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Many Fontan patients with and without systolic ventricular dysfunction are being treated with angiotensin-converting enzyme (ACE) inhibitors, despite its effectiveness remaining unclear. In the present study, we evaluated the short-term effect of enalapril on exercise capacity, vascular and ventricular function in pediatric Fontan patients with moderate-good systolic ventricular function. Fontan patients between 8 and 18 years with moderate-good systolic ventricular function and without previous ACE inhibitor treatment were included and were treated with enalapril for 3 months. During the first 2 weeks, the dosage was titrated according to systolic blood pressure (SBP). Exercise tests, ventricular function assessed by echocardiography, arterial stiffness measurements, and plasma levels of N-terminal pro-B-type natriuretic peptide assessed before and after a 3-month enalapril treatment period was compared. A total of 28 Fontan patients (median age 13.9 years, 6 to 15 years after Fontan operation) completed the study with a mean dosage of 0.3 ± 0.1 mg/kg/d. A total of 6 patients (21%) experienced a significant drop in SBP and 6 others (21%) experienced other adverse events. Enalapril treatment lowered the SBP (from 110 to 104 mmHg, p = 0.003) and levels of N-terminal pro-B-type natriuretic peptide (from 80 to 72 ng/L, p = 0.036). However, enalapril treatment did not improve exercise capacity, ventricular function, or arterial stiffness. In conclusion, short-term ACE inhibition has no beneficial effect in Fontan patients with moderate-good systolic ventricular function., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Angiotensin-converting enzyme inhibitors (ACEIs) are a mainstay of medical management in pediatric cardiology. However, there are no data defining how best to initiate and uptitrate the dose of these medications in children., Methods and Results: Retrospective chart review revealed only 24% of our pediatric cardiology inpatients were discharged on predefined optimal doses of ACEIs and few underwent further dose uptitration in the 8 weeks after hospital discharge. Therefore, 2 alternative protocols for initiation of captopril were compared in a prospective randomized clinical trial. A "rapid uptitration" protocol reached an optimal dose on day 3, whereas the alternative, "prolonged uptitration" protocol, reached an optimal dose on day 9. Forty-6 patients (54% male) were recruited to the trial, with a median age of 0.7 year (IQR 0.5-2.3 years). Captopril was initiated while in intensive care in 39% of patients and on the cardiology ward in 61%. There were no differences between the protocols in episodes of hypotension, symptomatic hypotension, or indices of renal function. Patients following the rapid protocol reached higher doses of captopril (0.93±0.24 versus 0.57±0.38 mg/kg per dose, P<0.0001) and were more likely to have achieved the predefined target (88% versus 43%, P=0.002) and optimal ACEI doses (80% versus 29%, P=0.001) before discharge., Conclusions: A protocol of rapid ACEI dose uptitration for infants and children with cardiovascular disease can be introduced safely, even in patients receiving intensive care therapy. Compared with standard clinical practice or with a more prolonged protocol, rapid ACEI dose uptitration achieves a higher dosage in this population with no evident disadvantages., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00742040., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Angiotensin-converting enzyme (ACE) inhibitors are widely used for the treatment of cardiovascular disease since they improve blood pressure control in patients with hypertension and prolong survival in patients with acute myocardial infarction, asymptomatic left ventricular dysfunction and congestive heart failure. Most of the information about the therapeutic role of ACE-inhibitors has been achieved during the last 20 years since the publication of some pivotal trials mostly involving the use of ACE-inhibitors like captopril and enalapril. In particular the treatment with enalapril has considerably improved the clinical outcome of patients with either mild-to-moderate (SOLVD studies) or severe (CONSENSUS trial) congestive heart failure. The benefit of ACE-inhibitors in patients with congestive heart failure has also involved a remarkable reduction in the rate of hospitalization, thus contributing to improve the pharmaco-economic approach to the disease. Most of the beneficial effect of ACE-inhibitors in clinical practice is dependent on their capacity of inhibiting the renin-angiotensin system, although some recent trials have supported a primary role for such drugs (in particular enalapril) in the prevention of atrial fibrillation. After more than 25 years from their discovery, ACE-inhibitors must be again considered among the first-line treatment in many patients with cardiovascular disease.

This paper reports the rationale for the cardiovascular protective effects of angiotensin-converting enzyme (ACE) inhibitors and reviews the overall results of recent randomized clinical trials. ACE-inhibitors prevent degradation of bradykinin, exert anti-ischemic action, inhibit thrombosis and platelet aggregation, are antiatherogenic, improve endothelial function and vessel remodeling, and have anti-inflammatory properties. Previous trials have shown that ACE-inhibitors reduce cardiovascular events in patients with heart failure or ventricular dysfunction. These findings have recently been extended to patients with lower risk profile, no evidence of heart failure and in secondary prevention using lipophilic ACE-inhibitors with high affinity for tissue ACE, i.e. those most likely to have high antiatherosclerotic efficacy. The central role of long-acting lipophilic ACE-inhibitors for cardiovascular protection has been clearly established and they should now be considered as a routine treatment for secondary prevention in the same way as aspirin, beta-blockers and statins.

Background: The evidence-based benefit/risk evaluation of therapeutic interventions in randomised clinical trials should include both the assessment of the benefits and of the adverse outcomes. There is ample evidence that ACE inhibitors improve the symptoms and prognosis of chronic heart failure (CHF) and ventricular dysfunction. However, there is little systematic information on the tolerability and adverse effects associated with their use in these conditions., Objective: To estimate the adverse events related to ACE inhibitor use in the treatment of CHF and ventricular dysfunction., Design and Methods: Description of adverse events in reports of randomised clinical trials of ACE inhibitors in CHF or ventricular dysfunction was examined, and a meta-analysis was performed. Trials were included if they were placebo- or standard treatment-controlled, and if the treatment duration was at least 8 weeks. Relative risks and their 95% CIs were estimated with a random effects model., Results: Only 22 (43%) of 51 original reports contained information on the number of withdrawals and their causes. Missing information from the remaining 29 trials was obtained from the authors. The weighted mean duration of treatment was 100.2 weeks. After excluding administrative reasons, heart failure, myocardial infarction and hypertension, the withdrawal rates attributed to adverse events were 13.8% and 9.4% for the ACE inhibitor and control groups, respectively (RR = 1.54 [95% CI 1.30-1.83]; weighted difference = 3.1 per 100 treated patients [95% CI 1.8-4.4]). Cough, hypotension, renal dysfunction, dizziness, hyperkalaemia, and impotence were all significantly more prevalent among patients treated with ACE inhibitors than among those in the control groups., Conclusions: Among patients with CHF or ventricular dysfunction enrolled in randomised clinical trials, treatment with an ACE inhibitor for an average of 2 years leads to an additional 3% of treatment withdrawals. In a significant proportion of the reports on these randomised clinical trials, information on adverse events leading to treatment withdrawal was inadequate. Proper evidence-based evaluation of the benefit/risk of therapeutic interventions needs a more systematic approach to reporting of adverse events experiences recorded in clinical trials.

The development of angiotensin-converting enzyme inhibitors (ACE inhibitors) has been one of the most remarkable stories in the treatment of cardiovascular diseases. Angiotensin converting enzyme inhibitors have several acute and sustained hemodynamic effects that are beneficial in the presence of left ventricular (LV) dysfunction. They increase cardiac output and stroke volume and reduce systemic vascular resistance as well as pulmonary capillary wedge pressure. The hemodynamic benefits are associated with improvement in the signs and symptoms of congestive heart failure (CHF) as well as decreased mortality, regardless of the severity of CHF. In patients with asymptomatic LV dysfunction, therapy with ACE inhibitors prevented the development of CHF and reduced hospitalization and cardiovascular death. They also increase survival when administered early after an acute myocardial infarction (MI). Most recently, ACE inhibition was associated with improved clinical outcomes in a broad spectrum of high-risk patients with preserved LV function. The mechanism of ACE inhibitors benefits is multifactorial and includes prevention of progressive LV remodeling, prevention of sudden death and arrhythmogenicity and structural stability of the atherosclerotic process. Evidence suggests that ACE inhibitors are underutilized in patients with cardiovascular diseases. Efforts should be directed to prescribe ACE inhibitors to appropriate patients in target doses. It is reasonable to believe that ACE inhibitors have a class effect in the management of LV dysfunction with or without CHF and acute MI. Whether the same is true for ACE inhibitors in the prevention of ischemic events is not known yet.

We documented chronic ventricular arrhythmias in a first group of 58 rats after myocardial infarction (MI), then assessed the effects of spironolactone and fosinopril on morphological indexes and arrhythmias in a second group (n = 33). Rats underwent Holter monitoring at 2 months after MI. Treatment was randomly given from 1 until 4 months after MI: placebo in 12 rats (P), fosinopril in 9 (F) and spironolactone + fosinopril in 12 (SF). The score of ventricular premature beats (VPBs) was related to the MI size and the delay from MI (p < 0.01). VPB's reduction/increase required to demonstrate anti/pro-arrhythmic effects were 55 and 59%. Mass indexes were lower in F and SF (p = 0.01). VPB's difference (4 months vs. 1) was positive in P, significantly lower in F and negative in SF (p = 0.04). In this relevant model of spontaneous and chronic ventricular arrhythmias, SF association did not increase mortality but lowered the arrhythmic score., (Copyright 2001 S. Karger AG, Basel)

Background: It is not known whether quality of care for congestive heart failure (CHF) at rural hospitals is similar to that in larger, urban hospitals., Methods: We reviewed hospital charts for 310 Medicare patients hospitalized with CHF at six hospitals in rural Georgia., Results: Of the 310 patients, 101 (33%) had left ventricular systolic dysfunction, and 60 (19%) had preserved systolic function. Information on left ventricular function was not available for 48% (range, 29% to 87% across the six hospitals). Among patients with systolic dysfunction, 77% were prescribed an angiotensin converting enzyme (ACE) inhibitor at discharge, and 73% were prescribed digoxin. However, the mean daily ACE inhibitor dose was only 48% of the recommended target dose. Only 30% of all patients with atrial fibrillation were prescribed warfarin., Conclusions: Overall quality of care for CHF at rural hospitals appears similar to that in other settings, though many patients may not receive evaluation of ventricular function.

Over the past 20 to 30 years there have been significant advances in the management of heart failure related to improved understanding of pathophysiology, better methods of assessment, and improved drug treatments. The aims of treatment have broadened, with increased emphasis on earlier intervention. Clinical research activity in this area has been considerable, increasingly allowing an evidence-based approach to management. Most earlier trials of treatment were relatively short-term, small-group studies with various clinical end points, including severity of symptoms, exercise performance, and left ventricular function assessment; however, increasingly a higher standard of evidence has been required, including a provision of reliable, large-scale mortality trial data. This has been further encouraged, if not mandated, by the relatively recent appreciation that some agents may demonstrate dissociation of treatment effects, possibly dose related, with improved short-term outcomes but adverse effects on survival with prolonged treatment. The general principles of management of congestive heart failure encompass patient evaluation and confirmation of the diagnosis, consideration, and correction of underlying remediable causes and precipitating factors, pharmacological treatment, patient education and counseling, and planned follow-up, as summarized in recently published guidelines. This review focuses primarily on the available randomized controlled clinical trial evidence related to the pharmacological treatment of the clinical congestive heart failure syndrome. Other aspects of management, such as patient education, counseling, and planned follow-up, should be regarded as complementary to pharmacological treatment and important to ensure compliance and optimal long-term outcomes.

Recent studies have shown that ACE inhibitors reduce morbidity and mortality after myocardial infarction (MI). While these trials have obvious clinical implications, the widespread introduction of a new treatment for a condition as common as MI also has clear cost implications. The results of the post-MI studies with ACE inhibitors suggest that restricted use of treatment-in high-risk patients-is likely to be most cost effective, whereas treatment of all MI survivors, many of whom are at low risk, will be least cost effective. An approach somewhere in between may maximise clinical benefit at an acceptable cost. Economic analysis may help in deciding how these drugs might be best used after MI. We have conducted a cost-effectiveness and cost-utility analysis of the Survival and Ventricular Enlargement (SAVE) study, which reported the benefit of ACE inhibitors in intermediate-risk patients. Assuming all MI survivors require measurement of left ventricular function before selection for treatment (the approach used in the SAVE study), the incremental cost per life-year gained (LYG), over 4 years, using prophylactic captopril is approximately 10000 pounds sterling (Pounds) [1994 to 1995 values]. The cost per quality-adjusted life-year (QALY) is similar. These incremental cost per LYG and cost per QALY ratios compare favourably with other commonly used symptomatic and prophylactic treatments, and argue for extending post-MI use of ACE inhibitors to intermediate-as well as high-risk patients.

Nine pediatric symptomatic patients infected with human immunodeficiency virus with elevated pulmonary arterial pressure (MPA pressure) and ejection fraction (EF); and with fractional shortening, (FS) mean velocity of circumferential fiber shortening (MVCfc) and left ventricular peak systolic wall stress (PS) were prospectively evaluated using 2-dimensional and M-mode serial echocardiography and Doppler cardiography after administration of an ACE inhibitor (Inhibace 0.025 mg/kg/D orally) for 12 weeks. The MPA pressure was not decreased, however the MVCfc and PS improved significantly (p < 0.05). Further, long term evaluation is required to determine its effect in preventing dilated cardiomyopathy and elevated mean pulmonary pressure.