Angiotensin-converting Enzyme Inhibitor Therapy Research Articles

Effect of Angiotensin‐converting Enzyme Inhibition on Systemic and Renal RAS Components in a Hyperandrogenemic Rat Model of PCOS

Polycystic Ovary Syndrome (PCOS) is characterized by androgen excess, oligo/anovulation, and polycystic ovaries. Obesity, insulin resistance (IR) and increased blood pressure (BP) are associated with PCOS. Therapeutic options for PCOS are limited and the mechanisms responsible for the cardiometabolic complications seen in PCOS are uncertain. It is unclear if androgen-mediated increases in BP contribute to obesity and/or IR in PCOS. The renin angiotensin system (RAS), a regulator of BP, is affected by androgens and is associated with increased BP in PCOS. To investigate the role of androgens and the contribution of the RAS in PCOS, RAS inhibition via an angiotensin-converting enzyme inhibitor (ACEi) was performed in a PCOS-like rat model. We hypothesized that ACEi would attenuate obesity and IR in PCOS. Female SD rats (4 week old) received dihydrotestosterone (DHT, 7.5 mg/ 90 days) pellets (HAF) subcutaneously or sham surgeries (CON). The rats were then assigned tap water or tap water with the ACEi, enalapril (ENA) (250mg/L) for n=10/group. At the end of the study (16 week old) body weight (BW), body composition by EchoMRI, and IR by HOMA-IR were assessed. Renal RAS gene expression was assessed by qPCR. BP was measured by radiotelemetry and plasma and renal ACE and ACE2 activities were assessed. HAF had increased BW, fat mass and IR vs CON. ENA reduced BW in only HAF. Overall, ENA decreased fat mass, and the decrease in HAF neared significance. ENA did not attenuate IR in HAF. In HAF, angiotensinogen (Agt) mRNA was increased in the renal cortex and medulla, while ACE and angiotensin II receptor type 1a (Atr1a) mRNA was increased in the medulla vs CON. In HAF, ENA had no impact on renal Agt, ACE or Atr1a mRNA. ACE2 mRNA was increased in the medulla of HAF vs CON, and ENA increased medulla ACE2 mRNA in both HAF and CON. HAF had increased BP, and ENA decreased BP in both HAF and CON by a similar degree. Overall, ENA decreased plasma ACE activity but only increased plasma ACE2 activity in HAF. ENA increased cortical ACE2 activity in both HAF and CON. In summary, ACEi therapy in a PCOS model reduced BW, BP and adiposity but had no impact on IR. Renal classic RAS gene expression is upregulated in the HAF but unchanged by ENA. Furthermore, only ACE2 mRNA expression was altered in the HAF with ENA. In addition, the expression of other RAS component genes that were unchanged by ACEi in HAF were significantly impacted by ACEi in CON. This reveals a complex interaction between androgen exposure and renal RAS component gene expression. Increased BP in the HAF did not correlate with plasma or renal ACE or ACE2 activities. Chronic RAS inhibition may be a promising therapeutic approach for androgen-mediated increases in BP and obesity in AE-PCOS, though additional therapy would be needed for IR.

The Impact of Angiotensin Converting Enzyme Inhibition and/or Angiotensin Receptor Blockade on Tissue Expression of the SARS‐CoV‐2 Receptor ACE2 in Mice

The angiotensin‐converting enzyme 2 (ACE2) is an established receptor and entry point for the novel SARS‐CoV‐2 coronavirus, as the spike protein on the viral envelope binds the ACE2 receptor. Published histological profiling revealed ACE2 to be highly expressed on human lung alveolar epithelial cells and on enterocytes of the small intestine, as well as on arterial and venous endothelial cells. Given the widespread abundance of ACE2 across tissues, there has been much speculation regarding whether ACE inhibitors (ACEi) and/or Angiotensin Receptor Blockers (ARB) might alter tissue ACE2 expression and thereby change the risk of transmission or development of severe complications. Therefore, the aim of this ongoing study is to measure the impact of ACEi and ARB singly and in combination versus placebo control on tissue distribution of ACE2 in male and female mice.A factorial design was employed with the following exposures: ACEi (lisinopril, 10 mg/kg/day), ARB (losartan, 10 mg/kg/day), both drugs, or water control. Drugs were delivered via drinking water. C57BL/6J Mice were 8 weeks of age at the start of the experiment. After 21 days of treatment, four mice (two males and two females) from each treatment group were euthanized, followed by perfusion and tissue collection. 12 more untreated mice were combined with the placebo group to increase the sample size of this reference group to 16 (8 males, 8 females). ACE2 protein abundance in brain, kidney, liver, lung, and small intestine was measured by ELISA (Abcam) and normalized to BCA‐measured total protein. Two‐way ANOVA was performed to test for differences in ACE2 levels by organ or sex among untreated mice; Mann‐Whitney tests were performed to compare each drug treatment group to the control group.Among untreated mice, ACE2 levels differed by organ (p < 0.01), but there were no differences between males and females for a given organ (p = 0.20). Males and females were combined for subsequent analyses. After 21 days of treatment, ACEi, ARB, and the combination therapy lowered ACE2 tissue abundance compared to untreated mice in the brain (ACEi p = 0.04; ARB p = 0.04; ACEi+ARB p = 0.01), kidney (ACEi p = 0.03; ARB p = 0.02; ACEi+ARB p = 0.02), and lung (ACEi p = 0.01; ARB p = 0.01; ACEi+ARB p = 0.01). ACEi, but not ARB or combination therapy, lowered ACE2 tissue abundance in the liver (p = 0.02). None of the treatments changed ACE2 tissue abundance in the small intestine.These results indicate that ACEi, ARB, or combination therapy reduces levels of ACE2, the SARS‐CoV‐2 receptor, in key tissues affected by the virus, including lung, kidney, and brain. An ongoing validation study will evaluate ACE2 protein and gene expression at earlier time points, as well as after discontinuation of treatment. These results will provide valuable insight into the risk or potential benefit of starting or stopping ACEi, ARB, or combination therapy during the COVID‐19 pandemic.

REFERENCE RANGES AND CUT-OFF VALUES FOR SIMULTANEOUS MONITORING OF RAS BLOCKER EFFICACY AND SCREENING FOR SECONDARY HYPERTENSION USING RAAS TRIPLE-A PROFILING

Objective: Uncontrolled hypertension is caused by various factors including compliance issues, patient specific drug uptake and elimination profiles or secondary forms of hypertension, resulting in blood pressure control rates of less that 50%. RAAS Triple-A profiling is based on a high-throughput mass-spectrometry assay for Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone in serum samples. Quantified hormone levels are used to calculate markers for plasma-renin-activity (PRA-S), plasma angiotensin-converting-enzyme activity (ACE-S) and adrenal aldosterone secretion (AA2-Ratio). The integrated analysis of these molecular markers together with drug prescription information allows to identify the underlying cause of uncontrolled hypertension, including primary aldosteronism and insufficiency in drug adherence or dosing for ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs). Design and method: 500 participants with prescribed antihypertensive drugs were selected from the “Cooperative Health Research in South Tyrol” (CHRIS) study, a population-based study from an Alpine rural environment. Five age- and sex-matched groups (N = 100 each) selected were individuals on single therapy with ARBs, ACEi or beta blockers, and on single pill dual therapy of ACEi or ARBs in combination with diuretics. Three age and sex-matched control groups of 100 participants each were included, being normotensive, hypertensive (treated with non-antihypertensive drugs) and hypertensive participants without any prescribed medication. Results: RAAS Triple-A analysis was performed in all individuals and reference values for Ang I, Ang II, Aldosterone, PRA-S, ACE-S and AA2-Ratio were established in appropriate sub-populations. Drug monitoring by LC-MS/MS based quantification of anti-hypertensive drugs in serum was used as a gold standard to determine cut-off values for compliance with ARB and ACEi therapy and ROC analysis was performed using angiotensin-based biomarkers. Conclusions: RAAS Triple-A profiling for the first time provides an interpretation of blood pressure regulating effector hormone levels under consideration of individual drug prescriptions and its dynamic molecular impact on a patient's physiology. The resulting model for patient stratification paves the way for personalized treatment of hypertension, simultaneously screening for secondary hypertension and drug adherence/dosing based on a single high throughput routine blood test applied to patients while being on their standard therapy.

SCREENING OF PRIMARY ALDOSTERONISM WITH A NOVEL RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM TRIPLE-A ANALYSIS

Abstract Objective: Primary aldosteronism (PA) is the most frequent cause of endocrine hypertension and its screening is expected to become a routine evaluation in hypertensive patients. The interference of antihypertensive medications with the Aldosterone-to-Renin-Ratio (ARR) is a major confounder during screening testing. Renin-angiotensin-aldosterone system (RAAS) triple-A analysis is a novel liquid chromatography/tandem mass spectrometry diagnostic assay that allows simultaneous quantification of aldosterone, equilibrium angiotensin I (eqAngI) and equilibrium angiotensin II (eqAngII) from a single serum sample. The aim of the present study was to assess the reliability of RAAS triple-A analysis for the screening of PA. Design and method: We performed a comparative evaluation of the diagnostic performance of the Aldosterone-to-AngII-Ratio (AA2R) and five renin based diagnostic ratios, differing in methods to determine aldosterone levels and renin activity, either based on chemiluminescence or radioimmunoassay. Results: We prospectively enrolled a cohort of 110 patients with hypertension and suspected PA referred to a single hypertension unit (33 patients with confirmed PA and 77 with essential hypertension). All ratios showed comparable areas under the curves ranging between 0.924 and 0.970 without significant differences between each other. The evaluation of the AngII-to-AngI ratio revealed persistent ACE inhibitor intake in some patients as cause for suppressed renin-based diagnostic ratios, while AA2R remained unaffected, allowing a AA2-R-based PA screening in presence of ACE inhibitor and providing major advantage over currently available tests. The Youden-Index optimal cut-off value for the AA2R was 6.6 [(pmol/L)/(pmol/L)] with a sensitivity of 90% and a specificity of 93%, non-inferior compared with the ARR while pointing to the potential for an interference free application in patients under ACE-inhibitor therapy. Conclusions: This study shows for the first time the accuracy and reliability of RAAS triple-A analysis for the screening of PA, even in the presence of theraphy with ACE inhibitors. Combining informations on drug efficacy and compliance monitoring with PA screening, this method might have a significant impact on the overall performance of PA screening procedures.

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m², and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m², and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m² despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. Discussion/Conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

Ace in the Hole Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in the First Year after Heart Transplant

<h3>Purpose</h3> Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are first line agents for treatment of hypertension in the general population, particularly in the setting of diabetes. However, safety data for their use after heart transplant (HT) is limited due to concerns regarding renal insufficiency and hyperkalemia. <h3>Methods</h3> Retrospective single-center study of HT recipients from January 2017 to December 2019 who received ACEi or ARB therapy within the first-year post-transplant. Patients were evaluated for development of acute kidney injury (AKI), hyperkalemia or other complications after initiation of ACEi/ARB therapy. <h3>Results</h3> A total of 42 patients were included. The cohort was primarily male (81%), with a median (IQR) age of 55.3 (37.7-61.3) years at initiation of therapy. SMX-TMP was used in 39 (83%) while on ACEi/ARB therapy. Median (IQR) estimated glomerular filtration rate (eGFR) at initiation of therapy was 70.2 (56-102.2) mL/min/1.73 m². The lowest eGFR within the first two weeks after initiation of ACEi/ARB was 57.7 (54.4-96.2) mL/min/1.73 m² (Fig 1A). Only one (2.2%) patient had a >50% decline in eGFR within the first 2 weeks of therapy. Hyperkalemia (potassium >5.4 mmol/L) within in the first month after initiation of therapy was observed in 3 (6.5%) patients (Fig 1B). Within the first year post-transplant, therapy was discontinued in 12 (32.4%) patients receiving ACEi, mostly due to AKI or hyperkalemia, and therapy was discontinued in 1 (11.1%) patient receiving ARB (Fig 1B). Of the 9 ARB patients, 4 (44.4%) were previously on ACEi therapy. <h3>Conclusion</h3> ACEi and ARB therapies can be safely initiated in patients with preserved renal function within the first-year post-transplant; however, a third of patients eventually discontinued therapy, mainly due to worsening renal function and hyperkalemia. Close monitoring is required when initiating a patient on ACEi/ARB to ensure safety while using these medications.

Left Ventricular Dilatation Impacts Heart Transplant and Death in Left Ventricular Non-Compaction Cardiomyopathy

<h3>Purpose</h3> Patients with left ventricular non-compaction cardiomyopathy (LVNC) and end-stage heart failure (HF) are transplanted less often than dilated cardiomyopathy (DCM) patients. We aimed to describe a cohort of LVNC patients and to identify risk factors associated with death or heart transplant (HTX). <h3>Methods</h3> We reviewed all patients < 18 years included in our HF database (2001 - 2018) with LVNC, either isolated (I-LVNC) or with dilated phenotype (D-LVNC) and at least mildly reduced ejection fraction (EF). Patients with DCM were included as controls for comparison. Descriptive statistics, multivariate analysis, and time-to-event analysis were used. <h3>Results</h3> We included 239 patients, 37 (15%) with I-LVNC, 38 (16%) with D-LVNC, and 164 (69%) with DCM. The overall median age at diagnosis was 4.8 years (IQR 1.1 - 10.1) with a median follow-up of 1.2 (IQR 0.2-4.1) years. I-LVNC patients presented less often with HF than D-LVNC and DCM patients (24%, 45%, 76%; p=0.0001). As expected, baseline LV dimensions were smaller in I-LVNC than in the D-LVNC and DCM groups (median z-scores 0.8, 3.84, 3.76; p < 0.0001). I-LVNC patients had higher baseline EF (median EF 47%, 30%, 22%; p<0.0001), however 64% of these patients did develop moderate to severe LV dysfunction during follow-up. I-LVNC patients had less admissions to ICU (46%, 61%, 70%, p=0.0005), 1 patient required ECMO and none underwent VAD implant (0%, 11%, 18%; p = 0.01). Significantly less patients from the I-LVNC group underwent HTX, as compared to their D-LVNC and DCM counterparts (11%, 21%, 33%; p = 0.02). This resulted in a significantly improved HTX-free survival for the I-LVNC group (p<0.0001) - Figure 1. On multivariable analysis, baseline EF and LV dimension, ACE inhibitor therapy and ICU admission during follow-up were significantly associated with death or HTX -Table 1. <h3>Conclusion</h3> In this cohort of LVNC and DCM patients, LV dilation with dysfunction was associated with death or HTX. Further studies on the outcomes of LVNC subtypes are warranted.

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.

Angioedema without wheals: a clinical update

Angioedema without wheals (urticaria) represents a heterogeneous group of clinically indistinguishable diseases of hereditary or acquired etiology. Hereditary angioedema is a rare inherited condition leading to recurrent, sometimes life-threatening angioedema attacks in subcutaneous tissues and gastrointestinal and oropharyngeal mucosa dating back to childhood or adolescence. Most of these patients have mutations in the SERPING1 gene, causing either low C1 inhibitor production (hereditary angioedema with C1 inhibitor deficiency type I) or the production of dysfunctional C1 inhibitor (hereditary angioedema with C1 inhibitor deficiency type II). Hereditary angioedema with normal C1 inhibitor has been defined later. Although C1 inhibitor concentration and function are in the normal range, it leads to typical hereditary angioedema symptoms owing to mutations in FXII, PLG, ANGPT1, KNG1, and MYOF genes. Patients who exhibit none of these genetic mutations despite having a similar clinical presentation are classified as having unknown hereditary angioedema. Fewer than 1 in 10 patients with C1 inhibitor deficiency have acquired angioedema with C1 inhibitor deficiency. The clinical presentation is very similar to that of hereditary angioedema, making it difficult to distinguish these 2 conditions clinically. Unlike hereditary angioedema, there are no genetic mutations, and family history and symptoms tend to appear later in life. Acquired angioedema with C1 inhibitor deficiency is commonly associated with lymphoproliferative and autoimmune diseases. Angioedema attacks might start 1 year before the underlying disease in acquired angioedema with C1 inhibitor deficiency. Approximately half of the patients admitted to the hospital for acute angioedema are patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema typically occurs on the lips, tongue, mouth, pharynx, and subglottic regions. Patients may require hospitalization and intensive care monitoring owing to airway involvement. Idiopathic histaminergic acquired angioedema may be diagnosed only when any possible causes of histaminergic angioedema are excluded (foods, drugs, animal dander, aeroallergens, insect stings, latex, and others), and the symptoms respond well to antihistamine treatment. Idiopathic nonhistaminergic acquired angioedema should be considered when all other types of recurrent angioedema have been ruled out and patients do not respond to high-dose antihistamines. The lack of a standard biochemical laboratory test for patients with idiopathic histaminergic acquired angioedema, idiopathic nonhistaminergic acquired angioedema, angiotensin-converting enzyme inhibitor-induced acquired angioedema, and hereditary angioedema with normal C1 inhibitor makes the diagnosis more challenging. Future efforts should focus on increasing awareness of all the rare types of angioedema among physicians and developing more straightforward and more accessible diagnostic methods.

A systematic review of pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy.

To perform a systematic review of studies evaluating pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy (DMD). PubMed, Google Scholar, and Embase were searched through October 8, 2020. Articles were selected using pre-determined criteria; 26 underwent detailed review by two co-authors. Study quality was assessed with the Newcastle-Ottawa scoring system (NOS); GRADE assessment evaluated their overall clinical importance. There were few randomized controlled trials. Two of four trials of angiotensin converting enzyme inhibitors (ACEI) or ACEI plus beta-blockers (BB) found improved LV function. Two of two randomized trials of aldosterone antagonists (AA), when added to ACEI and BB therapy, demonstrated less decline of LV circumferential strain over 1 year of treatment. Observational studies of ACEI and BB had differing patient ages, symptomatology, cohort size, study duration and baseline heart function. LV function, assessed via unblinded imaging, was the most frequent outcome measure. LV dysfunction improved in some trials but was unconfirmed in others. Class IV heart failure patients had transient improvement of symptoms and LVEF. Most NOS scores reflected a low level of study quality. The Grade certainty rating, used for the summation of studies, was between "low" and "moderate." Randomized trial evidence was inconsistent that either ACEI or BB or their combination improve LV function and/or alter progressive LV dysfunction. When ACEI and BB therapy are initiated for symptomatic Class IV heart failure, symptoms and LVEF improve transiently. AAs retard the rate of decline of LV function when initiated in younger DMD patients.

Personalizing heart failure management in chronic kidney disease patients.

Chronic kidney disease (CKD) in heart failure (HF) patients is common, present in 49%, and is associated with a higher mortality hazard ratio [2.34 (95% confidence interval 2.20-2.50); P &lt; 0.001] and multiple hospital admissions. The management of HF in CKD can be challenging due to drug-induced electrolyte and creatinine changes, resistance to diuretics and infections related to device therapy. Evidence for improvement in mortality and HF hospitalizations exists in HF with reduced ejection fraction (HFrEF) in Stage 3 CKD patients from randomized controlled trials of angiotensin-converting enzyme inhibitor (ACEi) and mineralocorticoid receptor antagonist therapy but not in dialysis patients, where higher doses can cause hyperkalaemia. Evidence of improvement in cardiovascular death and HF hospitalizations has emerged with the angiotensin receptor neprilysin inhibitor ivabradine and more recently with sodium-glucose cotransporter inhibitors in HFrEF patients with CKD Stages 1-3. However, these studies have excluded CKD Stages 4 and 5 patients. Evidence for β-blocker therapy exists in CKD Stages 1-3 and separately in haemodialysis patients. Cardiac resynchronization therapy reduces HF hospitalizations and mortality in patients with CKD Stages 1-3 but has not been shown to do so in CKD Stages 4 and 5 or dialysis patients. Internal cardioverter and defibrillator therapy in HFrEF patients has been shown to be beneficial in CKD 3 patients but not in dialysis patients, where it is associated with high rates of infection. For HFpEF patients with CKD, therapy is symptomatic, as there is no proven therapy for improvement in survival or hospitalizations. HF patients with end-stage kidney disease with fluid overload may benefit from peritoneal dialysis. A multidisciplinary, personalized approach has been associated with better care and improved patient satisfaction.

L-type calcium channel blocker use and proteinuria among children with chronic kidney diseases.

Hypertension is common among children with chronic kidney disease (CKD), and dihydropyridine calcium channel blockers (dhCCBs) are frequently used as treatment. The impact of dhCCBs on proteinuria in children with CKD is unclear. Data from 722 participants in the Chronic Kidney Disease in Children (CKiD) longitudinal cohort with a median age of 12 years were used to assess the association between dhCCBs and log transformed urine protein/creatinine levels as well as blood pressure control measured at annual visits. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use was evaluated as an effect measure modifier. Individuals using dhCCBs had 18.8% higher urine protein/creatinine levels compared to those with no history of dhCCB or ACEi and ARB use. Among individuals using ACEi and ARB therapy concomitantly, dhCCB use was not associated with an increase in proteinuria. Those using dhCCBs had higher systolic and diastolic blood pressures. Use of dhCCBs in children with CKD and hypertension is associated with higher levels of proteinuria and was not found to be associated with improved blood pressure control.

Hypertension Editors' Picks: Hyperaldosteronism.

Hypertension Editors' Picks: Hyperaldosteronism.

Comparison of Patients With Nonobstructive Coronary Artery Disease With Versus Without Myocardial Infarction (from the VA Clinical Assessment Reporting and Tracking [CART] Program)

Comparisons of the outcomes of patients with myocardial infarction with nonobstructive coronary artery disease (MINOCA) and patients with nonobstructive coronary artery disease (CAD) without myocardial infarction (MI) are limited. Here we compare the outcomes of patients with MINOCA and patients with nonobstructive CAD without MI and assess the influence of medical therapy on outcomes in these patients. Veterans who underwent coronary angiography between 2008 to 2017 with nonobstructive CAD were divided into those with or without pre-procedural troponin elevation. Patients with prior revascularization, heart failure, or who presented with cardiogenic shock, STEMI, or unstable angina were excluded. After propensity matching, outcomes were compared between groups. The primary outcome was major adverse cardiovascular events (MACE: mortality, myocardial infarction, and revascularization) within one year: 3,924 patients with nonobstructive CAD and a troponin obtained prior to angiography were identified (n=1,986 with elevated troponin) and restricted to 1,904 patients after propensity-matching. There was a significantly higher risk of MACE among troponin-positive patients compared with those with a negative troponin (HR 2.37; 95% CI, 1.67 to 3.34). Statin (HR 0.32; 95% CI, 0.22 to 0.49) and ACE inhibitor (HR 0.49; 95% CI, 0.32 to 0.75) therapy after angiography was associated with decreased MACE, while P2Y12 inhibitor, calcium-channel and beta-blocker therapy were not associated with outcomes. In conclusion, Veterans with MINOCA are at increased risk for MACE compared with those with nonobstructive CAD and negative troponin at the time of angiography. Specific medications were associated with a reduction in MACE, suggesting an opportunity to explore novel approaches for secondary prevention in this population.

Onset of Hyperkalemia following the Administration of Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker.

Introduction In spite of the established importance of detecting angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker- (ARB-) induced hyperkalemia, there have not been many studies on the time of its occurrence. Methods We retrospectively analyzed electronic medical records to determine the onset time and incidence rate of hyperkalemia (serum potassium > 5.5 mEq/L or 6.0 mEq/L) among hospitalized patients newly started on a 15-day ACEI or ARB therapy. Results Among 3101 hospitalized patients, hyperkalemia incidence was 0.5%–0.9% and 0.8%–2.1% in the ACEI and ARB groups, respectively. However, it was not significantly different among different ARB types. Hyperkalemia's onset was distributed throughout 15 days, without any trend. Hyperkalemia incidence was 7.3 and 35.1 times higher at 5.5 mEq/L (hazard ratio (HR) = 7.31, 95%confidence interval (CI) = 4.19–12.76, p < 0.001) and 6.0 mEq/L (HR = 35.11, 95%CI = 8.25–149.52, p < 0.001), respectively, than the baseline creatinine level. Hyperkalemia incidence in patients with chronic renal failure was 5.7 and 9.2 times higher at 5.5 mEq/L (HR = 5.72, 95%CI = 3.24–10.12, p < 0.001) and 6.0 mEq/L (HR = 9.16, 95%CI = 4.02–20.88, p < 0.001), respectively. Conclusions It is unlikely that it is necessary to monitor hyperkalemia immediately after administration of ACEI or ARB. However, when prescribed for patients with abnormal kidney function, clinicians should always consider the possibility of developing hyperkalemia.

Life-threatening airway obstruction caused by angioedema in a morbidly obese postoperative patient: a case report

BackgroundWe report a case of a morbidly obese patient who developed life-threatening airway obstruction due to angioedema.Case presentationA 50-year-old Japanese morbidly obese female was treated with enalapril for 10 years, with no history of angioedema. After 3 h of completion of breast cancer resection under general anesthesia with tracheal intubation, she developed airway obstruction and respiratory arrest. Her oral cavity was occupied with a swollen tongue. It was extremely difficult to determine the airway anatomical orientation although tracheal intubation was attempted using a videolaryngoscope. At this time, she probably started gasping respiration, which generated a faint bubble and revealed a possible airway. Her airway was established using a tracheal tube without confirming the glottis or the vocal cord.ConclusionsAngioedema induced by angiotensin-converting enzyme (ACE) inhibitors is rare; however, once it occurs, it can be potentially life threatening, especially for patients with possible difficult airway. Considering the risk–benefit ratio, we must be careful in administering ACE inhibitor therapy in morbidly obese patients.

The prescription of best medical therapy following infrainguinal bypass grafting in Australia and New Zealand: a multicentre Australasian audit.

The benefits of best medical therapy (BMT) for secondary prevention of cardiovascular events in patients with peripheral arterial disease are well established. Guidelines recommend prescription of BMT should consist of anti-platelet, statins and angiotensin-converting enzyme inhibitor or angiotensin receptor blocking therapy, with evidence this regimen reduces cardiovascular mortality following vascular surgery and improves vascular bypass graft patency. This multicentre study examines the BMT prescription on discharge after infrainguinal bypass (IIB) in Australia and New Zealand (ANZ). Primary outcome measure was discharge prescription of three BMT pharmacological agents, defined for study purposes as an anti-platelet/anti-coagulant, a lipid-lowering agent, and an anti-hypertensive medication if hypertension was diagnosed. This study retrospectively examined discharge prescriptions and summaries of all patients discharged following IIB in five ANZ hospitals, between January 2015 and April 2018. A total of 688 admissions for IIB were included (76.9% male; mean age 67.8 ± 12.0). A total of 72.4% of procedures were for chronic limb ischaemia, compared to acute limb ischaemia (12.6%), and aneurysmal disease (15%). The primary outcome of adherence with complete BMT prescription occurred in 66.9% of admissions. Anti-thrombotic agents were most frequently prescribed (96.4%), followed by anti-lipidaemic agents (82.1%). Of the patients with documented hypertension, 43.8% were not prescribed an angiotensin-converting enzyme inhibitor/angiotensin receptor blocking, while 19.2% were discharged without any anti-hypertensive medications. Almost one third of patients were not prescribed complete BMT following IIB. There is potential to improve the outcomes after IIB in ANZ through a focus on risk-factor control and BMT prescription.

Central and peripheral hemodynamic responses to orthostasis in hypertensive males with chronic venous disorders taking combined therapy with a calcium channel blocker and an angiotensin-converting enzyme inhibitor

Aim . To study the characteristics of central and peripheral hemodynamic responses to orthostasis in hypertensive (HTN) males with chronic venous disorders (CVD) taking combined therapy with a calcium channel blocker (CCB) and an angiotensinconverting enzyme (ACE) inhibitor. Material and methods . In 46 men 30-50 years old with uncontrolled HTN taking antihypertensive therapy, a comparative assessment of the dynamics of systolic blood pressure (SBP), diastolic blood pressure (DBP), peripheral venous pressure (PVP), lumen diameter and area, blood flow velocity of superficial and deep veins of the left leg in response to orthostasis. Venous hemodynamics was studied by duplex ultrasound. PVP was assessed by oscillometry on the thigh and ultrasound of the great superficial vein. A comparative dynamic analysis of these parameters was carried out in patients of two groups: 23 hypertensive patients without CVD and 23 patients with HTN and CVD. CVD was assessed using Comprehensive Energy Assistance Program (CEAP). Orthostasis was performed before and after 14 days of antihypertensive therapy with a combination of CCB and ACE inhibitors. Results . Central and peripheral hemodynamic responses to orthostasis before treatment in patients of both groups was the same — a decrease in SBP, DBP and PVP, expansion of superficial and deep veins, and a decrease in venous blood flow velocity. As a result of treatment, 43 patients achieved the first target office SBP (&lt;140 mm Hg). Of these, there were 21 HTN patients without CVD and 22 patients with CVD. After treatment, most responses to orthostasis in both groups was similar to pre-treatment ones. However, differences were also noted — in both groups, the DBP increased; SBP decreased only in men with CVD. In patients with CVD, the posterior tibial vein (PTV) dilated and blood flow velocity decreased after treatment in response to orthostasis, while in patients without CVD, there was a narrowing of PTV and blood flow acceleration. After treatment, patients with CVD were characterized by a larger diameter and area of the lumen of superficial and deep veins than those without CVD in response to orthostasis. Conclusion . Orthostasis before antihypertensive therapy in patients both with and without CVD is characterized by an identical hemodynamic response — a decrease in SBP, DBP, PVP expansion of superficial and deep veins, and a decrease in venous blood flow velocity. After 14-day antihypertensive therapy, there were differences in hemodynamic response between the study groups. In patients with HTN and CVD, CCB and ACE inhibitors therapy leads to a redistribution of central and peripheral circulation and increases the dilatation of the veins in response to orthostasis.

Prospective Cohort Study of Renin-Angiotensin System Blocker Usage after Hospitalized Acute Kidney Injury.

The risk-benefit ratio of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy after AKI may be altered due to concerns regarding recurrent AKI. We evaluated, in a prospective cohort, the association between use (versus nonuse) of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the subsequent risk of AKI and other adverse outcomes after hospitalizations with and without AKI. We studied 1538 patients recently discharged from the hospital who enrolled in the multicenter, prospective ASSESS-AKI study, with approximately half of patients experiencing AKI during the index hospitalization. All participants were seen at a baseline visit 3 months after their index hospitalization and were categorized at that time on whether they were using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or not. We used multivariable Cox regression, adjusting for demographics, comorbidities, eGFR, urine protein-creatinine ratio, and use of other medications, to examine the association between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and subsequent risks of AKI, death, kidney disease progression, and adjudicated heart-failure events. The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 50% (386/769) among those with AKI during the index hospitalization and 47% (362/769) among those without. Among those with AKI during the index hospitalization, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was not associated with a higher risk of recurrent hospitalized AKI (adjusted hazard ratio, 0.88; 95% confidence interval, 0.69 to 1.13). Associations between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and death, kidney disease progression, and adjudicated heart-failure events appeared similar in study participants who did and did not experience AKI during the index hospitalization (all interaction P values >0.05). The risk-benefit ratio of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy after hospital discharge appears to be similar regardless of whether AKI occurred during the hospitalization.

Adverse impact of renin\u2013angiotensin system blockade on the clinical course in hospitalized patients with severe COVID-19: a retrospective cohort study

The association between angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) and the risk of mortality in hospitalized patients with severe coronavirus disease 2019 (COVID-19) was investigated. This retrospective cohort study was performed in all hospitalized patients with COVID-19 in tertiary hospitals in Daegu, Korea. Patients were classified based on whether they received ACE-I or ARB before COVID-19 diagnosis. The analysis of the primary outcome, in-hospital mortality, was performed using the Cox proportional hazards regression model. Of 130 patients with COVID-19, 30 (23.1%) who received ACE-I or ARB exhibited an increased risk of in-hospital mortality (adjusted hazard ratio, 2.20; 95% confidence interval [CI], 1.10–4.38; P = 0.025). ACE-I or ARB was also associated with severe complications, such as acute respiratory distress syndrome (ARDS) (adjusted odds ratio [aOR], 2.58; 95% CI, 1.02–6.51; P = 0.045) and acute kidney injury (AKI) (aOR, 3.06; 95% CI, 1.15–8.15; P = 0.026). Among the patients with ACE-I or ARB therapy, 8 patients (26.7%) used high equivalent doses of ACE-I or ARB and they had higher in-hospital mortality and an increased risk of ARDS and AKI (all, P < 0.05). ACE-I or ARB therapy in patients with severe COVID-19 was associated with the occurrence of severe complications and increased in-hospital mortality. The potentially harmful effect of ACE-I or ARB therapy may be higher in patients who received high doses.