Angiotensin-converting Enzyme Inhibitor-associated Angioedema Research Articles

Isolated Laryngeal Angioedema in a Patient with Long-term ACE Inhibitor Use: A Case Report.

Angiotensin converting enzyme (ACE) inhibitor-associated angioedema is the most common cause of angioedema seen in the emergency department (ED) and can be associated with a high morbidity. Most cases occur within months of initiation of an ACE inhibitor and are associated with facial and/or oropharyngeal swelling. We present a case of isolated laryngeal edema requiring intubation following 10years of ACE inhibitor therapy. An 82-year-old female, who was on lisinopril therapy for 10years, presented to the ED with shortness of breath and a sensation that her throat was swelling. She appeared to be in mild respiratory distress and could only speak in one-word sentences. On the physical exam, there was no swelling in the tongue, lips, or face, and the uvula was midline. There was mild posterior pharyngeal edema and swelling noted, but the airway was not visibly obstructed. She was tachypneic and stridor was present. After no improvement with medications, anesthesia successfully intubated her in the operating room. It was deemed a difficult airway secondary to posterior pharyngeal erythema and edema. She was diagnosed with ACE inhibitor-associated angioedema and was extubated four days later. Her lisinopril was discontinued, and she has not had a recurrence of angioedema. ACE inhibitor-induced angioedema commonly presents with facial and oropharyngeal swelling. Its recognition, even years after starting an ACE inhibitor, is necessary to ensure swift and appropriate treatment of potentially life-threatening posterior pharyngeal edema.

RECURRENT ANGIOEDEMA FOLLOWING ANGIOTENSIN CONVERTING ENZYME INHIBITOR DISCONTINUATION

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Angiotensin converting enzyme inhibitors (ACEIs) are guideline recommended first-line treatment for hypertension. Angioedema is a recognized side effect of ACEI therapy, yet clinicians are often unaware that limited case reports describe recurrent angioedema following ACEI discontinuation. This is a case of ACEI-induced angioedema occurring after discontinuing ACEI therapy. CASE PRESENTATION: An elderly male with medical history of hypothyroidism, hypertension, and heart failure presented from his long-term care facility complaining of face, tongue, and throat swelling with dysphagia and voice changes starting 24 hours prior. Examination showed normal vital signs and edema of aforementioned areas. He denied family history of similar occurrences. It was reported 12 days prior he was seen for unilateral lip swelling and his enalapril was discontinued without further treatment. Medication administration record review showed ACEI was appropriately discontinued by his care facility. He was given methylprednisolone, diphenhydramine, intramuscular epinephrine, C1 esterase inhibitor, and 2 units of fresh frozen plasma prior to admission. The patient was monitored in the intensive care unit due to mild airway compromise but did not require invasive airway protection. A serum complement factor 4 level was checked and returned normal. He was discharged after 5 days in stable condition with resolution of symptoms. DISCUSSION: ACEIs are the most common cause of drug induced angioedema in the United States. ACEI-induced angioedema is a self-limiting swelling that may involve the lips, tongue, upper airway, and rarely intestinal wall. Swelling is said to occur because of ACEI inhibition on the angiotensin converting enzyme preventing degradation of vasoactive substances such as bradykinin (1). Recurrence of angioedema after ACEI discontinuation was reported in 46% of cases in one retrospective study (2). The precise etiology of this delayed reaction is not well described, though it is reasonable to hypothesize in part, a drug washout period must occur. The adverse drug reaction probability scale score was 5 (probable) in this patient (3). Recurrence has been documented more commonly in elderly male patients (2). The mainstay of treatment for non-allergic angioedema caused by ACEIs is discontinuation of the offending drug and acute airway management if needed. No drug therapy has been proven effective in the treatment of this condition (1). CONCLUSIONS: Increased awareness of delayed ACEI-induced angioedema following ACEI discontinuation is important among health care providers for appropriate diagnosis and monitoring. While self-limiting without a known effective treatment, close airway monitoring is critical for patient survival. Improved awareness would also allow patients with a history of ACEI-induced angioedema to be cognizant of the potential for recurrence early following drug discontinuation. REFERENCE #1: Erickson DL, Coop CA. Angiotensin-converting enzyme inhibitor-associated angioedema treated with c1-esterase inhibitor: A case report and review of the literature. Allergy Rhinol (Providence). 2016;7(3):168-171. REFERENCE #2: Beltrami L, Zanichelli A, Zingale L, Vacchini R, Carugo S, Cicardi M. Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema. J Hypertens. 2011 Nov;29(11):2273-7. REFERENCE #3: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury. [Updated 2019 May 4]. DISCLOSURES: No relevant relationships by Mark Malesker, source=Web Response No relevant relationships by Shraddha Narechania, source=Web Response No relevant relationships by Bryton Perman, source=Web Response

Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema: From Bed to Bench.

Angiotensin-converting enzyme inhibitor-associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood. Objective: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE. The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients. A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed. Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE.

Endogenous bradykinin and B1-B5 during angiotensin-converting enzyme inhibitor–associated angioedema

Capsule Summary Bradykinin concentrations and the ratio of bradykinin to its stable metabolite BK1-5 (RPPGF) were significantly increased in patients presenting with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema compared to ACE inhibitor-treated controls. Cleavage of high molecular weight kininogen was not increased in patients with ACE inhibitor-associated angioedema, indicating that increased bradykinin concentrations result from decreased degradation.

Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema

The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema in 1 study of European patients. We sought to test the hypothesis that a bradykinin B2 receptor antagonist would shorten time-to-resolution from ACE inhibitor-associated angioedema. Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6hours of presentation to subcutaneous icatibant 30mg or placebo at 0 and 6hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge. Thirty-three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two-thirds of patients were black and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups (P=.19 for the primary symptom and P>.16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time-to-resolution of symptoms was similar in black and white patients. This study does not support clinical efficacy of a bradykinin B2 receptor antagonist in ACE inhibitor-associated angioedema.

Angiotensin-converting enzyme inhibitor-associated angioedema treated with c1-esterase inhibitor: A case report and review of the literature.

Case Report:A 59-year old man currently on >5 years of angiotensin-converting enzyme inhibitor (ACEI) therapy presented to the emergency department with angioedema of the tongue and difficulty swallowing. After receiving conventional therapy of antihistamine, steroids, and epinephrine, the patient's condition continued to deteriorate, with imminent intubation. The patient was treated with a C1-esterase inhibitor (C1-INH) and experienced rapid resolution of symptoms, which avoided airway complications.Discussion:Although no therapy has been approved for the treatment of ACEI–associated angioedema (AAE), the conventional therapy (antihistamine, steroids, and epinephrine) often proves ineffective in this bradykinin-mediated angioedema. There are drugs approved and used for hereditary angioedema that may be effective in the acute phase of ACEI-AAE that may prevent the need for further interventions, such as intubation and tracheotomy. These drugs include icatibant, ecallantide, fresh frozen plasma, and C1-INH.Conclusion:The literature and clinical evidence indicate C1-INH can be effectively used in the treatment of ACEI-AAE to halt the progression of the condition, prevent airway compromise and the need for intervention, and lead to rapid resolution of symptoms.

Icatibant in angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.

Angioedema occurs in up to 2% of those taking angiotensin-converting enzyme (ACE) inhibitors. Upper airway angioedema may potentially require endotracheal intubation or cricothyrotomy, and is usually unresponsive to adrenaline. The bradykinin receptor antagonist icatibant is proven to be effective in the treatment of acute attacks of hereditary angioedema, and has also been reported effective in the treatment of angioedema associated with ACE inhibitors. To describe the use of icatibant for ACE inhibitor-associated airway angioedema. We treated 13 consecutive emergency department (ED) patients, who had not improved with adrenaline and/or corticosteroids, with icatibant 30 mg subcutaneously for ACE inhibitor-associated upper respiratory tract angioedema according to an agreed protocol. Four patients were intubated in the ED either before or after receiving icatibant; three of these were extubated within 24 h of treatment. Eight patients received early icatibant and did not require intubation. The time from onset of airway angioedema to ED presentation ranged from 1 h to 3 days (median 4 h); from ED presentation to receiving icatibant, from 30 minutes to 3 days (median 3 h); and to onset of symptom improvement after icatibant, 15 minutes to 7 h (median 2 h). One patient received a second dose of icatibant. All patients improved after receiving icatibant, consistent with its bradykinin receptor blocking mechanism. Icatibant rapidly reversed symptoms, and appeared to avert the need for intubation or expedite extubation. Timely use of icatibant in ACE inhibitor-associated angioedema may avert the need for invasive airway procedures and intensive care unit admission.

Angiotensin-converting Enzyme Inhibitor Angioedema Requiring Admission to an Intensive Care Unit

ObjectiveThe purpose of this study was to review consecutive cases of angiotensin-converting enzyme (ACE) inhibitor angioedema admitted to an intensive care unit. MethodsFifty subjects with ACE-inhibitor angioedema admitted from 1998-2011 were reviewed. ResultsAll 50 subjects were men, 62.8 ± 8.4 years of age, 76% African Americans. Fifteen (30%) required ventilatory support and 2 (4%) required tracheostomy. Over half (56%) had taken ACE inhibitors for over a year. Logistic regression identified dyspnea and tongue involvement with the need for ventilatory support (P < .01). Hypercapnia (PaCO2 = 45.2 ± 6.7; P = 0.046) also identified patients needing ventilatory support. ConclusionsVentilatory support was provided for about one-third of those with ACE inhibitor-associated angioedema. Angioedema can occur even after extended use. Dyspnea and tongue involvement identified patients requiring ventilatory support.

Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema

The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans. Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.

Pollen Count and Presentation of Angiotensin-Converting Enzyme Inhibitor–Associated Angioedema

The incidence of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema is increased in patients with seasonal allergies. We tested the hypothesis that patients with ACE inhibitor-associated angioedema present during months when pollen counts are increased. Cohort analysis examined the month of presentation of ACE inhibitor-associated angioedema and pollen counts in the ambulatory and hospital setting. Patients with ACE inhibitor-associated angioedema were ascertained through (1) an observational study of patients presenting to Vanderbilt University Medical Center, (2) patients presenting to the Marshfield Clinic and participating in the Marshfield Clinic Personalized Medicine Research Project, and (3) patients enrolled in The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Measurements include date of presentation of ACE inhibitor-associated angioedema, population exposure to ACE inhibitor by date, and local pollen counts by date. At Vanderbilt, the rate of angioedema was significantly associated with tree pollen months (P = .01 from χ(2) test). When separate analyses were conducted in patients with a history of seasonal allergies and patients without, the rate of ACE inhibitor-associated angioedema was increased during tree pollen months only in patients with a history of seasonal allergies (P = .002). In Marshfield, the rate of angioedema was significantly associated with ragweed pollen months (P = .025). In ONTARGET, a positive trend was observed between the ACE inhibitor-associated angioedema rate and grass season, although it was not statistically significant (P = .057). Patients with ACE inhibitor-associated angioedema are more likely to present with this adverse drug event during months when pollen counts are increased.

Role of angiotensin-converting enzyme inhibitors in visceral angioedema

A rare complication that occurs in patients taking ACE-inhibitors is visceral angioedema. It can affect about 1 in 2500 patients during the first week of exposure [ 1 Brown N.J. Snowden M. Griffin M.R. Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. JAMA. Jul 16 1997; 278: 232-233 Crossref PubMed Google Scholar , 2 Israili Z.H. Hall W.D. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. Aug 1 1992; 117: 234-242 Crossref PubMed Scopus (887) Google Scholar , 3 Messerli F.H. Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet. Aug 19 2000; 356: 608-609 Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar ]. The prevalence of angioedema secondary to the use of ACE inhibitors varies anywhere from 0.1 to 0.7 % and usually manifests itself with the involvement of the face, tongue, lips and in rare cases the gastrointestinal wall. Middle aged female patients on an ACE inhibitor presenting with abdominal pain, vomiting, diarrhea, leukocytosis, ascites and small bowel wall thickening on the imaging studies should be examined closely [ 4 Weber M.A. Messerli F.H. Angiotensin-converting enzyme inhibitors and angioedema: estimating the risk. Hypertension. Jun 2008; 51: 1465-1467 Crossref PubMed Scopus (47) Google Scholar , 5 Oudit G. Girgrah N. Allard J. ACE inhibitor-induced angioedema of the intestine: case report, incidence, pathophysiology, diagnosis and management. Can J Gastroenterol. Dec 2001; 15: 827-832 Crossref PubMed Scopus (37) Google Scholar , 6 Gibbs C.R. Lip G.Y. Beevers D.G. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol. Dec 1999; 48: 861-865 Crossref PubMed Scopus (116) Google Scholar , 7 Johnsen S.P. Jacobsen J. Monster T.B. Friis S. McLaughlin J.K. Sorensen H.T. Risk of first-time hospitalization for angioedema among users of ACE inhibitors and angiotensin receptor antagonists. Am J Med. Dec 2005; 118: 1428-1429 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ]. Multiple invasive and unnecessary procedures can be avoided by raising awareness of this complication. Most of the patients diagnosed with angioedema required hospitalization due to the severity of symptoms and the exclusion of other possible diseases [ [7] Johnsen S.P. Jacobsen J. Monster T.B. Friis S. McLaughlin J.K. Sorensen H.T. Risk of first-time hospitalization for angioedema among users of ACE inhibitors and angiotensin receptor antagonists. Am J Med. Dec 2005; 118: 1428-1429 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ].

Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema

Angioedema is a rare adverse effect of angiotensin-converting enzyme (ACE) inhibitors, which occurs more commonly in women and black Americans. Angioedema is thought to result from decreased degradation of vasoactive peptides. During ACE inhibition, bradykinin is primarily inactivated by aminopeptidase P (APP). Earlier studies have provided conflicting data with regard to serum APP activity in patients with a history of ACE inhibitor-associated angioedema. A single nucleotide polymorphism, -2399C>A (rs3788853, C-2399A), in XPNPEP2, the X-linked gene that encodes membranous APP, has been reported to associate with APP activity. To test the hypothesis that the relationship between XPNPEP2 C-2399A genotype and APP activity or ACE inhibitor-associated angioedema is sex-dependent and race-dependent. We compared C-2399A genotype frequencies in 169 cases with a history of ACE inhibitor-associated angioedema and 397 ACE inhibitor-exposed controls. Controls were prespecified to be 50% white, 50% black, and 50% women. Cases and controls were group matched for age and smoking. XPNPEP2 C-2399A genotype associated with serum APP activity in both men and women. Serum APP activity was lower in men than in women, independent of genotype. XPNPEP2 -2399 A/ genotype was associated with an increased risk of angioedema in men [odds ratio 2.17 (1.09-4.32), P=0.03] in multivariate analysis. The A/ genotype was associated with angioedema in black men (P=0.03) but not in white men. APP activity is lower in men and the XPNPEP2 C-2399A polymorphism associates with ACE inhibitor-associated angioedema in men but not women.

Association of angiotensin‐converting enzyme inhibitor‐associated angioedema with transplant and immunosuppressant use

Immunosuppressants decrease circulating dipeptidyl peptidase IV (DPPIV) activity in transplant patients, and decreased DPPIV activity has been associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. One study has reported an increased incidence of ACE inhibitor-associated angioedema among transplant patients compared to published rates, while several case series report angioedema in patients taking specific immunosuppressant agents. To test the hypothesis that transplant patients are at increased risk of ACE inhibitor-associated angioedema. We assessed the proportion of transplant patients in 145 cases with ACE inhibitor-associated angioedema and 280 ACE inhibitor-exposed controls. We measured the relationship between case-control status, transplant status, and immunosuppressant use and circulating DPPIV activity. We also assessed the incidence of angioedema among consecutive patients who underwent renal or cardiac transplant and were treated with an ACE inhibitor. Transplant patients were significantly overrepresented among ACE inhibitor-associated angioedema cases compared to controls (odds ratio 18.5, 95% CI 2.3-147.2, P = 0.0004). Immunosuppressant use, chronic renal failure, seasonal allergies and smoking were also associated with ACE inhibitor-associated angioedema in univariate analysis. The association of transplant status with ACE inhibitor-associated angioedema was no longer significant after inclusion of immunosuppressant therapy in a multivariate analysis. Dipeptidyl peptidase IV activity was significantly decreased in sera from cases compared to ACE inhibitor-exposed controls, as well as in individuals taking immunosuppressants. Two of 47 ACE inhibitor-treated renal transplant patients and one of 36 ACE inhibitor-treated cardiac transplant patients developed angioedema. Transplant patients are at increased risk of ACE inhibitor-associated angioedema possibly because of the effects of immunosuppressants on the activity of DPPIV.

Dipeptidyl Peptidase-IV Inhibitor Use Associated With Increased Risk of ACE Inhibitor-Associated Angioedema

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

Endoscopic Visualization of Angiotensin-converting Enzyme Inhibitor-induced Small Bowel Angioedema as a Cause of Relapsing Abdominal Pain using Double-balloon Enteroscopy

A 40-year-old woman presented with 3 episodes of abdominal pain. Abdominal ultrasound demonstrated edema of the small bowel. Double-balloon enteroscopy (DBE) showed diffuse swelling of the small intestine, petechial bleeding in the jejunum, and focal inflammation of the ileum. Pain and small bowel edema resolved spontaneously within 48 h during each episode. Review of the patient's history revealed that she had been started on enalapril for arterial hypertension two weeks before her first episode. Angiotensin-converting enzyme (ACE) inhibitor-associated angioedema of the small bowel was suspected and enalapril was discontinued. The patient remained symptom-free after discontinuing the ACE inhibitor. Review of the literature reveals only 11 similar cases with this case being the first to apply DBE to visualize macroscopic alterations to the small intestine. Angioedema of the intestine is a diagnostic pitfall frequently leading to prolonged diagnostic procedures and is a potential cause for abdominal pain in patients taking ACE inhibitors.

A Variant in XPNPEP2 Is Associated with Angioedema Induced by Angiotensin I–Converting Enzyme Inhibitors

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

Angiotensin converting enzyme inhibitor-associated angioedema: More common than recognized

Angiotensin converting enzyme inhibitor (ACEI) drugs are one of the most common causes of non-hereditary angioedema. The patients who are on ACEI are predisposed to develop angioedema which may be triggered by a second ‘hit’ like trauma, airway instrumentation, infection and irritant fumes in high risk patients. The incidence of life-threatening angioedema related to ACEI has been rising over the past decade due to popularity of the longer-acting drugs. Yet this is still a clinically under-recognized phenomenon which may be due to under reporting. The airway compromise can be progressive, rapid and life-threatening. A heightened awareness amongst the clinicians is needed to recognize patients who are at increased risk of developing ACEI-induced angioedema to prevent the morbidity and potential mortality. We present three cases of life-threatening airway compromise thought to be related to ACEI therapy. In two patients the airway oedema was post-operative and thought to be triggered by airway instrumentati...

Angiotensin converting enzyme inhibitor-associated angioedema: More common than recognized

Angiotensin converting enzyme inhibitor (ACEI) drugs are one of the most common causes of non-hereditary angioedema. The patients who are on ACEI are predisposed to develop angioedema which may be triggered by a second ‘hit’ like trauma, airway instrumentation, infection and irritant fumes in high risk patients. The incidence of life-threatening angioedema related to ACEI has been rising over the past decade due to popularity of the longer-acting drugs. Yet this is still a clinically under-recognized phenomenon which may be due to under reporting. The airway compromise can be progressive, rapid and life-threatening. A heightened awareness amongst the clinicians is needed to recognize patients who are at increased risk of developing ACEI-induced angioedema to prevent the morbidity and potential mortality. We present three cases of life-threatening airway compromise thought to be related to ACEI therapy. In two patients the airway oedema was post-operative and thought to be triggered by airway instrumentation and in one of them the trigger was paint fumes. These cases are discussed including a review of literature, methods of diagnosis, pathophysiology, risk factors and treatment of ACEI-induced angioedema.

Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin.

Angioedema (AE) is a rare but potentially life-threatening side effect of therapy with inhibitors of angiotensin-converting enzyme (ACE), the main bradykinin (BK)- inactivating metallopeptidase in humans. The pathogenesis of ACE inhibitor (ACEi)- associated AE (AE+) is presently unknown, although there is increasing evidence of a kinin role. We analyzed the metabolism of endogenous BK (B(2) receptor agonist) and its active metabolite, des-Arg(9)-BK (B(1) receptor agonist), in the presence of an ACEi during in vitro contact activation of plasma from hypertensive patients (n = 39) who presented AE+. Kinetic parameters were compared with those measured in a control group (AE-) of hypertensive patients (n = 39) who never manifested any acute or chronic side effects while treated with an ACEi. The different kinetic parameters were analyzed using a mathematical model (y = k t(alpha) e(-beta t)) previously applied to a normal, healthy population. The slope of BK degradation, but not its formation from high-molecular-weight kininogen, was lower in AE+ patients when compared with the AE- controls. des-Arg(9)-BK accumulation during the kinetic measurements was significantly higher in AE+ plasma. This accumulation of the B(1) agonist in AE+ patients paralleled its half-life of degradation. In conclusion, our results show, for the first time, that an abnormality of endogenous des-Arg(9)-BK degradation exists in the plasma of patients with ACEi-associated AE, suggesting that its pathogenetic mechanism lies in the catabolic site of kinin metabolism.

Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema

Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (ACEi) is a rare, but potentially life-threatening adverse reaction. Several studies have suggested that bradykinin (BK) is responsible for ACEi-induced AE, but the mechanism remains unclear. We investigated the metabolism of BK and des-Arg9-BK in the serum of 20 patients with a history of ACEi-associated AE and 21 control (C) subjects. Synthetic BK was incubated with the sera for various periods of time and residual BK and generated des-Arg9-BK were quantified by specific and sensitive enzyme immunoassays. No significant difference of half-life (t1/2) of both BK and des-Arg9-BK could be measured between C subjects and patients with AE (AE) in absence of ACEi. However, an analysis according to the prolonged (+) or not (−) t1/2 of des-Arg9-BK allowed a new stratification of C subjects and AE patients in four subgroups. The preincubation of sera with enalaprilat at a concentration inhibiting ACE significantly prevented the rapid degradation of BK and des-Arg9-BK in these four subgroups. In presence of ACEi, a subgroup (50%) of AE patients (AE+) had a particularly significant rise of the t1/2 of des-Arg9-BK. Once ACE was inhibited, the concentration or the nature of the ACEi had no significant effect on the t1/2 of des-Arg9-BK. However, a test dilution of AE+ sera with a control (C) serum showed that an enzyme defect rather than a circulating inhibitor could be responsible for the abnormal metabolism of des-Arg9-BK when ACE is inhibited. In conclusion, half of the patients with ACEi-associated AE present in serum had an enzyme defect involved in the des-Arg9-BK metabolism leading to its accumulation. The B1 agonist could be responsible, at least in part, for the local inflammatory reaction associated with the AE.