Faculty Bibliography

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-Arg(9)-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.

BACKGROUND:Defects in the handling of renal salt reabsorption may contribute to interindividual differences in blood-pressure regulation and susceptibility to hypertension. Sodium chloride reabsorption in the thick ascending limb (TAL) is dependent in part on the chloride channel, ClC-Kb (encoded by CLCNKB), and its accessory subunit, barttin (encoded by BSND). METHODS:We investigated genetic variations in BSND in a screening population, and genotyped a homogenous cohort of normotensive and hypertensive Ghanaian subjects, in addition to four ethnically defined control populations. Functional consequences of the identified BSND variants were examined using a heterologous expression system. RESULTS:Three novel, nonsynonymous coding-sequence single-nucleotide polymorphisms were identified (V43I, E255Q, and G284D) in the screening population. BSND-V43I was identified in African American, Asian, and Hispanic subjects, with minor allele frequencies of 0.14, 0.18, and 0.01, respectively, but it was absent in the Caucasian population. BSND-E225Q and BSND-G284D were rare variants. Two of these variants (V43I and G284D) exhibited partial loss-of-function phenotypes when heterologously expressed with ClC-Kb chloride channels in cultured cells. In logistic regression analyses, we observed no association between hypertension and BSND-I43 in our study population. However, we did observe significant deviation from Hardy-Weinberg equilibrium in the normotensive population. CONCLUSIONS:We conclude that BSND-V43I, a common variant conferring partial loss of function, exhibits significant deviation from Hardy-Weinberg equilibrium in the Ghanaian normotensive control population. However, it does not independently confer protection against hypertension.

BACKGROUND:Postoperative atrial fibrillation (AF), leading to significant morbidity and prolongation of hospital stay, complicates 20% to 40% of surgical procedures requiring cardiopulmonary bypass (CPB). This study tests the hypothesis that biomarkers predict the development of postoperative AF. METHODS AND RESULTS/RESULTS:We enrolled 253 adult patients undergoing elective cardiac surgery requiring CPB and who were in sinus rhythm at the time of surgery. Blood samples were obtained for measurement of 21 biomarkers immediately after separation from CPB and administration of protamine. Patients who developed postoperative AF (67 subjects, 26.5%) were significantly older (P<0.001), more likely to have a remote history of AF (P<0.001), and tended to be more likely to have had valve surgery (P=0.082). Plasminogen activator inhibitor-1 (P=0.014), interleukin (IL)-6 (P=0.019), and N-terminal prohormone brain natriuretic peptide (P=0.028) concentrations were significantly higher in the blood of patients who developed postoperative AF. Logistic regression identified age (P<0.001), remote history of AF (P=0.001), and postoperative PAI-1 (P=0.036) as independent predictors of postoperative AF. When preoperative PAI-1 antigen concentrations were included in the model age (P<0.001), remote history of AF (P<0.001) and preoperative PAI-1 (P=0.015) were identified as independent predictors of postoperative AF. The Chi-squared Automatic Interaction Detection (CHAID) model indicated that age was the primary determinant for the development of postoperative AF (17% in age < or = 67.3 years versus 49% in age > 67.3 years). Within younger patients (age < or = 67.3 years) without remote history of AF, postoperative PAI-1 antigen concentration next determined risk of AF (13% if PAI-1 < or = 28.5 ng/mL versus 46% if PAI-1 > 28.5 ng/mL). CONCLUSION/CONCLUSIONS:An elevated preoperative or postoperative PAI-1 antigen concentration is an independent predictor for development of AF after CPB. Studies are needed to determine whether drugs that reduce PAI-1 concentrations can also reduce the risk of postoperative AF.

BACKGROUND:The occurrence of hepatitis A in the United States is heterogeneous because of disease cycles with substantial variation in incidence among states and involvement of numerous behavioral risk factors. In spite of the Advisory Committee on Immunization Practices' (ACIP) 1999 recommendation for routine hepatitis A immunization in states with high rates of disease and the fact that disease rates are at a historic low, outbreaks continue to occur. METHODS:We reviewed outbreaks of hepatitis A in the United States occurring from 1994 through 2004. We searched PubMed, ProMed, Google, and the CDC Foodborne Disease Outbreak and Epi-X Internet sites to ascertain the number and type of hepatitis A outbreaks. The CDC's MMWR publication and the Hepatitis Control Report were also searched. RESULTS:A total of 256 hepatitis A outbreaks were identified from 1994 through 2004. The mean number of outbreaks was 23 per year (median 25). The number of outbreaks in states with traditionally low/intermediate endemic rates of hepatitis A remained relatively constant during the study period. Outbreaks declined significantly (P = 0.01) in states with previously high rates of disease--most of which have implemented hepatitis A vaccination programs. CONCLUSIONS:Outbreaks of hepatitis A continue to occur in the United States despite the licensure of two safe and effective vaccines in 1995 and the apparent decline in the number of outbreaks in states with previously high rates of hepatitis A. The recent ACIP recommendation for universal hepatitis A vaccination at age 1 year in all states will contribute to a further reduction in hepatitis A outbreaks.

Oxidative stress may play a role in the pathogenesis of systemic lupus erythematosus (SLE). We examined the hypothesis that oxidative stress was associated with indices of lupus disease activity and severity of symptoms. Urinary F2 isoprostane excretion, a validated marker of oxidative stress, was measured in 95 patients with SLE and 103 healthy controls. Outcome measures included SLEDAI and SLICC scores, the modified health assessment questionnaire, the fatigue severity scale (FSS), and visual analogue scales (VAS) for fatigue, pain and overall disease activity. F2 isoprostane excretion was compared in patients and controls, and its relationship with clinical variables in SLE examined. F2 isoprostane excretion did not differ significantly among patients with lupus (2.7 +/- 2.3 ng/mg Cr) and control subjects (2.2 +/- 1.4 ng/mg Cr) (P = 0.70). In patients with lupus, F2 isoprostane concentrations were independently associated with higher patient reported disease activity (VAS) (OR = 1.52, P = 0.01), fatigue (FSS, OR = 1.52, P = 0.03) and lower quality of life (OR = 0.73, P = 0.05), but not with objective markers or inflammation or disease activity. In conclusion, F2 isoprostane excretion is associated with patient-reported symptoms in SLE but not with measures of inflammation, SLEDAI or SLICC. Oxidative stress may contribute to debilitating symptoms such as fatigue in SLE.

This study tested the hypothesis that angiotensin promotes oxidative stress and inflammation in humans via aldosterone and the mineralocorticoid receptor. We measured the effect of intravenous aldosterone (0.7 mug/kg per hour for 10 hours followed by 0.9 mug/kg per hour for 4 hours) and vehicle in a randomized, double-blind crossover study in 11 sodium-restricted normotensive subjects. Aldosterone increased interleukin (IL)-6 (from 4.7+/-4.9 to 9.4+/-7.1 pg/mL; F=4.94; P=0.04) but did not affect blood pressure, serum potassium, or high-sensitivity C-reactive protein. We next conducted a randomized, double-blind, placebo-controlled, crossover study to measure the effect of 3-hour infusion of angiotensin II (2 ng/kg per minute) and norepinephrine (30 ng/kg per minute) on separate days after 2 weeks of placebo or spironolactone (50 mg per day) in 14 salt-replete normotensive subjects. Angiotensin II increased blood pressure (increase in systolic pressure: 13.7+/-7.5 and 15.2+/-9.4 mm Hg during placebo and spironolactone, respectively; P<0.001 for angiotensin II) and decreased renal plasma flow (-202+/-73 and -167+/-112 mL/min/1.73 kg/m(2); P<0.001 for angiotensin II effect) similarly during placebo and spironolactone. Spironolactone enhanced the aldosterone response to angiotensin II (increase of 17.0+/-10.6 versus 9.0+/-5.7 ng/dL; P=0.002). Angiotensin II transiently increased free plasma F(2)-isoprostanes similarly during placebo and spironolactone. Angiotensin II increased serum IL-6 concentrations during placebo (from 1.8+/-1.1 to 2.4+/-1.4 pg/mL; F=4.5; P=0.04) but spironolactone prevented this effect (F=6.4; P=0.03 for spironolactone effect). Norepinephrine increased blood pressure and F(2)-isoprostanes but not aldosterone or IL-6. Aldosterone increases IL-6 in humans. These data suggest that angiotensin II induces IL-6 through a mineralocorticoid receptor-dependent mechanism in humans. In contrast, angiotensin II-induced oxidative stress, as measured by F(2)-isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent.

BACKGROUND:Patient complaints are associated with increased malpractice risk but it is unclear if complaints might be associated with medical complications. The purpose of this study was to determine whether an association exists between patient complaints and surgical complications. METHODS:A retrospective analysis of 16,713 surgical admissions was conducted over a 54 month period at a single academic medical center. Surgical complications were identified using administrative data. The primary outcome measure was unsolicited patient complaints. RESULTS:During the study period 0.9% of surgical admissions were associated with a patient complaint. 19% of admissions associated with a patient complaint included a postoperative complication compared with 12.5% of admissions without a patient complaint (p = 0.01). After adjusting for surgical specialty, co-morbid illnesses and length of stay, admissions with complications had an odds ratio of 1.74 (95% confidence interval 1.01 to 2.98) of being associated with a complaint compared with admissions without complications. CONCLUSIONS:Admissions with surgical complications are more likely to be associated with a complaint than surgical admissions without complications. Further research is necessary to determine if patient complaints might serve as markers for poor clinical outcomes.

BACKGROUND:Intradialytic parenteral nutrition (IDPN), with or without exercise, has been shown to reverse the net negative whole-body and forearm muscle protein balances observed during hemodialysis. Pharmacologic doses of recombinant human growth hormone (rhGH) constitute another potential anabolic therapy in chronic hemodialysis patients. OBJECTIVE:Our goal was to examine the potential additive anabolic effects of rhGH compared with IDPN and exercise on protein and energy homeostasis. DESIGN/METHODS:We studied 7 chronic hemodialysis patients in a crossover design study in which each subject participated in 2 protocols: GH (rhGH + IDPN + exercise) and no GH (IDPN + exercise). During the GH protocol, the subjects were studied after 3 daily doses of rhGH. Each subject was studied 2 h before, 4 h during, and 2 h after a hemodialysis session with the use of a primed, constant infusion of l-[1-(13)C]leucine. RESULTS:Whole-body net protein balance was -0.50 +/- 0.07 mg x kg fat-free mass(-1) x min(-1) when the patients did not receive rhGH and -0.39 +/- 0.04 mg x kg fat-free mass(-1) x min(-1) when the patients received rhGH, a 22% improvement in prehemodialysis whole-body protein homeostasis (P < 0.05). Essential amino acid muscle loss was also significantly less during the prehemodialysis period when rhGH was administered (-18 +/- 23 compared with -71 +/- 20 mmol/L; P < 0.05). The whole-body anabolic effects of rhGH observed during the prehemodialysis period persisted throughout the entire study, as evidenced by a lack of significant interaction or main effect of treatment during hemodialysis and in the posthemodialysis period. CONCLUSION/CONCLUSIONS:rhGH improves whole-body protein homeostasis in chronic hemodialysis patients.

This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen (P=0.006 for drug effect). In normotensive subjects, triamterene (from 10.1+/-7.8 to 16.9+/-9.9 ng/mL at 9 am, P=0.019; from 7.6+/-5.4 to 11.5+/-7.3 ng/mL at 11 am, P=0.027; from 9.3+/-7.7 to 13.7+/-8.5 ng/mL for average of all time points, P=0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0+/-23.4 to 16.7+/-19.0 ng/mL at 10 am, P=0.041; from 17.5+/-21.7 to 12.7+/-16.8 ng/mL at 11 am, P=0.043; from 20.3+/-22.6 to 16.6+/-19.7 ng/mL for average of all time points, P=0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene (P=0.014), hypertension (P=0.002), and PAI-1 response to HCTZ (P=0.019), with a trend for aldosterone (P=0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.

OBJECTIVE:In spite of numerous studies demonstrating the serious gastrointestinal (GI) toxicity associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), many patients at high GI risk continue to receive prescriptions for these drugs, often without gastroprotective agents. Etoricoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than non-selective NSAIDs. We compared the incidence of upper GI Perforations, symptomatic gastroduodenal Ulcers, and upper GI Bleeding (PUBs) in a combined analysis of all randomized, double-blind, clinical trials of chronic treatment with etoricoxib versus NSAIDs completed by June 2003. RESEARCH DESIGN AND METHODS/METHODS:Data for 5441 individual subjects with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis were pooled from all 10 multinational etoricoxib trials completed by June 2003. Information on suspected PUBs was prospectively collected in all protocols, and all investigator-reported PUBs were judged by a blinded, external adjudication committee using pre-specified criteria. PUBs were analyzed using COX proportional hazards models using terms for treatment and known PUB risk factors. MAIN OUTCOME MEASURE/METHODS:The incidence of confirmed PUBs among patients treated with etoricoxib 60 mg, 90 mg, or 120 mg (combined N=3226) was compared to that among patients treated with ibuprofen, diclofenac, or naproxen (combined N=2215). RESULTS:The incidence of PUBs over 44.3 months was significantly lower with etoricoxib vs. NSAIDs [cumulative incidence 1.24% vs. 2.48%, p < 0.001; rate/100 patient-years 1.00 vs. 2.47; relative risk 0.48, 95% Confidence Interval (CI) 0.32, 0.73]. Results of analysis of events occurring during the first year of treatment and subgroup analyses were consistent with the primary result. CONCLUSIONS:Treatment with etoricoxib was associated with a significantly lower incidence of PUBs than was treatment with non-selective NSAIDs. The difference was consistent in subgroups of patients defined by a variety of known risk factors.