Doses Of Angiotensin-converting Enzyme Research Articles

Response to ECG, August 2020

A prophylactic implantable cardioverter defibrillator (ICD) in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) is only indicated when left ventricular ejection fraction (LVEF) reassessment remains ≤35% after 3–6 months on optimal pharmacological therapy. However, LVEF may not improve during this period and the patient may be exposed to an unnecessary risk of sudden cardiac death. This study aimed to determine the incidence and predictors of the absence of left ventricular reverse remodeling (LVRR) after pharmacological treatment optimization in patients with HFrEF to design a risk score of absence of LVRR.Consecutive outpatients with LVEF ≤35% were included in this observational prospective study. Up-titration of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and ivabradine was performed in our Heart Failure (HF) Unit. The absence of LVRR was defined as the persistence of an LVEF ≤35% at the 6-month follow-up.One hundred and twenty patients were included. At the 6-month follow-up, 64%, 76%, 72%, and 7% of patients were at 100% of the target dose of ACE inhibitors/ARBs, beta-blockers, MRAs, and ivabradine, respectively. LVRR was observed in 48% of the patients. Ischemic cardiomyopathy, prolonged HF duration, and larger left ventricular end-diastolic diameter index (LVEDDI) were independent predictors of the absence of LVRR. The risk score based on these predictors showed a c-statistic value of 0.81.Pharmacological treatment optimization is associated with LVRR in approximately half of cases, reducing potential ICD indications in parallel. However, ischemic cardiomyopathy, prolonged HF duration, and larger LVEDDI predict the absence of LVRR and favor ICD implantation without delay. The risk score based on the former predictors may help the clinician with the timing of ICD implantation.

Abstract 120: Effectiveness of a Pharmacist Population Health Intervention for Sacubitril/valsartan in Systolic Heart Failure

Purpose: Previous literature demonstrates higher prescribing rates by providers after contact with a pharmaceutical representative or after obtaining drug information from an external source. This study aims to evaluate the effectiveness of an Electronic Health Record (EHR), pharmacist-based, population health intervention on physician prescribing patterns of sacubitril/valsartan in patients at Michigan Medicine General Cardiology clinics. Methods: The institutional review board approved this prospective, cluster-randomized controlled study. Patients seen by providers at the General Cardiology clinics of Michigan Medicine between 3/21/2017 and 6/1/2018 were included. Twenty-seven cardiology providers were clustered based on specialty. Fourteen providers were included in the intervention group while 13 providers were included in the control group. Within each arm, study personnel prospectively screened patients by preliminarily filtering those with a diagnosis of systolic heart failure and a left ventricular ejection fraction (LVEF) of 40% or less. Practice-based guideline criteria were then used to determine final patient eligibility. Intervention notifications were sent by pharmacists to providers using the EHR inbox within two-weeks prior to the clinic visit. The primary endpoint for this study was the proportion of patients prescribed sacubitril/valsartan within three months following the appointment. Baseline demographic data was collected on intervention patients. Additionally, the reasons for ineligibility were collected on all patients. Results: A total of 1559 patients were included (intervention=763, control=796). Fifty-two patients met eligibility criteria for sacubitril/valsartan (intervention=16, control=36). Of eligible patients, two in the intervention group and one in the control group had sacubitril/valsartan initiated (12.5% vs. 2.8%, OR 5.0, 95% CI 0.42-59.7, p=0.22). Of the 14 interventions that were not accepted, there was a common provider and 79% of the messages were ignored. The main reasons for ineligibility were patients not taking a dose of angiotensin converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) equivalent to enalapril 10 mg twice daily (92.6%) or not currently taking an ACE inhibitor or ARB (5.1%). Conclusion: Few patients met practice-based guideline criteria which reflected a conservative approach to initiating sacubitril/valsartan and limited sacubitril/valsartan initiation. EHR inbox interventions may be limited since most of the messages were ignored. Future research should explore tools to aid in optimizing medication therapy for patients with systolic heart failure which may lead to more successful pharmacist-based, population health interventions for this patient population.

P6295Relationship between different doses of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and prognosis in elderly patients with low ejection fraction and chronic kidney disease

P6295Relationship between different doses of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and prognosis in elderly patients with low ejection fraction and chronic kidney disease

A risk score to predict the absence of left ventricular reverse remodeling: Implications for the timing of ICD implantation in primary prevention

BackgroundA prophylactic implantable cardioverter defibrillator (ICD) in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) is only indicated when left ventricular ejection fraction (LVEF) reassessment remains ≤35% after 3–6 months on optimal pharmacological therapy. However, LVEF may not improve during this period and the patient may be exposed to an unnecessary risk of sudden cardiac death. This study aimed to determine the incidence and predictors of the absence of left ventricular reverse remodeling (LVRR) after pharmacological treatment optimization in patients with HFrEF to design a risk score of absence of LVRR. MethodsConsecutive outpatients with LVEF ≤35% were included in this observational prospective study. Up-titration of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and ivabradine was performed in our Heart Failure (HF) Unit. The absence of LVRR was defined as the persistence of an LVEF ≤35% at the 6-month follow-up. ResultsOne hundred and twenty patients were included. At the 6-month follow-up, 64%, 76%, 72%, and 7% of patients were at 100% of the target dose of ACE inhibitors/ARBs, beta-blockers, MRAs, and ivabradine, respectively. LVRR was observed in 48% of the patients. Ischemic cardiomyopathy, prolonged HF duration, and larger left ventricular end-diastolic diameter index (LVEDDI) were independent predictors of the absence of LVRR. The risk score based on these predictors showed a c-statistic value of 0.81. ConclusionsPharmacological treatment optimization is associated with LVRR in approximately half of cases, reducing potential ICD indications in parallel. However, ischemic cardiomyopathy, prolonged HF duration, and larger LVEDDI predict the absence of LVRR and favor ICD implantation without delay. The risk score based on the former predictors may help the clinician with the timing of ICD implantation.

Aldosterone breakthrough does not alter central hemodynamics.

Introduction:Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are widely used in congestive heart failure and chronic kidney disease, but up to 40% of patients will experience aldosterone breakthrough, with aldosterone levels rising above pre-treatment levels after 6–12 months of renin-angiotensin-aldosterone system blockade. Aldosterone breakthrough has been associated with worsening congestive heart failure and chronic kidney disease, yet the pathophysiology remains unclear. Breakthrough has not been associated with elevated peripheral blood pressure, but no studies have assessed its effect on central blood pressure.Methods:Nineteen subjects with well-controlled peripheral blood pressure on stable doses of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker had aldosterone levels checked and central blood pressure parameters measured using the SphygmoCor system. The central blood pressure parameters of subjects with or without breakthrough, defined as serum aldosterone >15 ng/dl, were compared.Results:Of the 19 subjects, six had breakthrough with a mean aldosterone level of 33.8 ng/dl, and 13 were without breakthrough with a mean level of 7.1 ng/dl. There was no significant difference between the two groups in any central blood pressure parameter.Conclusions:We found no correlation between aldosterone breakthrough and central blood pressure. The clinical impact of aldosterone breakthrough likely depends on its non-genomic, pro-fibrotic, pro-inflammatory effects rather than its regulation of extracellular volume.

Angiotensin-Converting Inhibitors and Angiotensin II Receptor Blockers and Longitudinal Change in Percent Emphysema on Computed Tomography. The Multi-Ethnic Study of Atherosclerosis Lung Study.

Although emphysema on computed tomography (CT) is associated with increased morbidity and mortality in patients with and without spirometrically defined chronic obstructive pulmonary disease, no available medications target emphysema outside of alpha-1 antitrypsin deficiency. Transforming growth factor-β and endothelial dysfunction are implicated in emphysema pathogenesis, and angiotensin II receptor blockers (ARBs) inhibit transforming growth factor-β, improve endothelial function, and restore airspace architecture in murine models. Evidence in humans is, however, lacking. To determine whether angiotensin-converting enzyme (ACE) inhibitor and ARB dose is associated with slowed progression of percent emphysema by CT. The Multi-Ethnic Study of Atherosclerosis researchers recruited participants ages 45-84 years from the general population from 2000 to 2002. Medication use was assessed by medication inventory. Percent emphysema was defined as the percentage of lung regions less than -950 Hounsfield units on CTs. Mixed-effects regression models were used to adjust for confounders. Among 4,472 participants, 12% used an ACE inhibitor and 6% used an ARB at baseline. The median percent emphysema was 3.0% at baseline, and the rate of progression was 0.64 percentage points over a median of 9.3 years. Higher doses of ACE or ARB were independently associated with a slower change in percent emphysema (P = 0.03). Over 10 years, in contrast to a predicted mean increase in percent emphysema of 0.66 percentage points in those who did not take ARBs or ACE inhibitors, the predicted mean increase in participants who used maximum doses of ARBs or ACE inhibitors was 0.06 percentage points (P = 0.01). The findings were of greatest magnitude among former smokers (P < 0.001). Indications for ACE inhibitor or ARB drugs (hypertension and diabetes) and other medications for hypertension and diabetes were not associated independently with change in percent emphysema. There was no evidence that ACE inhibitor or ARB dose was associated with decline in lung function. In a large population-based study, ACE inhibitors and ARBs were associated with slowed progression of percent emphysema by chest CT, particularly among former smokers. Randomized clinical trials of ACE and ARB agents are warranted for the prevention and treatment of emphysema.

Improving medication titration in heart failure by embedding a structured medication titration plan

BackgroundTo improve up-titration of medications to target dose in heart failure patients by improving communication from hospital to primary care. MethodsThis quality improvement project was undertaken within three heart failure disease management (HFDM) services in Queensland, Australia. A structured medication plan was collaboratively designed and implemented in an iterative manner, using methods including awareness raising and education, audit and feedback, integration into existing work practice, and incentive payments. Evaluation was undertaken using sequential audits, and included process measures (use of the titration plan, assignment of responsibility) and outcome measures (proportion of patients achieving target dose) in HFDM service patients with reduced left ventricular ejection fraction. ResultsComparison of the three patient cohorts (pre-intervention cohort A n=96, intervention cohort B n=95, intervention cohort C n=89) showed increase use of the titration plan, a shift to greater primary care responsibility for titration, and an increase in the proportion of patients achieving target doses of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) (A 37% vs B 48% vs C 55%, p=0.051) and beta-blockers (A 38% vs B 33% vs C 51%, p=0.045). Combining all three cohorts, patients not on target doses when discharged from hospital were more likely to achieve target doses of ACEI/ARB (p<0.0001) and beta blockers (p<0.0001) within six months if they received a medication titration plan. ConclusionsA medication titration plan was successfully implemented in three HFDM services and improved transitional communication and achievement of target doses of evidence-based therapies within six months of hospital discharge.

Cardiac resynchronization therapy allows the optimization of medical treatment in heart failure patients

AimCardiac resynchronization therapy (CRT) is recommended for selected patients with advanced heart failure (HF) despite optimal medical treatment. However, the doses of pharmaceuticals in this population are often limited by adverse effects. We compared the drug regimens of 21 patients before and 6months after they underwent the implantation CRT systems. MethodsWe studied 17 men and four women (mean age=63.4±11years) presenting in New York Heart Association HF classes III-IV, and with a left ventricular ejection fraction (LVEF)≤35% and cardiac dyssynchrony, who underwent implantation of CRT systems. ResultsAt baseline, 52% of patients were treated with β-adrenergic blockers (β-B), though in optimal doses in only 19%. The introduction of (β-B) was complicated by cardiogenic shock in three patients. At baseline, all patients were treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), of whom 76% received optimal doses. After 6months of CRT, β-B were administered to 76% of patients, in optimaklon ACE or ARB but 75% of them were receiving maximal doses. After 6months of CRT, β blockers have been introduced in 72% of patients and maximal doses have been achieved in 60% of them. Maximal doses of ACE or ARB were reached in 95% of the study population. We noticed that systolic blood pressure was higher after implantation. There was also a significant improvement in functional status and left ventricular ejection fraction compared to baseline. ConclusionCRT is an efficacious adjunctive device therapy to standard medical therapy for patients with heart failure and cardiac dyssynchrony. Its benefits are in addition to those afforded by standard pharmacological therapy. Achieving maximal doses of medical treatment and the possibility of introducing β blockers after CRT prove that CRT and pharmacological treatment are complementary strategies and should not be considered as competitive.

Involvement of brain ANG II in acute sodium depletion induced salty taste changes

Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste changes accompanied with sodium depletion. To further elucidate the mechanism of renin-angiotensin-aldosterone system (RAAS) action in mediating sodium intake behavior and accompanied salty taste changes, the present study examined the salty taste function changes accompanied with sodium depletion induced by furosemide (Furo) combined with different doses of angiotensin converting enzyme (ACE) inhibitor, captopril (Cap). Both the peripheral and central RAAS activity and the nuclei Fos immunoreactivity (Fos-ir) expression in the forebrain area were investigated. Results showed that sodium depletion induced by Furo+low-Cap increased taste preference for hypertonic NaCl solution with amplified brain action of ANG II but without peripheral action, while Furosemide combined with a high dose of captopril can partially inhibit the formation of brain ANG II, with parallel decreased effects on salty taste changes. And the resulting elevating forebrain ANG II may activate a variety of brain areas including SFO, PVN, SON and OVLT in sodium depleted rats injected with Furo+low-Cap, which underlines salty taste function and sodium intake behavioral changes. Neurons in SFO and OVLT may be activated mainly by brain ANG II, while PVN and SON activation may not be completely ANG II dependent. These findings suggested that forebrain derived ANG II may play a critical role in the salty taste function changes accompanied with acute sodium depletion.

Hepatocyte growth factor is a strong predictor of mortality in patients with advanced heart failure

ObjectiveTo assess the prognostic value of the mitogenic, antiapoptotic, angiogenic and antifibrotic hepatocyte growth factor (HGF) in heart failure (HF).DesignProspective cohort study.Setting/patientsAssessment of HGF levels at inclusion in 351 patients...

Optimizing treatment to reach therapeutic goals in fabry disease

Fabry disease is an X-linked lysosomal storage disorder caused by a-galactosidase A deficiency. This deficiency leads to the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids, particularly in vascular endothelial cells, renal cells, and cardiomyocytes. 1 Nephropathy is one of the major complications of Fabry disease. Biopsy results reveal GL-3 accumulation in tubular epithelial cells and glomerular and endothelial cells, with focal and global glomerulosclerosis as early as the second decade of life.2~ Affected males typically experience kidney failure by the fourth decade of life,7,8 Cardiovascular and cerebrovascular events also contribute to morbidity and mortality. Heterozygous females may either be asymptomatic or develop overt disease, presumably due to skewing of X chromosome inactivation.811 Various treatment trials have been conducted with agalsidase beta. 1214 Over the last decade, information regarding the diagnosis and treatment of Fabry nephropathy has grown; baseline proteinuria and glomerular filtration rate are now recognized as important factors that affect the rate of loss of kidney function. Furthermore, although enzyme replacement therapy (ERT) appears to effectively slow the progression of Fabry nephropathy in patients with proteinuria <1 g/d, ERT alone does not reduce urine protein excretion and does not appear to slow progression of Fabry nephropathy in patients with baseline proteinuria ~1 g/d. Results from a small (N = 11), single-center studyl5 suggest that controlling urine protein excretion to a target level of 0.5 g/d with angiotensinconverting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB) therapy, using agalsidase beta 1 mg/kg every 2 weeks, can slow and even stop the progression of Fabry nephropathy, including in those patients with fairly advanced disease. These results are undergoing confirmation in a multicenter trial. 16 The use of ACE inhibitor/ARB therapy in proteinuric patients with Fabry nephropathy is gaining acceptance, but several barriers have prevented widespread adoption of this approach. Because patients with Fabry disease generally have relatively low blood pressure, effective ACE inhibitor/ARB therapy can be a challenge to the physician and to the patient; in addition, hyperkalemia and anemia can complicate the use of this therapy in patients with advanced chronic kidney disease.J5 Furthermore, the response of ACE inhibitor/ARB therapy will not be optimized unless the urinary protein excretion is measured at regular follow-up visits and the doses of ACE inhibitor/ARB therapy adjusted to achieve reduction to the target level of 0.5 g/d. The benefits of reducing proteinuria using ACE inhibitor/ARB therapy have only been described with patients with Fabry disease treated with agalsidase beta 1 mg/kg every 2 weeks and not with lower doses or other ERT preparations.J5 The use of ACE inhibitor/ARB therapy in patients with Fabry nephropathy for reduction of proteinuria as a temporizing measure to forestall initiation of ERT has no evidentiary support and should be strongly discouraged. Optimal care of the patient with Fabry nephropathy includes initial staging of disease severity, which may involve a baseline renal biopsy. Regular follow-up with attention to blood pressure control, reduction of urine protein excretion to <500 mg/d with antiproteinuric therapy, and optimal dosing with ERT are essential to preserving kidney function and preventing further decline in the patient's condition.

What is the Optimal Angiotensin‐Converting Enzyme Inhibitor Dose in Heart Failure?

Doses of angiotensin-converting enzyme (ACE) inhibitors used in the landmark heart failure trials that demonstrated survival benefit are rarely reached in routine practice. The authors review the current literature regarding optimal dosing of ACE inhibitors in heart failure with specific focus on neurohormonal, functional capacity, and clinical outcomes. Neurohormonal studies have shown that lower ACE inhibitor dosing may provide inadequate suppression of the renin-angiotensin-aldosterone system. Higher doses of ACE inhibitors have resulted in greater increments in exercise and functional capacity. Clinically, patients on high-dose ACE inhibitor therapy had significant reductions in all-cause mortality or hospitalization, cardiovascular hospitalizations, and heart failure-specific hospitalizations. There is, however, conflicting evidence, and so continued uncertainty exists regarding optimal dosing. Despite underutilization of ACE inhibitors, there is insufficient evidence to support lower doses. Likewise, limited data exist for doses higher than those used in the landmark trials. Clinicians should therefore attempt to reach target doses in heart failure whenever possible.

Management of Cardiac Failure—Do Practitioners Follow Guidelines?

Objective: To assess the use of β-blockers, spironolactone, and the dose of angiotensin-converting enzyme (ACE) inhibitors in patients with congestive cardiac failure. Methods: The medical records of patients discharged with a diagnosis of congestive cardiac failure between January 1, 2001, and June 30, 2001, from the internal medicine and cardiology services at Capital and Coast District Health Board, Wellington, New Zealand, were identified and analyzed for cardiac drugs on admission and discharge. These records were also reviewed for New York Heart Association status and left-ventricular ejection fraction. Results: Two hundred ninety-two patients (146 from each service) were identified as having congestive cardiac failure; 84 were excluded due to death, admission being procedure related, notes being unavailable, or transfers from other services. The patients' mean age was 73 years. Four of 74 eligible patients were started on β-blockers, while 11 of 30 eligible patients were started on spironolactone. Sixteen patients were prescribed spironolactone inappropriately, and 27 were prescribed target recommended doses of ACE inhibitors. Conclusions: This study has shown that guidelines for the treatment of cardiac failure are difficult to follow in clinical practice. Adequate studies in older individuals with congestive cardiac failure are indicated.

Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure

ObjectivesWe sought to compare the neurohormonal responses and clinical effects of long-term, high-dose versus low-dose enalapril in patients with chronic heart failure (CHF). BackgroundExamination of neurohormonal and clinical responses in patients receiving different doses of angiotensin-converting enzyme (ACE) inhibitors may provide insight into the potential for additional suppression with angiotensin II (AT-II) or aldosterone antagonists. MethodsSeventy-five patients with CHF were randomized to receive either high-dose (40 mg/day, n = 37) or low-dose (5 mg/day, n = 38) enalapril over six months. The results from exercise testing, echocardiography, tissue-specific ACE activity and monthly pre- and post-enalapril neurohormonal levels were compared. ResultsDespite greater intra-group improvements in plasma renin activity and serum aldosterone levels in the high-dose group, no statistically significant differences were observed between the two groups in all variables, except for serum ACE activity at the end of study. Elevated serum aldosterone and plasma AT-II levels were observed in 35% and 85% of patients, respectively, at 34 weeks, an inter-group difference that was not statistically significant. A trend toward higher levels of tissue-specific ACE activity in the high-dose group compared with the low-dose group at the end of study was observed (p = 0.054). A predefined composite end point of clinical events had a trend toward better improvement in the high-dose group. ConclusionsThis study could not demonstrate a difference between high- and low-dose enalapril in terms of serum aldosterone and plasma AT-II suppression, despite a dose-dependent reduction in serum ACE activity. Even at maximal doses of enalapril, elevated serum aldosterone and plasma AT-II levels were frequently observed.

The influence of angiotensin converting enzyme inhibitors on lipid peroxidation in sera and aorta of rabbits in diet-induced hypercholesterolemia.

In hypercholesterolemia increased lipid and lipoprotein peroxidation occurs. The renin-angiotensin system plays an important role in atherogenesis. Angiotensin II induces smooth muscle cells proliferation and stimulates oxidation of LDL particles and foam cell accumulation. Inhibition of ang II production leads to decrease in lipid peroxide production. The aim of this study was to assess the lipid peroxidation expressed as concentration of thiobarbituric acid reactive species (TBARS) in sera and aorta homogenates after administration of two doses of angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril and quinapril) in diet-induced hypercholesterolemia in rabbits. Sixty-four New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: i), equivalent to applied to humans, ii), dose 10 times higher. The animals were divided into 8 groups: control, standard fodder; B, special diet; C1, C2, special diet + captopril in doses 2.5 and 25 mg/kg/24 h, respectively; E1, E2, special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 h, respectively; Q1 and Q2, special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. In cholesterol-fed rabbits and in groups receiving lower doses of tested ACE inhibitors, the serum TBARS concentration at 6 months was significantly higher in comparison to the control. The higher doses of enalapril, quinapril and captopril, prevented the cholesterol-induced rise in TBARS concentration. Lower dose of captopril attenuated the rise in TBARS concentration, it was significantly lower in comparison to group B, but higher than in the control group. In animals from groups B, E1, C1, Q1 TBARS concentration in aortae was significantly higher as compared to control group. Both doses of captopril and higher doses of enalapril and quinapril inhibited the rise of lipid peroxides concentration induced by cholesterol-rich diet.

What does atlas really tell us about “High” dose angiotensin-converting enzyme inhibition in heart failure?

The Assessment of Treatment with Lisinopril and Survival (ATLAS) results have been widely quoted by proponents advocating the use of “high” doses of angiotensin-converting enzyme (ACE) inhibitors for the treatment of heart failure. In ATLAS, however, the relative benefits of “high” versus “low” dose ACE inhibition were small. Intermediate doses of ACE inhibitors proven effective in previous placebo-controlled trials provide benefit that appears likely to equal or exceed the benefit from “high” dose ACE inhibition. Therefore, we recommend that physicians continue to prescribe ACE inhibitors for patients with heart failure based on the target doses used in the placebo-controlled trials and not on the “high” dose target used in ATLAS.

Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: Randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy

Background Most patients with chronic heart failure (CHF) receive the same dose of angiotensin-converting enzyme (ACE) inhibitors because there is currently no measure of treatment efficacy. We sought to determine whether titration of vasodilator therapy according to plasma brain natriuretic peptide (BNP) concentration may be of value in the individual optimization of vasodilator therapy in CHF. Methods and Results Twenty patients with mild to moderate CHF receiving stable conventional therapy including an ACE inhibitor were randomly assigned to titration of ACE inhibitor dosage according to serial measurement of plasma BNP concentration (BNP group) or optimal empirical ACE inhibitor therapy (clinical group) for 8 weeks. Only the BNP-driven approach was associated with significant reductions in plasma BNP concentration throughout the duration of the study and a significantly greater suppression when compared with empiric therapy after 4 weeks [–42.1% (–58.2, –19.7) vs –12.0% (–31.8, 13.8), P = .03]. Both treatment strategies were well tolerated and associated with favorable neurohormonal and hemodynamic effects; however, in comparison between groups, mean heart rate fell ( P = .02) and plasma renin activity rose ( P = .03) in the BNP group when compared with the clinical group. Conclusions Plasma BNP concentration may be chronically reduced by tailored vasodilator therapy in CHF. Furthermore, titration of vasodilator therapy according to plasma BNP was associated with more profound inhibition of the renin-angiotensin-aldosterone system and significant fall in heart rate when compared with empiric therapy. (Am Heart J 1999;138:1126-32.)

Bolus versus Continuous Low Dose of Enalaprilat in Congestive Heart Failure with Acute Refractory Decompensation

The first dose of angiotensin-converting enzyme (ACE) inhibitors may trigger a considerable fall of blood pressure in chronic heart failure. The response may be dose-related. To determine hemodynamic and systemic oxygenation effects of low-dose enalaprilat, we administered intravenous enalaprilat (0.004 mg/kg) as bolus (group B) or continuous 1-hour infusion (group C) in 20 patients with congestive heart failure due to ischemic heart disease with acute decompensation refractory to inotropic, vasodilator and diuretic therapy. Hemodynamic and systemic oxygenation variables were recorded at baseline (+0 min), +30, +60, +120, +180, and +360 min after the start of intervention. Mean arterial pressure (MAP) (p < 0.001), mean pulmonary artery pressure (MPAP) (p < 0.001), pulmonary artery occlusion pressure (PAOP) (p < 0.001), oxygen extraction ratio (ER) (p < 0.026) decreased regardless of enalaprilat application. Compared to group B, there was in group C prolonged decrease of MAP, MPAP, PAOP, ER and increase of pulmonary artery oxyhemoglobin saturation in regard to baseline values. Cardiac index, heart rate, central venous pressure and oxygen consumption index did not change. A low dose of intravenous enalaprilat (0.004 mg/kg) can be used to safely improve hemodynamics and systemic oxygenation in congestive heart failure due to ischemic heart disease with acute refractory decompensation.

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension.

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Pharmacological Demonstration of the Additive Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Antagonism in Sodium Depleted Healthy Subjects

A blockade of the hemodynamic and tissue effects of angiotensin II (Ang II) more complete than that presently achieved with usual daily doses of angiotensin converting enzyme (ACE) inhibitors or type 1 Ang II receptor antagonists has potential advantages and risks. Therefore, it is worthwhile to investigate the biological and the hemodynamic effects of the simultaneous blockade of the renin-angiotensin system (RAS) at the two sites where it can be currently achieved, ACE and type 1 Ang II receptors. To investigate this issue, 2 double-blind randomized crossover studies were performed in a model of mild sodium depletion in normotensive volunteers. They ingested single oral doses of captopril 50 mg, losartan 50 mg, their combination or matched placebos, and in a second study, single oral doses of enalapril 10 mg, enalapril 20 mg and the combination of losartan 50 mg with enalapril 10 mg. The combination captopril 50 mg and losartan 50 mg had additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. When compared to enalapril 10 mg and the doubling of its dose, the combination of losartan 50 mg and enalapril 10 mg significantly increased both the area under the time curve of mean blood pressure fall and plasma active renin levels. It did not further decrease plasma aldosterone levels. The conclusion is that a more complete blockade of the RAS can be achieved by concomitant administration of an type 1 Ang 11 receptor antagonist and an ACE inhibitor.