James Brian Byrd

Dipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor–Associated Angioedema

Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor–associated angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor–associated angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor–associated angioedema and 176 angiotensin-converting enzyme inhibitor–exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg9-bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6±7.8 versus 29.6±7.3 nmol/mL per minute; P=0.026) and antigen (465.8±260.8 versus 563.1±208.6 ng/mL; P=0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor–associated angioedema compared with angiotensin-converting enzyme inhibitor–exposed control subjects without angioedema. Dipeptidyl peptidase IV activity (21.5±4.9 versus 29.8±6.7 nmol/mL per minute; P=0.001) and antigen (354.4±124.7 versus 559.8±163.2 ng/mL; P=0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema.

EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research

We argue that the field of extracellular vesicle (EV) biology needs more transparent reporting to facilitate interpretation and replication of experiments. To achieve this, we describe EV-TRACK, a crowdsourcing knowledgebase (http://evtrack.org) that centralizes EV biology and methodology with the goal of stimulating authors, reviewers, editors and funders to put experimental guidelines into practice.

Data quality of an electronic health record tool to support VA cardiac catheterization laboratory quality improvement: The VA Clinical Assessment, Reporting, and Tracking System for Cath Labs (CART) program

BACKGROUND Electronic health records (EHRs) have been identified as a key tool for quality improvement (QI) in health care. However, EHR data must be of sufficient quality to support QI efforts. In 2005, the Department of Veterans Affairs (VA) began using a novel EHR tool-the CART Program-to support QI in cardiac catheterization laboratories. We evaluated whether data collected by the CART Program were of sufficient quality to support QI. METHODS We evaluated the data validity, completeness, and timeliness of CART Program data using a random sample of 200 coronary procedures performed in 10 geographically diverse VA medical centers. RESULTS Of 1690 observations in the CART Program data repository, 1664 (98.5%) were valid, as compared to the VA medical record. The CART Program reports were more complete than cardiac catheterization laboratory reports generated prior to CART Program implementation (79% vs. 63.1%, P < .001). Finally, there was a trend toward earlier availability of completed procedure reports to treating providers after CART Program implementation, with 75% of CART Program reports available within 1 day compared to 4 days for reports generated prior to CART Program implementation (P = .06). CONCLUSIONS Cardiac catheterization reports generated by the VAs CART Program demonstrate excellent data validity, superior completeness, and a trend toward more timely availability to referring providers relative to cardiac catheterization laboratory reports generated prior to CART Program implementation. This demonstration of data quality is a key step in realizing CART Programs aim of supporting QI efforts in VA catheter laboratories.

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

Background 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. Objective 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. Methods 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. Results 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. Conclusion APP activity is lower in men and the XPNPEP2 C-2399A polymorphism associates with ACE inhibitor-associated angioedema in men but not women.

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

Objective The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. Participants and methods 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). Results 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<10–4) 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. Conclusion 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.

Combination therapy as initial treatment for newly diagnosed hypertension

BACKGROUND The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that clinicians consider the use of multidrug therapy to increase likelihood of achieving blood pressure goal. Little is known about recent patterns of combination antihypertensive therapy use in patients being initiated on hypertension treatment. METHODS We investigated combination antihypertensive therapy use in newly diagnosed hypertensive patients from the Cardiovascular Research Network Hypertension Registry. Multivariable logistic regression was used to assess the relationship between combination antihypertensive therapy and 12-month blood pressure control. RESULTS Between 2002 and 2007, a total of 161,585 patients met criteria for incident hypertension and were initiated on treatment. During the study period, an increasing proportion of patients were treated initially with combination rather than with single-agent therapy (20.7% in 2002 compared with 35.8% in 2007, P < .001). This increase in combination therapy use was more pronounced in patients with stage 2 hypertension, whose combination therapy use increased from 21.6% in 2002 to 44.5% in 2007. Nearly 90% of initial combination therapy was accounted for by 2 combinations, a thiazide and a potassium-sparing diuretic (47.6%) and a thiazide and an angiotensin-converting enzyme inhibitor (41.4%). After controlling for relevant clinical factors, including subsequent intensification of treatment and medication adherence, combination therapy was associated with increased odds of blood pressure control at 12 months (odds ratio compared with single-drug initial therapy 1.20; 95% CI 1.15-1.24, P < .001). CONCLUSIONS Initial treatment of hypertension with combination therapy is increasingly common and is associated with better long-term blood pressure control.

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

To cite this article: Byrd JB, Woodard‐Grice A, Stone E, Lucisano A, Schaefer H, Yu C, Eyler AE, Salloum NE, Brown NJ. Association of angiotensin‐converting enzyme inhibitor‐associated angioedema with transplant and immunosuppressant use. Allergy 2010; 65: 1381–1387.

Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema

Background 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. Objective We sought to test the hypothesis that a bradykinin B2 receptor antagonist would shorten time‐to‐resolution from ACE inhibitor‐associated angioedema. Methods 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 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge. Results 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. Conclusions This study does not support clinical efficacy of a bradykinin B2 receptor antagonist in ACE inhibitor‐associated angioedema.

Anxiety in the “Age of Hypertension”

In the USA, hypertension affects one in three adults, and anxiety disorders are the most commonly diagnosed mental health disorders. Both hypertension and anxiety have been studied extensively. Yet, a full understanding of anxiety’s relationship to hypertension has been elusive. In this review, we discuss the spectrum of anxiety disorders. In addition, we consider the evidence for acute and long-term effects of anxiety on blood pressure. We review the effect on blood pressure of several “real-world” stressors, such as natural disasters. In addition, we review the effect of anxiety treatments on blood pressure. We explain the American Heart Association’s recent recommendations regarding meditation and other relaxation methods in the management of hypertension. We conclude that novel research methods are needed in order to better elucidate many aspects of how anxiety relates to hypertension.

Detection and recognition of hypertension in anxious and depressed patients.

Objective: Hypertension management requires detection (i.e. confirmation of persistently high blood pressure (BP) after an initial elevated measurement) and recognition of the condition (evidenced by a formal diagnosis and/or initiation of treatment). Our objective was to determine whether disparities exist in detection of elevated BP and recognition (i.e. diagnosis or treatment) of hypertension in patients with depression and anxiety. Methods: Using data from the Cardiovascular Research Network Hypertension Registry, we assessed time-to-detection of elevated BP and recognition of hypertension in patients with comorbid anxiety and depression compared with patients with neither disorder. We performed multivariable survival analysis of time to detection and recognition in patients who entered the registry in 2002–2006. We adjusted for primary care visit rate and other relevant clinical factors. Results: In 168 630 incident hypertension patients, detection occurred earlier among patients with anxiety and depression compared with patients without these diagnoses [adjusted hazard ratio for anxiety and depression 1.30, 95% confidence interval (CI) 1.26–1.35]. Recognition of hypertension within 12 months of the second elevated BP was similar (adjusted hazard ratio for anxiety and depression 0.94, 95% CI 0.89–1.00) or delayed (adjusted hazard ratio for anxiety 0.93, 95% CI 0.88–0.99 and for depression 0.93, 95% CI 0.90–0.97). Conclusions: Detection of elevated BP occurred earlier in patients with anxiety and depression. Time from detection to diagnosis or treatment was similar or delayed in patients with and without these diagnoses. Our findings suggest that as-yet-unidentified factors contribute to disparities in hypertension detection and recognition.