Pharmacogenetic markers of development of angioneurotic edema as a secondary side effect to enalapril in patients with essential arterial hypertension.

BACKGROUND: Angioneurotic edema is the most dangerous complication in angiotensin-converting enzyme inhibitors (ACEIs) therapy. Based on the current data, the clinical and genetic predictors of angioedema development are still understudied, which demonstrates the relevance of this study. OBJECTIVE: To reveal the pharmacogenetic predictors of the angioedema as a secondary side effect to enalapril in patients with essential arterial hypertension. METHODS: The study enrolled 111 subjects randomized into two groups: study group, patients with the angioedema as a secondary side effect to enalapril; and control group, patients without adverse drug reaction. All patients underwent pharmacogenetic testing. RESULTS: An association between the development of the angioneurotic edema and the genotypes AA rs2306283 of gene SLCO1B1, TT rs4459610 of gene ACE, and CC rs1799722 of gene BDKRB2 in patients was revealed. CONCLUSION: The findings justify further investigations of the revealed genetic predictors of angioedema with larger-size patient populations.

Efficacy and Safety of Sacubitril/Valsartan in Japanese Patients With Heart Failure According to Baseline Systolic Blood Pressure　- Results From a Subgroup Analysis of the PARALLEL-HF Study.

BACKGROUND: Lower systolic blood pressure (SBP) is known to be associated with poor prognosis in heart failure (HF). We evaluated the efficacy and safety of sacubitril/valsartan according to baseline SBP tertiles in Japanese patients from the PARALLEL-HF study.Methods and Results: In all, 223 patients were stratified into tertiles according to baseline SBP (≤114 mmHg: n=75; >114 and ≤130 mmHg: n=76; and >130 mmHg: n=72). Patients with lower SBP (≤114 mmHg) had the highest median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations at baseline (P=0.0184). No significant difference was observed between sacubitril/valsartan and enalapril for the composite outcome of cardiovascular death and HF hospitalization across SBP tertiles (P-interaction=0.2682). Although the P-interaction value was not significant (0.2106), a greater reduction in NT-proBNP with sacubitril/valsartan compared with enalapril was observed in patients with SBP >130 mmHg (P=0.0076). The incidence of hypotension-related events and reduction or discontinuation of treatment due to hypotension-related events was higher in the lower SBP subgroup, and these events were more frequent in the sacubitril/valsartan than enalapril group. CONCLUSIONS: The efficacy of sacubitril/valsartan compared with enalapril was consistent across baseline SBP tertiles in Japanese patients from the PARALLEL-HF study. Hypotension-related events were more common in patients treated with sacubitril/valsartan with lower SBP.

A randomized controlled trial comparing the efficacy of nifedipine and enalapril in the postpartum period.

BACKGROUND: Postpartum hypertension is a common medical complication of pregnancy and is associated with increased healthcare use, including unplanned interactions with the medical system and readmission, which can add significant stress to both a newly postpartum patient and the medical care delivery system. We currently do not know what the best antihypertensive treatment for postpartum hypertension is and tend to use antihypertensives commonly used during pregnancy. However, the mechanism of action of angiotensin-converting enzyme inhibitors may be well suited for the pathophysiology of hypertension in the postpartum period and may help to provide better control of hypertension and, in turn, decrease healthcare use. OBJECTIVE: This study aimed to determine if enalapril is superior to nifedipine in preventing prolonged hospitalizations, unplanned medical visits, and/or readmission among women with postpartum hypertension. STUDY DESIGN: We performed an open-label, randomized controlled trial (ClinicalTrials.gov registered: NCT04236258) in which patients ≥18 years with chronic hypertension, gestational hypertension, or preeclampsia were recruited to receive either 10 mg enalapril daily or 30 mg extended-release nifedipine daily as an initial antihypertensive agent in the period from delivery to 6 weeks postpartum. Recruitment occurred at a tertiary academic hospital from January 2020 to February 2021. Exclusion criteria included being on an antihypertensive when pregnancy started or requiring ≥2 daily antihypertensives during pregnancy. The antihypertensive regimen was managed by the participants' obstetrical provider after the initial randomization. The primary outcome was a composite of prolonged hospitalization, unplanned clinic visits, triage visits, and/or readmission. A total of 40 patients in each arm were needed to detect a decrease in the primary outcome rate from 70% to 40% (α=0.05; power 0.80). Analyses were performed based on the intention-to-treat principal, and each arm was oversampled because of the risk for participant dropout. RESULTS: A total of 47 patients were randomized to each arm. Aside from the mode of delivery and twin gestation, the maternal demographics were similar between the 2 groups. The primary outcome occurred in 31 of 47 patients (66%) randomized to the nifedipine group and in 30 of 47 (64%) randomized to the enalapril group (P=.83). There was no significant difference in the primary outcome after controlling for mode of delivery and twin gestation. More patients in the enalapril arm had a second antihypertensive added during their primary hospitalization (16 vs 6) and more patients in the nifedipine arm were still on their antihypertensive at 2 weeks postpartum (42 vs 36). There were no adverse events in either group. CONCLUSION: Enalapril was not superior to nifedipine when used as an initial antihypertensive in the immediate postpartum period in terms of decreasing healthcare use.

Long-Term Treatment With Sacubitril/Valsartan in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction　- Open-Label Extension of the PARALLEL-HF Study.

BACKGROUND: The PARALLEL-HF study assessed the efficacy and safety of sacubitril/valsartan vs. enalapril in Japanese patients with chronic heart failure with reduced ejection fraction (HFrEF). This open-label extension (OLE) assessed long-term safety with sacubitril/valsartan.Methods and Results: This study enrolled 150 patients who received sacubitril/valsartan 50 or 100 mg, b.i.d., in addition to optimal background heart failure (HF) therapy. A dose level of sacubitril/valsartan 200 mg, b.i.d., was targeted by Week 8. At OLE baseline, higher concentrations of B-type natriuretic peptide (BNP) and urine cGMP, and lower concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), were observed in the sacubitril/valsartan core group (patients who received sacubitril/valsartan in both the core and extension study) than in the enalapril core group (patients who received enalapril in the core study and were then transitioned to sacubitril/valsartan). The mean exposure to study drug was 98.9%. There was no trend of worsening of HF at Month 12. No obvious changes in cardiac biomarkers were observed, whereas BNP and urine cGMP increased and NT-proBNP decreased in the enalapril core group, which was evident at Weeks 2-4 and sustained to Month 12. CONCLUSIONS: Long-term sacubitril/valsartan at doses up to 200 mg, b.i.d., has a positive risk-benefit profile; it was safe and well tolerated in Japanese patients with chronic HFrEF.

Aerobic Physical Exercise is Essential for Cardiac Autonomic Regulation in Hypertensive Patients Undergoing Chronic Treatment with Renin- Angiotensin System Inhibitors.

BACKGROUND: Hypertension treatment with renin-angiotensin system inhibitors (RASi) presents contradictions about the recovery of damage in cardiovascular autonomic modulation characterized by reduced heart rate variability (HRV) and increased blood pressure variability (BPV). Conversely, the association of RASi with physical training can influence achievements in cardiovascular autonomic modulation. OBJECTIVE: To investigate the effects of aerobic physical training on hemodynamics and cardiovascular autonomic modulation in hypertensive volunteers untreated and treated with RASi. METHODS: A non-randomized controlled trial in which 54 men (≅ 40-60 years old) with a history of hypertension for >2 years were allocated in accordance with their characteristics into three groups: untreated (Control; n=16), treated with type 1 angiotensin II (AT1) receptor blocker (losartan; n=21), and treated with angiotensin-converting enzyme inhibitor (enalapril; n=17). All participants underwent hemodynamic, metabolic, and cardiovascular autonomic evaluation using baroreflex sensitivity (BRS) and spectral analysis of HRV and BPV, before and after 16 weeks of supervised aerobic physical training. RESULTS: The volunteers treated with RASi had lower BPV and HRV, both in the supine position and in the tilt test, with the losartan group having the lowest values. Aerobic physical training increased HRV and BRS in all groups. However, the association of enalapril with physical training appears to be more prominent. CONCLUSION: Long-term treatment with enalapril and losartan may harm the autonomic modulation of HRV and BRS. Aerobic physical training is essential to promote positive adjustments in the autonomic modulation of HRV and BRS in hypertensive patients treated with RASi, especially with enalapril.

Pharmacogenetic predictors of development of secondary to enalapril dry cough in hypertensive patients.

OBJECTIVES: Development of the secondary to ACEI cough leads to discontinuation of the drugs of this group. Assessing the safety of the ACEIs with further development of customized approaches for their administration is a major scientific and practical problem. The objective of this study was to assess the association of the genetic markers with the development of the adverse drug reaction in the form of secondary to enalapril dry cough in the patients with essential arterial hypertension. METHODS: Study involved 113 patients with the secondary to enalapril cough and 104 patients without development of the secondary to enalapril adverse drug reaction. RESULTS: The patients carriers of the genotype AA rs2306283 of gene SLCO1B1 had 2-fold higher odds of developing the dry cough than those with the genotypes AG and GG (ОR=2.01, 95%CI=1.10-3.66, р=0.023). Similarly, the patients heterozygous for rs8176746 of gene АВО had 2.3-fold higher odds of developing the ADR in the form of dry cough than the carriers of the genotypes GG and TT (ОR=2.30, 95%CI=1.24-4.29, р=0.008). CONCLUSIONS: Statistically significant association between the development of the ADR in the form of secondary to enalapril dry cough and polymorphisms rs2306283 of gene SLCO1B1 and rs8176746 of gene ABO was revealed.

Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials.

BACKGROUND: Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. METHODS: We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. RESULTS: Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: - 0.24%, 95% CI - 0.33 to - 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62-1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05-2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63-0.89, P = 0.001), compared with enalapril or valsartan. CONCLUSIONS: Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711.

A Rare Case of Unilateral Tongue Edema with Angiotensin Converting Enzyme Inhibitors.

Angiotensin converting enzyme inhibitors (ACEi) are widely used for the treatment of multiple conditions such as hypertension, heart failure and chronic kidney disease. Angioedema is a rare but potentially fatal complication of ACEi use and unilateral tongue edema is a very rare presentation. We report a case of a 55-year-old man, with a history of hypertension, on enalapril for three years, who presented to the hospital with unilateral tongue swelling, without airway compromise. Other causes were excluded and the diagnosis of angioedema due to enalapril was established. The patient was discharged with discontinuation of ACEi with total resolution of symptoms and without relapse after several months. Although very rare, unilateral tongue swelling should be considered in the presentation of angioedema associated with ACEi. Tight surveillance is important to prevent fatal complications such as airway obstruction. ACEi discontinuation is crucial to avoid clinical relapse.

Os inibidores da enzima de conversão da angiotensina (iECAs) são amplamente usados no tratamento de várias patologias como a hipertensão arterial, insuficiência cardíaca e doença renal crónica. O angioedema é uma complicação rara mas potencialmente fatal desta medicação e o edema unilateral da língua é uma apresentação rara desta condição. Reportamos o caso de um homem de 55 anos com hipertensão, medicado há três anos com enalapril, que à admissão hospitalar apresentava edema unilateral da língua sem compromisso da via aérea. Outras etiologias foram excluídas, tendo-se assumido o diagnóstico de angioedema associado ao enalapril. Após suspensão do iECA os sintomas diminuíram progressivamente, sem recorrência do quadro após vários meses. Ainda que raro, o edema unilateral da língua deve ser considerado na apresentação do angioedema associado a iECA. É importante uma vigilância apertada para prevenir complicações fatais, tais como a obstrução da via aérea. A descontinuação do iECA é fundamental para evitar recidiva.

Topical Administration of ACE Inhibitor Interrupts the Progression of Cataract in Two Kidney One Clip Induced Hypertensive Cataract Model.

PURPOSE: Previously, we assessed that hypertension increases cataractogenesis. In the present study, we evaluated the effect of oral and topical administration of enalapril on two kidney one clip (2K1C)-induced hypertensive cataract model by evaluating the biochemical alteration of lenticular antioxidants, ionic content, ATPase activity, protein content and careful examination of the lenticular opacity. MATERIALS AND METHOD: Animals were divided into normal and hypertensive animals. Hypertensive animals were divided into hypertensive control group (0.3% CMC), enalapril (oral) treatment group (20 mg/kg/day; p.o), and enalapril (topical) treatment group (0.1% w/v on the eye cornea) for a period of twelve weeks. During experimental study blood pressure, heart rate and morphology of the eyes were monitored biweekly. After twelve weeks, lenses were photographed and various catractogenic biochemical parameters were assessed. RESULTS: Enalapril (oral) treatment conserved the blood pressure (systolic and diastolic), restored the level of antioxidants, restored the lipid peroxidation marker, nitrite content, ionic content, ATPase function, protein content, and thus delayed the cataract formation. While, enalapril (topical) treatment exhibited anti-cataract effect without affecting the systolic and diastolic blood pressure that could be by restoring the antioxidant level, maintaining the ionic balance, balancing the protein levels, and by inhibiting the upregulated ocular renin angiotensin system. The overall results suggest that enalapril (topical) treatment showed conspicuous effect than enalapril (oral) treatment in adjourning the cataract formation. CONCLUSION: Based on the results, it may be concluded that upregulated ocular RAS by increasing oxidative stress and by misbalancing the lenticular ionic and protein content may lead to cataract formation in hypertensive condition.

[Systematic review and sequential analysis of Tanshinone â ¡_A Sodium Sulfonate Injection combined with enalapril in treatment of acute exacerbation of pulmonary heart disease].

To systematically evaluate the clinical efficacy and safety of Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril in the treatment of patients with acute exacerbation of pulmonary heart disease. The randomized controlled trial(RCT) on Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril for acute exacerbation of pulmonary heart disease was screened from EMbase, PubMed, Web of Science, Cochrane Library, VIP, CNKI, and Wanfang from inception to March 20, 2022. Meta-analysis of each index was performed in RevMan 5.3 and TSA 0.9. Finally, 41 RCTs involving 3 865 patients were included. Meta-analysis showed that the observation group had higher total response rate(RR=1.21, 95%CI[1.18, 1.24], P<0.000 01), lower plasma viscosity(MD=-0.25, 95%CI[-0.34,-0.16], P<0.000 01), lower whole blood viscosity(MD=-0.99, 95%CI[-1.14,-0.85], P<0.000 01), and lower hematokrit(MD=-9.03, 95%CI[-10.57,-7.50], P<0.000 01) than the control group. The incidence of adverse effects showed no significant difference between groups(RR=1.42, 95%CI[0.82, 2.45], P=0.21). Sequential analysis showed that Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril exerted definite efficacy in the treatment of acute exacerbation of pulmonary heart disease, and the possibility of false positives was excluded. Based on the existing evidence, Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril can improve the total response rate and reduce plasma viscosity, whole blood viscosity, and hematocrit, demonstrating good safety in patients with acute exacerbation of pulmonary heart disease. In the future, more RCT with large sample size, rigorous design, and in accordance with international norms are needed to further validate the results.

Rationale and design of a multi-center, prospective randomized controlled trial on the effects of sacubitril-valsartan versus enalapril on left ventricular remodeling in ST-elevation myocardial infarction: The PERI-STEMI study.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNI) sacubitril-valsartan has been recommended as one of the first-line therapies in heart failure with reduced ejection fraction. However, whether ARNI could benefit patients with ST-segment elevation myocardial infarction (STEMI) by improving left ventricular (LV) remodeling remains unknown. The primary objective of the PERI-STEMI trial is to assess whether sacubitril-valsartan is more effective in preventing adverse LV remodeling for patients with STEMI than enalapril. HYPOTHESIS: We hypothesize that sacubitril/valsartan is superior to enalapril in preventing adverse LV remodeling evaluated by cardiovascular magnetic resonance imaging at the 6-month follow-up. METHODS: PERI-STEMI is an investigator-initiated, prospective, multi-center, randomized, open-label, superiority trial with blinded evaluation of outcomes. A total of 376 first-time STEMI patients with primary percutaneous coronary intervention (PPCI) within 12 h after symptom onset will be randomized to sacubitril-valsartan or enalapril treatment. All the patients will receive a baseline cardiovascular magnetic resonance (CMR) examination at 4-7 days post-PPCI. The primary endpoint is the change of indexed LV mass at the 6-month follow-up CMR. RESULTS: Enrollment of the first patient is planned in November 2021. Recruitment is anticipated to last for 12-18 months and patients will be followed for 5 years after randomization. The study is expected to complete in June 2027. CONCLUSIONS: The results of the PERI-STEMI trial are expected to provide CMR evidence on whether ARNI could benefit patients with STEMI, so as to facilitate the strategy of CMR-based risk stratification and therapy selection for these patients. PERI-STEMI is registered at ClinicalTrials.gov (NCT04912167).

Sacubitril/valsartan versus enalapril on exercise capacity in patients with heart failure with reduced ejection fraction: A randomized, double-blind, active-controlled study.

Sacubitril/valsartan reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) when compared with enalapril. However, it is unknown the effect of both treatments on exercise capacity. We compared sacubitril/valsartan versus enalapril in patients with HFrEF based on peak oxygen consumption (VO2) and 6-minute walk test (6-MWT). METHODS: We included 52 participants with HFrEF with a left ventricular ejection fraction <40% to receive either sacubitril/valsartan (target dose of 400 mg daily) or enalapril (target dose of 40 mg daily). Peak VO2 was measured by using cardiopulmonary exercise testing. Six-minute walk test was also performed. RESULTS: At 12 weeks, the sacubitril/valsartan (mean dose 382.6 ± 57.6 mg daily) group had increased peak VO2 of 13.1% (19.35 ± 0.99 to 21.89 ± 1.04 mL/kg/min) and enalapril (mean dose 34.4 ± 9.2 mg daily) 5.6% (18.58 ± 1.19 to 19.62 ± 1.25 mL/kg/min). However, no difference was found between groups (P = .332 interaction). At 24 weeks, peak VO2 increased 13.5% (19.35 ± 0.99 to 21.96 ± 0.98 mL/kg/min) and 12.0% (18.58 ± 1.19 to 20.82 ± 1.18 mL/kg/min) in sacubitril/valsartan (mean dose 400 ± 0 mg daily) and enalapril (mean dose 32.7 ± 11.0 mg daily), respectively. However, no differences were found between groups (P= .332 interaction). At 12 weeks, 6-MWT increased in both groups (sacubitril/valsartan: 459 ± 18 to 488 ± 17 meters [6.3%] and enalapril: 443 ± 22 to 477 ± 21 meters [7.7%]). At 24 weeks, sacubitril/valsartan increased 18.3% from baseline (543 ± 26 meters) and enalapril decreased slightly to 6.8% (473 ± 31 meters), but no differences existed between groups (P= .257 interaction). CONCLUSIONS: Compared to enalapril, sacubitril/valsartan did not substantially improve peak VO2 or 6-MWT after 12 or 24 weeks in participants with HFrEF. (NEPRIExTol-HF Trial, ClinicalTrials.gov number, NCT03190304).

Efficacy and Safety of Sacubitril/Valsartan in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction　- Results From the PARALLEL-HF Study.

BACKGROUND: In the Prospective Comparison of angiotensin receptor neprilysin inhibitor (ARNI) With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study, treatment with sacubitril/valsartan reduced the primary outcome of cardiovascular (CV) death and heart failure (HF) hospitalization compared with enalapril in patients with chronic HF and reduced ejection fraction (HFrEF). A prospective randomized trial was conducted to assess the efficacy and safety of sacubitril/valsartan in Japanese HFrEF patients.Methods and Results:In the Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients (PARALLEL-HF) study, 225 Japanese HFrEF patients (New York Heart Association [NYHA] class II-IV, left ventricular ejection fraction [LVEF] ≤35%) were randomized (1 : 1) to receive sacubitril/valsartan 200 mg bid or enalapril 10 mg bid. Over a median follow up of 33.9 months, no significant between-group difference was observed for the primary composite outcome of CV death and HF hospitalization (HR 1.09; 95% CI 0.65-1.82; P=0.6260). Early and sustained reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline were observed with sacubitril/valsartan compared with enalapril (between-group difference: Week 2: 25.7%, P<0.01; Month 6: 18.9%, P=0.01, favoring sacubitril/valsartan). There was no significant difference in the changes in NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score at Week 8 and Month 6. Sacubitril/valsartan was well tolerated with fewer study drug discontinuations due to adverse events, although the sacubitril/valsartan group had a higher proportion of patients with hypotension. CONCLUSIONS: In Japanese patients with HFrEF, there was no difference in reduction in the risk of CV death or HF hospitalization between sacubitril/valsartan and enalapril, and sacubitril/valsartan was safe and well tolerated.

Effects of sacubitril/valsartan on ventricular remodeling in patents with left ventricular systolic dysfunction following acute anterior wall myocardial infarction.

OBJECTIVE: The aim of this study was to investigate the effect of sacubitril/valsartan (Sal/Val) on left ventricular (LV) remodeling in patients with LV systolic dysfunction following acute anterior wall myocardial infarction (AAMI). METHODS: AAMI patients with LV systolic dysfunction were enrolled in this study. All patients underwent percutaneous coronary intervention. After hemodynamic stabilization, patients were randomly assigned either to group T (Sal/Val treatment) or group C (enalapril treatment). Changes in echocardiographic parameters and plasma biochemical markers were used to evaluate the effects of Sal/Val on LV remodeling and cardiac function. The incidence of major cardiac adverse events (MACEs) and adverse reactions during follow-ups was also recorded. RESULTS: In total, 137 eligible patients were prospectively included. Compared to group C, LV ejection fraction significantly improved (P < 0.05), while the LV end-systolic volume index and wall motion score index showed a tendency to decrease in group T. There was no difference in the LV end-diastolic volume index between groups. During follow-ups, the plasma N-terminal pro-B-type natriuretic peptide and soluble suppression of tumorigenesis-2 levels in both groups decreased (all P < 0.05), and the change was more prominent in group T. Additionally, drug-related adverse effects were similar between the two groups (P > 0.05); however, the incidence of MACEs was lower in group T than in group C (39.71% vs. 53.62%, P = 0.103), although the difference was insignificant. CONCLUSION: Sac/Val attenuated LV remodeling and dysfunction and was safe and effective in LV systolic dysfunction patients post AAMI.

Postnatal Enalapril to Improve Cardiovascular Function Following Preterm Preeclampsia (PICk-UP):: A Randomized Double-Blind Placebo-Controlled Feasibility Trial.

Hypertensive disease in pregnancy is associated with future cardiovascular disease and, therefore, provides an opportunity to identify women who could benefit from targeted interventions aimed at reducing cardiovascular morbidity. This study focused on the highest-risk group, women with preterm preeclampsia, who have an 8-fold risk of death from future cardiovascular disease. We performed a single-center feasibility randomized controlled trial of 6 months' treatment with enalapril to improve postnatal cardiovascular function. Echocardiography and hemodynamic measurements were performed at baseline (<3 days), 6 weeks, and 6 months postdelivery on 60 women. At randomization, 88% of women had diastolic dysfunction, and 68% had concentric remodeling/hypertrophy. No difference was seen in total vascular resistance (P=0.59) or systolic function (global longitudinal strain: P=0.14) between groups at 6 months. However, women treated with enalapril had echocardiographic measurements consistent with improved diastolic function (E/E'[the ratio of early mitral inflow velocity and early mitral annular diastolic velocity]: P=0.04) and left ventricular remodeling (relative wall thickness: P=0.01; left ventricular mass index: P=0.03) at 6 months, compared with placebo. Urinary enalapril was detectable in 85% and 63% of women in the enalapril arm at 6 weeks and 6 months, respectively. All women responded positively to taking enalapril in the future. Our study confirmed acceptability and feasibility of the study protocol with a recruitment to completion rate of 2.2 women per month. Importantly, postnatal enalapril treatment was associated with improved echocardiographic measurements; these early improvements have the potential to reduce long-term cardiovascular disease risk. A definitive, multicenter randomized controlled trial is now required to confirm these findings. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT03466333.

Safety of Enalapril in Infants: Data from the Pediatric Heart Network Infant Single Ventricle Trial.

OBJECTIVE: To assess the safety profile of angiotensin-converting enzyme inhibitor therapy in infants with single ventricle. STUDY DESIGN: The Pediatric Heart Network conducted a double-blind trial involving infants with single ventricle physiology randomized to receive enalapril or placebo and followed to 14 months of age. Data including demographics, drug administration, hemodynamic monitoring, laboratory measurements, adverse events, and survival were extracted from the public use data set and compared between the placebo and enalapril-treated groups. RESULTS: The Infant Single Ventricle trial randomized 230 patients, with 115 patients in each group. Initial enalapril dose was 0.10 mg/kg/d and median maximal dose was 0.38 mg/kg/d. There was no significant difference in change in blood pressure at study drug initiation or when resuming study drug after Glenn surgery. The incidence of hyperkalemia and neutropenia did not differ between groups. Renal dysfunction occurred in 3% of the enalapril group and none of the placebo patients, which was not statistically significant. There was a high frequency of serious adverse events in both groups. There was no difference in the frequency of heart transplant or death between groups. CONCLUSIONS: Enalapril did not have sustained hemodynamic effects at initiation or up-titration of drug. Creatinine and potassium were not different between groups, although renal dysfunction occurred more often in the patients on enalapril. Although efficacy of enalapril in neonates with single ventricle has not been demonstrated, the safety profile of angiotensin-converting enzyme inhibitors appears to be low risk in infants and children with significant heart disease.

Enalapril inhibits inflammatory osteolysis induced by wear debris in a mouse model.

OBJECTIVE: Aseptic loosening, the most frequent complication after total joint replacement, is probably caused by an inflammatory response to the shedding of wear debris from the implant. The only effective treatment is surgical revision. Using a mouse model, we investigated whether enalapril inhibits wear debris-induced inflammatory osteolysis. METHODS: Titanium (Ti) alloy particles were introduced, and calvarial bone from syngeneic mice was implanted into air pouches established in BALB/c mice. Histological and molecular analyses were performed with inflammatory tissue samples obtained from mice treated with and without enalapril. RESULTS: Enalapril inhibited tissue inflammation and inflammatory osteolysis induced by Ti particles, reducing pouch membrane thickness and decreasing inflammatory cell infiltration. In addition, enalapril inhibited the expression of the inflammatory cytokines vascular endothelial growth factor and tumor necrosis factor-α. CONCLUSIONS: Our study provides evidence that enalapril inhibits Ti particle-induced inflammatory osteolysis, and it may be a potentially useful treatment for aseptic loosening.