with ramipril in high-risk women

ObjectivesWe evaluated the effects of long-term therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on major cardiovascular (CV) outcomes in high-risk women. BackgroundThe effect of long-term ACE inhibitor therapy in high-risk women without heart failure and with preserved left ventricular (LV) systolic function has not been previously reported. MethodsThe Heart Outcomes Prevention Evaluation (HOPE) trial is a large, randomized clinical trial that evaluated ramipril and vitamin E in high-risk patients. We present the preplanned analysis of the effects of ramipril in women in the HOPE study. The study randomized 2,480 women aged ≥55 years with vascular disease or diabetes and at least one additional CV risk factor and without heart failure or a known low LV ejection fraction to ramipril (10 mg/day) or placebo. The primary outcome was the composite of myocardial infarction, stroke or CV death. Average follow-up was 4.5 years. ResultsTreatment with ramipril resulted in reduced primary end point rates (11.3% vs. 14.9% in the placebo arm; relative risk [RR] 0.77, 95% confidence interval [CI] 0.62 to 0.96; p = 0.019), fewer strokes (3.1% vs. 4.8%; RR 0.64, 95% CI 0.43 to 0.96; p = 0.029) and fewer CV deaths (4.2% vs. 6.9%; RR 0.62, 95% CI 0.44 to 0.88; p = 0.0068). There were trends toward reduced rates of myocardial infarction, heart failure and all-cause death. The beneficial effect of ramipril was similar in women and men. ConclusionsTreatment with ramipril reduces the CV risk in high-risk women without heart failure and with preserved LV systolic function.

Prolonged refractory hypotension in cardiac surgery after institution of cardiopulmonary bypass

HYPOTENSION WITH LOW systemic vascular resistance (SVR) is a recognized complication of induction of anesthesia and of cardiopulmonary bypass (CPB). The mechanism behind low SVR after institution of CPB is poorly understood, but preoperative use of angiotensin-converting enzyme (ACE) inhibitor therapy is a possible predisposing factor.1 The authors report a case of hypotension with failure to respond to 1-receptor agonists after the initiation of normothermic CPB in a patient receiving long-term ACE inhibitor therapy. Hypotension on initiation of CPB has not been reported previously as a potential side effect of ACE inhibitor therapy.

Angiotensin-converting enzyme inhibitor-related angioedema necessitating endotracheal intubation

We present the case of a patient who had tolerated angiotensin converting-enzyme inhibitor (ACEI) therapy for several months without adverse effects until he suddenly developed life-threatening angioedema of the upper airway, necessitating tracheal intubation. The patient had undergone heart transplantation two years prior to the episode of angioedema. Besides the condition of long-term ACEI therapy we identified three possible triggers for the development of angioedema: consumption of alcoholic beverages, acute pneumonia and long-term use of cyclosporin A. The patient responded slowly to conventional pharmacologic therapy, could be extubated after seven days, and left the hospital after 34 days.

Effects of Long-Term Enalapril and Losartan Therapy of Hypertension on Cardiovascular Aldosterone

Background: Plasma aldosterone escape is found during long-term angiotensin-converting enzyme inhibitor therapy. Evidence for aldosterone production in cardiovascular tissues raised the question of whether or not aldosterone escape occurs in these tissues. Method: Spontaneously hypertensive rats were treated with enalapril (20 mg/kg/day) and losartan (50 mg/kg/day) for 20 weeks; untreated spontaneously hypertensive and Wistar rats were used as positive and normal controls, respectively. Ex vivo mesenteric artery and heart perfusion, high-performance liquid chromatography, and radioimmunoassay for aldosterone were performed. Results: The results showed that enalapril failed to significantly inhibit aldosterone production in mesenteric artery, myocardium and plasma. Losartan significantly inhibited aldosterone production to that of Wistar rats in the mesenteric artery, myocardium and plasma. Conclusion: This study provides the first evidence that long-term angiotensin-converting enzyme inhibition therapy induces aldosterone escape in hypertensive cardiovascular tissues, and angiotensin II subtype 1 receptor antagonist does not induce aldosterone escape in mesenteric artery, myocardium and plasma of spontaneously hypertensive rats.

Acute Angioedema Associated with Long-Term Benazepril Therapy

Objective: To report a case of acute angioedema associated with long-term use of benazepril in an elderly patient. Case Summary: A 78-year-old white woman with no past history of angioedema presented to the emergency department in respiratory distress. The patient failed to improve after receiving intravenous methylprednisolone, diphenhydramine, and famotidine. Due to pending airway compromise, the patient required emergency tracheostomy. Based on her presentation and medical history, we attributed the angioedema to long-term benazepril use. Discussion: Angiotensin-Converting enzyme (ACE) inhibitors are known to be associated with angioedema. Most cases of angioedema occur within the first week of therapy. The association of acute onset of angioedema early in the course of ACE inhibitor therapy is well described in published reports. However, angioedema associated with long-term ACE inhibitor therapy has rarely been reported. Conclusions: ACE inhibitor-induced angioedema occurring late in therapy is not well understood and has been infrequently reported in published articles. Aggressive intervention is often needed in severe cases of angioedema, which may compromise airway integrity.

Acute and long-term effects of the angiotensin-converting enzyme inhibitor, enalapril, on adrenergic activity and sensitivity during exercise in patients with left ventricular systolic dysfunction

Patients with heart failure and left ventricular systolic dysfunction exhibit increased adrenergic activity but blunted adrenergic responsiveness. We studied patients enrolled in the Studies of Left Ventricular Dysfunction, examining exercise responses of heart rate (HR) and plasma norepinephrine (PNE). Eighty-seven patients were studied before randomization; 65 of these were examined 1 year after randomization to placebo or enalapril. Compared with prevention trial (asymptomatic) patients, patients in the treatment trial (symptomatic) had higher resting HR and PNE levels and less increase in HR with a greater increase in PNE with exercise. Acute administration of enalapril increased the resting HR in patients in the prevention trial only but had no significant effect on PNE. After 1 year of therapy, patients in the prevention trial exhibited no change. Within the treatment trial, the placebo group displayed both a higher peak PNE and increase in PNE with exercise than did the enalapril group, whose HR response was maintained in spite of a reduction of exercise PNE. We conclude that (1) compared with asymptomatic patients, symptomatic patients with reduced left ventricular ejection fraction manifest greater resting and exercise adrenergic activity, with blunted HR response; and (2) in symptomatic patients, 1 year of enalapril treatment effected an augmented HR response to adrenergic stimulation, supporting an interaction between the renin/angiotensin and adrenergic nervous systems. Normalization of adrenergic tone and response likely contributes to the benefits of long-term angiotensin-converting enzyme inhibitor therapy. (Am Heart J 1997;134: 37-43.)

Ongoing clinical trials of angiotensin-converting enzyme inhibitors for treatment of coronary artery disease in patients with preserved left ventricular function

At present there is considerable activity in the area of prevention of atherosclerosis-related events using angiotensin-converting enzyme inhibitors. Large trials have demonstrated significant reduction in cardiovascular morbidity and mortality with long-term use of angiotensin-converting enzyme inhibitors in patients with left ventricular dysfunction, heart failure or acute myocardial infarction. Reductions in acute ischemic events (e.g., myocardial infarction, unstable angina and need for early revascularization) were independent of ejection fraction and were greater than would be expected from the small reduction in blood pressure that occurred, suggesting that other patients with coronary artery disease may benefit from angiotensin-converting enzyme inhibitor therapy. This hypothesis is being tested in multiple double-blind, randomized, controlled clinical trials with durations of follow-up of 3 to 5 years that will involve approximately 30,000 patients. The trials vary with respect to patient population (e.g., normotensive vs. hypertensive, normolipidemic vs. hyperlipidemic, with vs. without diabetes mellitus), angiotensin-converting enzyme inhibitor used and outcome measures. When available, the results of these clinical trials could have very important implications for the role of long-term angiotensin-converting enzyme inhibitor therapy for preventing or delaying the development of atherosclerosis-related ischemic events.

Brain natriuretic peptide as a marker for hypertensive left ventricular hypertrophy: Changes during 1-year antihypertensive therapy with angiotensin-converting enzyme inhibitor

Secretion of brain natriuretic peptide (BNP), a cardiac hormone, is accelerated via hypertrophied ventricles in experimental hypertension. The present study examined whether regression of left ventricular (LV) hypertrophy by long-term treatment with an angiotensin-converting enzyme inhibitor (ACEI) affects plasma BNP concentration in patients with essential hypertension. Thirty-one hypertensive patients with LV hypertrophy were treated with ACEI (16 with enalapril; 15 with lisinopril) for 1 year. Serial changes were recorded in LV mass index, LV systolic function, and plasma concentrations of BNP and atrial natriuretic peptide (ANP). ACEI therapy significantly reduced LV mass index at 6 months, and more so at 1 year. Septal and posterior wall thicknesses were also reduced. Plasma BNP and ANP were markedly elevated at study entry, but only BNP levels correlated with LV mass index. Both peptide levels declined after 6 months, and this decline was enhanced at 1 year. There was a close relation between BNP decline and LV mass index reduction overall and with enalapril and lisinopril separately. Changes in ANP and in LV mass index were not related. Long-term ACEI therapy can reduce elevated plasma BNP. In this study, changes in BNP reflected the magnitude of regression of LVH. Plasma BNP may be a useful marker for LVH during antihypertensive therapy in patients with essential hypertension and LVH.

Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure

Objectives. The objective of this investigation was to evaluate the changes in parasympathetic tone associated with long-term angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure.Background. Angiotensin-converting enzyme inhibitors provide hemodynamic and symptomatic benefit and are associated with improved survivel in patients with congestive heart failure. Angiotensin II, whose production is ultimately inhibited by these agents, exerts significant regulatory influence on a variety of target organs including the central and peripheral nervous systems. Accordingly, it would be anticipated that angiotensin-converting enzyme inhibitors would significantly alter the autonomic imbalance characteristic of patients with congestive heart failure and that this influence over neural mechanisms of cardiovascular control may significantly contribute to the hemodynamic benefit and improved survival associated with angiotensin-converting enzyme inhibitor therapy.Methods. In the current investigation, changes in autonomic tone associated with long-term administration of an angiotensin-converting enzyme inhibitor were measured using spectral analysis of heart rate variability in 13 patients with congestive heart failure who were enrolled in a double-blind randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor zofenopril. Both placebo and treatment groups were balanced at baseline study in terms of functional class, ventricular performance and autonomic tone.Results. After 12 weeks of therapy with placebo, there was no change in total heart rate variability, parasympathetically governed high frequency heart rate variability or sympathetically influenced low frequency heart rate variability. In contrast, therapy with zofenopril was associated with a 50% increase in total heart rate variability (p = 0.09) and a significant (p = 0.03) twofold increase in high frequency heart rate variability, indicating a significant augmentation of parasympathetic tone.Conclusions. These results demonstrate that long-term treatment of patients having congestive heart failure with an angiotensin-converting enzyme inhibitor is associated with a restoration of autonomic balance, which derives in part from a sustained augmentation of parasympathetic tone. Such augmentation of vagal tone is known to be protective against malignant ventricular arrhythmias in patients with ischemic heart disease and therefore may have similar benefit in the setting of ventricular failure, thus contributing to the improved survival associated with angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure.