Converting Enzyme Inhibitor Therapy Research Articles

IgA Crescentic Nephropathy Post COVID-19 Infection: A Case Report

Background: Since the Coronavirus Disease 2019 (COVID-19) outbreak, individuals affected by COVID19 may be at risk of acquiring certain forms of glomerular disease. Several biopsy researches reveal that acute tubular injury, as well as glomerular nephropathy were common histological findings. However, to our knowledge, there is limited data regarding de novo diagnosis of IgA vasculitis in an adult following a COVID-19 infection. Case presentation: In the present case report, we document a 24-year-old Bahraini woman with new onset hypertension, microhematuria, proteinuria and decreased renal function after she recovered from COVID-19 infection. Renal biopsy after COVID-19 infection was performed and revealed IgA nephropathy without any evidence of COVID-19 infection. After a regimen of immunosuppression and angiotensin converting enzyme inhibitor therapy, the patient recovered and remained stable upon follow-up. Conclusions: When dealing with patient with COVID-19 infection and kidney involvement, it is vital to evaluate the underlying glomerular disease aggravation as well as virus-induced consequences. A kidney biopsy may be necessary to roll out rapidly progressive glomerular disease (RPGN). Keywords: COVID-19, microscopic hematuria, IgA nephropathy, acute kidney injury, case report.

Benefits and risks of dual inhibition of the renin– angiotensin aldosterone system for kidney disease

A In most cases, neither angiotensin converting enzyme (ACE) inhibitor therapy nor angiotensin II receptor blockers (ARBs) therapy alone inhibits completely the renin-angiotensin aldosterone system (RAAS). The drawbacks of ACE inhibitors are the ACE escape and aldosterone escape phenomenon, which are related to the tissue construction of angiotensin II and aldosterone by enzymes besides ACE. Combination of RAAS inhibition may avoid the ACE and aldosterone escape events that increases the efficiency of ACE inhibitors and ARBs and obstruct all angiotensin II and aldosterone actions accordingly. ONTARGET, largest trial of combination against alone RAAS blockade therapy in patients with vascular diseases or diabetes along with disease of such organs displayed that combination therapy advised no extra-benefit in reducing advance to end-stage renal disease in diabetic patients and decreasing the risk of cardiovascular. Certainly, in this trial, the administration of dual RAAS blockade therapy of an ACE inhibitor plus ARB was correlated with a higher degree of side effects in comparison to monotherapy. In addition to the study of ONTARGET, the ORIENT, VALIANT, VA NEPHRON-D and HALT-PKD trials also proved this finding. Adverse events associated with combination therapy of ACE inhibitor plus ARB is including hyperkalemia, low blood pressure, acute kidney injury (AKI) and withdrawal because of side effects.

ARNI versus ACEI/ARB in Reducing Cardiovascular Outcomes after Myocardial Infarction.

AimsThis study aimed to compare the efficacy of angiotensin receptor‐neprilysin inhibitor (ARNI) therapy with angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) therapy for cardiovascular outcomes in patients with acute myocardial infarction (AMI).Methods and resultsData were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University between January 2016 and December 2020. A total of 7556 AMI patients were screened for eligibility. Propensity score matching based on age, sex, blood pressure, kidney function, baseline left ventricular ejection fraction (LVEF), and cardiovascular medication were conducted, resulting in 291 patients with AMI being assigned to ARNI, ACEI, and ARB group, respectively. Patients receiving ARNI had significantly lower rates of the composite cardiovascular outcome than ACEI {hazard ratio [HR] 0.51, [95% confidence interval (CI), 0.27–0.95], P = 0.02}, and ARB users [HR 0.47, (95%CI, 0.24–0.90), P = 0.02]. Patients receiving ARNI showed lower rates of cardiovascular death than ACEI [HR 0.37, (95%CI, 0.18–0.79), P = 0.01] and ARB users [HR 0.41, (95%CI, 0.18–0.95), P = 0.04]. Subgroup analysis indicated that patients with LVEF no more than 40% tend to benefit more from ARNI as compared with ACEI [HR 0.30, (95%CI, 0.11–0.86), P = 0.01] or ARB [HR 0.21, (95%CI, 0.04–1.1), P = 0.05]. Patients aged no more than 60 years exhibited reduced composite endpoints [HR for ARNI vs. ARB: 0.11, (95%CI, 0.03–0.46), P = 0.002].ConclusionsIn patients with AMI, ARNI was superior to ACEI/ARB in reducing the long‐term adverse cardiovascular outcomes. Subgroup analysis further indicates that ARNI is more likely to benefit patients with LVEF less than 40% and aged less than 60 years.

Neprilysin inhibition does not alter dynamic of proenkephalin-A 119-159 and pro-substance P in heart failure.

AimsAs NEP degrades many substrates, the specific therapeutic mechanism of NEP inhibition with angiotensin receptor neprilysin inhibitor (ARNi) in heart failure with reduced ejection fraction (HFrEF) is not entirely evident. The aim of this study was to investigate the response of two substrates of NEP—the tachykinin and enkephalin systems—to the initiation of ARNi therapy in HFrEF.Methods and resultsBetween 2016 and 2018, 141 consecutive patients with stable HFrEF [74 with initiation of ARNi and 67 controls on continuous angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy] were prospectively enrolled. Plasma proenkephalin‐A 119‐159 (PENK) and pro‐substance P (pro‐SP) were serially determined. Proenkephalin‐A 119‐159 and pro‐SP correlated strongly with each other (rs = 0.67, P < 0.001) and kidney function (rs = −0.66, P < 0.001 and rs = −0.54, P < 0.001) and modestly with NT‐proBNP (r s = 0.32, P < 0.001 and r s = 0.24, P = 0.006, respectively). Concentrations of circulating PENK were slightly elevated after 1 and 2 year follow‐up compared with baseline (BL) [BL median: 67.4 pmol/L (IQR: 57.3–89.8), 1 year: 83.5 pmol/L (IQR: 62.4–111.6), 2 years: 92.3 pmol/L (IQR: 63.1–101.9); BL vs. 1 year: P = 0.017 and BL vs. 2 years: P = 0.019] in the overall analysis, but lost significance at 2 year follow‐up when assessed in paired subanalysis (P = 0.116). Plasma pro‐SP levels remained comparable during the entire follow‐up [BL median: 78.3 pmol/L (IQR: 67.9–90.6), 1 year: 75.9 pmol/L (IQR: 58.6–96.3), 2 years: 79.7 pmol/L (IQR: 59.9–105.3); P = ns for both timepoints]. Biomarker patterns of ARNi patients were independent from baseline therapy, that is, ACEi or ARB (P > 0.05 between groups).ConclusionsAlthough enkephalins and SP are known substrates of NEP, NEP inhibition by ARNi does not clearly affect the circulating precursors PENK and pro‐SP in HFrEF.

Cardiovascular disease and asymptomatic childhood cancer survivors: Current clinical practice.

BackgroundIt is poorly understood how cardiovascular screening in asymptomatic childhood cancer survivors (CCS) is applied to and impacts clinical care.ObjectivesTo describe the current role of cardiovascular screening in the clinical care of asymptomatic CCS.MethodsAt 50 pediatric academic medical centers, a childhood cancer survivorship clinic director, pediatric cardiologist, and adult cardiologist with a focus on CCS were identified and invited to participate in a survey. Surveys were managed electronically. Categorical data were analyzed using nonparametric methods.ResultsOf the 95 (63%) respondents, 39% were survivorship practitioners, and 61% were cardiologists. Eighty‐eight percent of survivorship practitioners reported that greater than half of CCS received cardiovascular screening. CCS followed by adult cardiology were more likely to be seen by a cardio‐oncologist. Those followed by pediatric cardiology were more likely to be seen by a heart failure/transplant specialist. Common reasons for referral to cardiology were abnormal cardiovascular imaging or concerns a CCS was at high risk for cardiovascular disease. Ninety‐two percent of cardiologists initiated angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy for mild systolic dysfunction. Adult cardiologists initiated beta‐blocker therapy for less severe systolic dysfunction compared to pediatric cardiologists (P < .001). Pediatric cardiologists initiated mineralocorticoid therapy for less severe systolic dysfunction compared to adult cardiologists (P = .025). Practitioners (93%) support a multi‐institutional collaboration to standardize cardiovascular care for CCS.ConclusionsWhile there is much common ground in the clinical approach to CCS, heterogeneity is evident. This highlights the need for cohesive, multi‐institutional, standardized approaches to cardiovascular management in CCS.

Cost-Effectiveness of Earlier Transition to Angiotensin Receptor Neprilysin Inhibitor in Patients With Heart Failure and Reduced Ejection Fraction

BackgroundAngiotensin receptor neprilysin inhibitor (ARNi) therapy improves clinical outcomes in patients with heart failure and reduced left ventricular ejection fraction. However, ARNi therapy uptake remains modest, potentially in part due to perceived cost considerations of early transition from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy. MethodsWe constructed a decision-analytic Markov model to assess cost-effectiveness of 3 different ARNi initiation strategies according to timing of initiation: (1) de novo, or immediate initiation at baseline, (2) Early or after 3 months, or (3) Late, or after 9 months. Initiation strategies were compared with (4) current care, with utilization of ARNi derived from a large observational database. Total costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) were estimated over a 5-year time horizon in the base case analysis. ResultsCurrent care was associated with the lowest total cost (CAD$26,664) and accrued benefit (3.28 QALYs). The de novo strategy yielded an ICER of $34,727 per QALY gained, whereas Early and Late initiation strategies yielded a less favourable ICER per QALY gained of $35,871 and $40,234, respectively. The model was most sensitive to the cost of ARNi therapy. ConclusionA strategy of de novo ARNi initiation is economically attractive and becomes less favourable as the delay of initiation increases. Our results suggest that ARNi therapy should be initiated as soon as possible for patients with heart failure and reduced left ventricular ejection fraction.

Phenotypic spectrum and antialbuminuric response to angiotensin converting enzyme inhibitor and angiotensin receptor blocker therapy in pediatric Dent disease.

BackgroundTo characterize the phenotypic spectrum and assess the antialbuminuric response to angiotensin converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB) therapy in a cohort of children with Dent disease.MethodsThe patients’ clinical findings, renal biopsy results, genetic and follow‐up data were analyzed retrospectively. Mutations in CLCN5 or OCRL were detected by next‐generation sequencing or Sanger sequencing.ResultsOf 31 Dent disease boys, 24 carried CLCN5 and 7 carried OCRL mutations. Low molecular weight proteinuria and albuminuria were detected in all cases. Nephrotic‐range proteinuria and severe albuminuria were identified in 52% and 62% of cases, respectively; by 7 years of age, 6 patients had hematuria and nephrotic‐range proteinuria, and 7 patients had hematuria and moderate to severe albuminuria. In addition to disease‐related renal features, patients with Dent‐1 disease also presented with congenital cataract (1/9) and developmental delay (2/7). Seventeen of 31 patients underwent renal biopsy. Glomerular changes included mild glomerular lesions, mesangial proliferative glomerulonephritis and focal segmental glomerular sclerosis. Thirteen of the 31 patients had follow‐up records and received ACE inhibitor and/or ARB treatment for more than 3 months. After a median 1.7 (range 0.3–8.5) years of treatment, a reduction in the urinary microalbumin‐to‐creatinine ratio was observed in 54% of children.ConclusionsHematuria with nephrotic‐range proteinuria or moderate to severe albuminuria was common in Dent disease patients. Extrarenal manifestations were observed in Dent‐1 patients, which extends the phenotypic spectrum. In addition, ACE inhibitors and ARBs are well tolerated, and they are partially effective in controlling albuminuria.

The Effect of Angiotensin Converting Enzyme Inhibitor Therapy on Mortality and Morbidity in Patients Undergoing Coronary Artery Bypass Grafting Surgery

The Effect of Angiotensin Converting Enzyme Inhibitor Therapy on Mortality and Morbidity in Patients Undergoing Coronary Artery Bypass Grafting Surgery

BAG6 Variant rs805303 is Nominally Associated with ACEi-induced Cough among Filipinos

Cough is a common side effect of angiotensin converting enzyme inhibitor (ACEi) therapy. The incidence of ACEi-induced cough has been shown to correlate with genetic variation among different populations. This study aimed to determine the association of candidate genetic polymorphisms with ACEi-induced cough among Filipinos. Two hundred twenty (220) participants on ACEi therapy pressure-lowering in an unmatched case-control study (82 cases with ACEi-induced cough and 138 controls). Genomic DNA samples were extracted and genotyped for selected genetic variants. The association of genetic variants and clinical factors with ACEi-induced cough was determined using regression analyses. Univariate logistic regression showed that the BAG6 variant rs805303 is nominally associated with ACEi-induced cough among Filipinos, at a per-comparison error rate (PCER) of 0.05 (OR 2.10, p = 0.016). The association of the variant with ACEi cough was statistically significant after multiple regression analysis (adjusted OR 2.09, p = 0.022) while adjusting for confounding clinical factors (sex, alcohol intake, and diastolic blood pressure). Further studies are needed to validate these findings.

P1568Cardiac biomarkers for the prediction of cardiotoxicity in cancer patients: a meta-analysis

Abstract Background Cancer therapy-related heart failure is the most concerning cardiac adverse event in patients undergoing cancer therapy. Valid diagnostic measures are fundamental for a timely diagnosis but systematic data on the use of diagnostic parameters in this collective is sparse. Cardiac biomarkers may be beneficial for diagnosis and screening of cancer therapy-related heart failure. Purpose Systematic data for cardiac biomarkers in cancer therapy-related cardiotoxicity is urgently needed to establish guideline recommendations. We therefore conducted the present systematic review and meta-analysis to assess cardiac troponin and (N-terminal pro) brain natriuretic peptide (BNP/NT-proBNP) in the prediction of left ventricular (LV) systolic dysfunction in cancer patients. Methods Cochrane, PubMed, Web of Science, and Wiley Library were screened for studies investigating cardiac troponin or BNP/NT-proBNP in cancer patients receiving cytotoxic chemotherapy with and without anthracyclines, human epidermal growth factor receptor 2 (HER2) inhibitor therapy and radiotherapy. Reduced LV ejection fraction (LVEF) was defined as primary endpoint. Results A total of 5772 patients from 58 studies were included. Chemotherapy and HER2 inhibitor therapy was associated with an elevation of troponin levels above the 99th percentile (odds ratio (OR) = 14.3; 95% confidence interval (CI): 6.9–29.5). Patients treated with anthracyclines and high-dose chemotherapy had the highest rates of troponin elevation (OR = 17.5; 95% CI: 10.1–30.2 for anthracyclines; OR = 75.1; 95% CI: 4.4–1296.9 for high-dose chemotherapy, respectively). The risk for LVEF impairment was increased in troponin positive patients compared to troponin negative patients under high-dose regimens (OR = 97.9; 95% CI: 52.1–183.8) and anthracyclines with and without concomitant HER2 inhibitors (OR = 7.0; 95% CI: 1.4–34.1 and OR = 10.5; 95% CI: 2.0–54.3). Cardiac troponin below the 99th percentile had a negative predictive value of 94% for the prediction of cardiotoxicity. Absolute plasma BNP/NT-proBNP was increased in patients with LV dysfunction (standardized mean difference = 0.6; 95% CI = 0.0–1.2) but pathologically increased BNP/NT-proBNP did not predict decreased LVEF (OR = 2.0; 95% CI: 0.9–7.2). Preventive β-blocker therapy and angiotensin converting enzyme (ACE) inhibitor therapy was associated with decreased troponin elevation compared to control (OR = 2.9; 95% CI: 1.1–7.3; Figure 4). The effect was more pronounced in ACE inhibitor-treated patients compared to β-blocker-treated patients (Chi2 = 4.4; p=0.04; I2 = 77.4%). Conclusion Elevated troponin levels predict left ventricular dysfunction in cancer patients and a decrease in troponin may indicate response to cardioprotective therapy in cancer therapy-related cardiotoxicity. Cardiac troponin qualifies as a screening test to identify patients at high risk for manifest cardiotoxicity who require referral to cardio-oncology units. Acknowledgement/Funding IFORES research grant of the Medical Faculty, University Duisburg-Essen, Essen, Germany

P3120Prevention of heart failure in treatments with trastuzumab and anthracyclines: a meta-analysis

Abstract Background Trastuzumab and anthracyclines are conventional chemotherapies used in breast cancer. Unfortunately, they are associated with a decrease in left ventricular function potentially leading to heart failure (HF). In order to prevent this, randomised controlled trials (RCTs) assess the preventive effect of concomitant beta-blocker (BB), angiotensin receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) therapy during chemotherapy. Purpose To assess the preventive effect of BB, ARB or ACEIs on left ventricular ejection fraction (LVEF) during trastuzumab and anthracycline treatment in patients without HF. Methods Our primary outcomes were the effect of BBs or ARB/ACEIs during 1) trastuzumab and 2) anthracycline treatment. Secondary outcomes were the distinct effects of 1) BBs and 2) ARB/ACEIs in either trastuzumab or anthracycline treatments. Through the search term “(RCTs), prevention, cancer chemotherapy and cardiotoxicity” in PubMed, studies were selected, excluding those without randomising to a BB, ARB/ACEI and a placebo control group during chemotherapy. Means of the LVEF and the standard deviation (SD) post-chemotherapy were applied. Meta-analyses estimated the standardised mean difference (SMD) in the LVEF. Heterogeneity was calculated as the I2. Results A total of 7 studies (Table 1) were included in the analysis. Between 93 and 100% were woman. Age varied from 41 to 51 years. Treatment time varied from 12 to 52 weeks. Concomitant BB or ARB/ACEI therapy during trastuzumab treatment was not associated with the LVEF, significantly (Fig. 1A; p=0.07). Oppositely, in the anthracycline regime the LVEF remained significant higher in the concomitant BB and ARB/ACEI groups as compared to controls (Fig. 1B). BB and ARB/ACEI separation in the analysis showed both to influence the LVEF positively independent of chemotherapy (P=0.03 &amp; p=0.005). Table 1 Study reference Year Chemotherapies Preventive drugs Pituskin et al., “Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity.” 2017 Trastuzumab Perindopril. bisoprolol Gulati et al., “Prevention of Cardiac Dysfunction during Adjuvant Breast Cancer Therapy (PRADA).” 2016 Trastuzumab Candesartan, metoprolol Boekhout et al., “Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.” 2016 Trastuzumab Candesartan Janbabai et al., “Effect of Enalapril on Preventing Anthracycline-Induced Cardiomyopathy.” 2017 Anthracycline Enalapril Nabati et al., “Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-Induced Cardiotoxicity.” 2017 Anthracycline Carvedilol Tashakori Beheshti et al., “Carvedilol Administration Can Prevent Doxorubicin-Induced Cardiotoxicity: A Double-Blind Randomized Trial.” 2016 Anthracycline Carvedilol Kaya et al., “Protective Effects of Nebivolol against Anthracycline-Induced Cardiomyopathy: A Randomized Control Study.” 2013 Anthracycline Nebivolol Figure 1 Conclusions Concomitant BB and ARB/ACEI therapy both favoured maintenance of the LVEF during trastuzumab and anthracyclines regimens as compared to controls.

Angiotensin receptor blockers as an alternative to angiotensin converting enzyme inhibitors

Cardiovascular disease is the leading cause of mortality in the UK with ischaemic heart disease and heart failure being the main contributors. The renin-angiotensin aldosterone system has an essential role in cardiovascular pathophysiology by increasing preload, afterload and left ventricular workload. Angiotensin converting enzyme inhibitor therapy is a first-line therapy in this patient population except for those who are intolerant of angiotensin converting enzyme inhibitors. Angiotensin receptor blockers are deemed as a safe alternative while achieving the same clinical benefit. Common adverse effects are hypovolaemia, hyperkalemia and renal dysfunction. The nursing role involves cardiovascular assessment, monitoring for adverse effects and patient education.

Perceptions of Canadian Vascular Surgeons Toward Pharmacologic Risk Reduction in Patients with Peripheral Artery Disease: 2018 Update

Vascular surgeons have a central role in managing peripheral artery disease (PAD). This study assessed their knowledge, attitudes, and behaviors regarding pharmacologic risk reduction in PAD and results were compared to a similar 2004 survey conducted by our group. An online questionnaire was administered to 161 active members of the Canadian Society for Vascular Surgery. Forty-eight participants (30%) completed the survey. Recommended targets for low-density lipoprotein cholesterol, blood pressure, and glucose were known by 52%, 38%, and 50% of vascular surgeons, respectively. Almost all participants recognized antiplatelet dosages and statin indications, but less than half could identify indications (29%) and precautions (44%) for angiotensin converting enzyme (ACE) inhibitor therapy. A majority (58%) routinely evaluate risk factors in <50% of their patients. Most vascular surgeons regularly provide risk reduction counseling, but less than 10% initiate or modify antihypertensive or ACE inhibitor therapy. Compared to 2004, knowledge of targets and indications/precautions for common cardiovascular medications and frequency of risk factor assessment have not changed. Rates of counseling for diabetes control and statin prescription have improved, but remain suboptimal. Regarding newer medications with cardiovascular benefit, less than 10% would prescribe proprotein convertase subtilisin/kexin type 9 and sodium-glucose cotransporter 2 inhibitors if they were available. The majority of vascular surgeons rate their PAD risk reduction knowledge as average and support an up-to-date Canadian PAD guideline. Most participants believe that risk reduction therapy is best provided by family physicians and internists, but also acknowledge that vascular surgeons should be well-versed in assessing and managing risk factors in PAD. Significant knowledge and action gaps exist among Canadian vascular surgeons with regards to pharmacologic cardiovascular risk reduction in PAD. Although there is recognition that vascular surgeons are central to the medical management of patients with PAD, few routinely evaluate risk factors and prescribe medications. There is little evidence of sufficient improvement since 2004. New educational and clinical strategies are needed to improve PAD risk reduction pharmacotherapy among Canadian vascular surgeons.

Reduction of Sympathetic Innervation Following Transition to Sacubitril/Valsartan in the Remodel (Reverse Remodeling Effects of Entresto) Study

Background Increased sympathetic nervous system activity is commonly observed in heart failure with reduced ejection fraction and is one cause of pathological structural remodeling of the left ventricle. Sacubitril/valsartan reduces mortality and heart failure hospitalizations, but its effect on sympathetic nervous system activity is unknown. Methods Patients enrolled in the prospective, longitudinal REMODEL study underwent 123-meta-iodobenzylguanidine scintigraphy prior to and three months following conversion from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy to sacubitril/valsartan. The early heart-to-mediastinum (H/M) ratio, late H/M ratio and washout rate were calculated. Baseline and on-therapy values were compared using a paired t-test analysis. Results 40 patients were enrolled in this study. The mean age was 55 ± 12 years, 25 (63%) were male, and 30 (75%) had a non-ischemic heart failure etiology. Following transition to sacubitril/valsartan therapy, the late H/M ratio increased from 1.39 ± 0.19 to 1.52 ± 0.19 (p Conclusions Addition of sacubitril/valsartan to baseline heart failure therapy resulted in a decrease in cardiac sympathetic activity, as shown by a decrease in both the early and late H/M ratio and an increase in the washout rate on MIBG imaging. The decrease in sympathetic nervous system activity may underlie the improvement in survival seen with sacubitril/valsartan and can serve as a good measure of medication response.

Angiotensin converting enzyme inhibitors and interstage failure in infants with hypoplastic left heart syndrome.

Angiotensin converting enzyme inhibitors are commonly prescribed medications after the Norwood procedure. There are little data that can be used to determine if angiotensin converting enzyme inhibitors improve interstage outcomes in children with single ventricle defects. The objective of this study was to investigate the relationship between angiotensin converting enzyme inhibitors and interstage failure among infants born with hypoplastic left heart syndrome. We conducted a retrospective cohort study using data from the National Pediatric Cardiology Quality Improvement Collaborative database (collected between 2008 and 2015). We used logistic regression models to assess the exposure-outcome associations and propensity score matching to account for differences in baseline patient characteristics associated with use of angiotensin converting enzyme inhibitors. A total of 1487 neonates participated in the study. Thirty-nine percent of patients were prescribed angiotensin converting enzyme inhibitors after the Norwood procedure; 11% experienced interstage failure (death, heart transplantation, and not being a candidate for the second-stage surgery). Before propensity score matching, patients receiving angiotensin converting enzyme inhibitors were significantly more likely to experience interstage failure, compared to patients not on angiotensin converting enzyme inhibitors (OR = 1.44; 95% CI: 1.04, 1.99; P = 0.03). Although there was an increased odds of interstage failure among patients receiving angiotensin converting enzyme inhibitors compared to patients not receiving angiotensin converting enzyme inhibitors in the propensity score-matched cohort, this association was not significantly different (adjusted OR = 1.29; 95% CI: 0.88, 1.95; P = 0.18). Angiotensin converting enzyme inhibitor therapy did not demonstrate a beneficial effect on interstage failure among infants with hypoplastic left heart syndrome, even when patient characteristics associated with the use of angiotensin converting enzyme inhibitors were considered.

SAFETY OF ENALAPRIL IN INFANTS: DATA FROM THE PEDIATRIC HEART NETWORK INFANT WITH SINGLE VENTRICLE TRIAL

Background: Angiotension converting enzyme (ACE) inhibitor therapy has been shown to improve ventricular function and clinical outcomes in adult patients with heart failure. Despite the lack of safety and efficacy data, empiric use of ACE inhibitor therapy is common in infants and children with

The effects of alpha 1-adrenoceptor blockade and angiotensin converting enzyme inhibition on central and brachial blood pressure and vascular reactivity: the doxazosin\u2013ramipril study

We aimed to study whether inhibition of the renin–angiotensin–aldosterone system has effects on vascular structure and function beyond the effects on blood pressure reduction alone. Patients with mild-to-moderate hypertension (n = 61, age 54 ± 12 years, 34% women) received the angiotensin converting enzyme inhibitor ramipril 10 mg or the alpha 1-adrenoceptor blocker doxazosin 8 mg double-blind for 12 weeks. Aortic blood pressure, pulse wave velocity, and augmentation index were assessed by applanation tonometry. Endothelial function was studied by forearm post-ischemic flow mediated vasodilatation and by pulse wave analysis with beta 2-adrenoceptor agonist stimulation. Skin microvascular reactivity was assessed by laser Doppler fluxmetry and iontophoresis. Treatment with doxazosin or ramipril reduced aortic and brachial blood pressures (all P < 0.001), with greater reductions in aortic than brachial systolic blood pressures (P = 0.021) and aortic/brachial pulse pressure ratio (P = 0.005). Compared to doxazosin, ramipril reduced carotid-femoral and carotid-radial pulse wave velocity (both P < 0.05). Forearm endothelial dependent and independent vasodilatation, assessed by post-ischemic flow mediated vasodilatation and glyceryl trinitrate, and by pulse wave analysis remained unchanged by both doxazosin and ramipril. In addition, skin microvascular endothelial dependent (acetylcholine) and independent vasodilatation (sodium nitroprusside) remained unchanged. In conclusion, ramipril reduced indices of aortic stiffness, suggesting that angiotensin converting enzyme inhibitor therapy may have effects beyond blood pressure reduction. However, treatment did not appear to influence endothelial function. Evidence of endothelial dysfunction and its possible improvement by antihypertensive treatment might require more advanced hypertension.This study is registered at ClinicalTrials.gov (NCT02901977) and at EudraCT (# 2007-000631-25).

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy.

Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects with an eGFR between 25 and 60 ml/min per 1.73 m2 and macroalbuminuria defined by a urinary albumin-to-creatinine ratio >300 mg/g, were randomly assigned 3:1, respectively, to receive PF-00489791 (20 mg) or placebo orally, once daily for 12 weeks. Using the predefined primary assessment of efficacy (Bayesian analysis with informative prior), we observed a significant reduction in urinary albumin-to-creatinine ratio of 15.7% (ratio 0.843; 95% credible interval 0.73 to 0.98) in response to the 12-week treatment with PF-00489791 compared with placebo. PF-00489791 was safe and generally well tolerated in this patient population. Most common adverse events were mild in severity and included headache and upper gastrointestinal events. In conclusion, the safety and efficacy profile of PDE5 inhibitor PF-00489791 supports further investigation as a novel therapy to improve renal outcomes in DN.

Simultaneous subacute coronary artery stent thrombosis in a carrier of two CYP2C19 loss–of function polymorphisms (*2/*3)

Simultaneous subacute coronary artery stent thrombosis in a carrier of two CYP2C19 loss–of function polymorphisms (*2/*3)

Pickering Syndrome precipitated by Angiotensin Converting Enzyme Inhibitor

Pickering syndrome is an under recognised cardio-renal syndrome where life threatening flash pulmonary edema develops in the setting of diastolic dysfunction of the heart. Renal artery stenosis induced activation of sympathetic nervous system and renin-angiotensin-aldosterone system result in fluid retention; such fluid retention in the setting of diastolic dysfunction results in flash pulmonary edema. Most patients who present with pickering syndrome have normal coronary circulation and left ventricular systolic function. We here present a case of pickering syndrome that was precipitated by initiation of angiotensin converting enzyme inhibitor therapy in a patient with undiagnosed unilateral renal artery stenosis. The incidence of flash pulmonary edema decreases on revascularization of renal artery stenosis. Underlying renal artery stenosis should be suspected in a patient with recurrent flash pulmonary edema as such patients merit from revascularization of renal artery stenosis. To the best of our knowledge we are the first to report angiotensin converting enzyme inhibitors as a precipitator of pickering syndrome.