A Pharmacologic “Stress Test” for Assessing Select Antioxidant Defenses in Patients with CKD

Background and objectivesOxidative stress is a hallmark and mediator of CKD. Diminished antioxidant defenses are thought to be partly responsible. However, there is currently no way to prospectively assess antioxidant defenses in humans. Tin protoporphyrin (SnPP) induces mild, transient oxidant stress in mice, triggering increased expression of select antioxidant proteins (e.g., heme oxygenase 1 [HO-1], NAD[P]H dehydrogenase [quinone] 1 [NQO1], ferritin, p21). Hence, we tested the hypothesis that SnPP can also variably increase these proteins in humans and can thus serve as a pharmacologic “stress test” for gauging gene responsiveness and antioxidant reserves.Design, setting, participants, & measurementsA total of 18 healthy volunteers and 24 participants with stage 3 CKD (n=12; eGFR 30–59 ml/min per 1.73 m2) or stage 4 CKD (n=12; eGFR 15–29 ml/min per 1.73 m2) were injected once with SnPP (9, 27, or 90 mg). Plasma and/or urinary antioxidant proteins were measured at baseline and for up to 4 days post-SnPP dosing. Kidney safety was gauged by serial measurements of BUN, creatinine, eGFR, albuminuria, and four urinary AKI biomarkers (kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, cystatin C, and N-acetyl glucosaminidase).ResultsPlasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (r=−0.85 to −0.95). All four proteins manifested statistically significant dose- and time-dependent elevations after SnPP injection. However, marked intersubject differences were observed. p21 responses to high-dose SnPP and HO-1 responses to low-dose SnPP were significantly suppressed in participants with CKD versus healthy volunteers. SnPP was well tolerated by all participants, and no evidence of nephrotoxicity was observed.ConclusionsSnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.Clinical Trial registry name and registration numberA Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3–4 Chronic Kidney Disease, NCT0363002 and NCT03893799

P1788 Prognostic value of stress echocardiography in preoperative risk stratification and management

Introduction The prognostic value of pharmacologic stress echocardiography has been extensively demonstrated in patients undergoing noncardiac surgery since 42% of the perioperative complications are cardiac. Coronary artery stenoses can became flow-limiting due to hemodynamic fluctuations in this period leading to myocardial ischemia. Purpose Evaluation of prognostic value of pharmacologic stress echocardiography in preoperative risk stratification. Methods Single center retrospective analysis of patients’ data referred to perform a preoperative risk stratification through pharmacological stress echocardiography between January 2014- December 2018. Data was collected regarding clinical and echocardiographic parameters to predict perioperative cardiac complications (myocardial infarction and development of arrythmias) and evaluate the impact of the result of DSE in patients´ clinical management. Results Of 910 pharmacological stress echocardiograms, 106 were performed to evaluate preoperative risk. Patients´ mean age was 66 ± 11 years, 85% males. 64% had hypertension, 45% dyslipidaemia, 38% current smokers and 18% diabetes. 189% had previously myocardial infarction and 9% stroke. All patients were proposed to intermediate-high risk surgeries: 73% to vascular surgery, 14% to kidney transplant and 13% to other type of surgery (especially abdominal surgery). Most of the stress tests (64%) were performed with dobutamine and the others 34% with dipyridamole. 91% of stress echocardiography were negative, 6% positive and 4% inconclusive. The patients with a positive stress test was submitted to coronary angiography to treat relevant lesions and cardiovascular risk factors were optimized. 72% of the patients has already been submitted to the proposed surgery; in this population, there was a 5% rate of cardiac complications following the surgery, all in patients with previous negative stress echocardiography. Complications were non-ST elevation myocardial infarction in 1% and de novo atrial fibrillation in 4%. Half of the patients with a positive stress echocardiography were operated with no cardiac perioperative complications, possibly related to patient´s optimization before the surgery; in the other half it was decided not to perform the surgery due to the potential cardiac risk. Predictor factors for perioperative cardiac complications, evaluated through univariate and multivariate analysis, were age (odds ratios (OR) 1.232, confidence interval (CI) 1.043-1.456, p 0.007) and stroke (OR 0.057, CI 0.947-44.592, p 0.033). Conclusion In our study, patients with a positive stress echocardiography were optimized before the surgery leading to none cardiac perioperative complications, emphasizing the importance of this test in preoperative patients´ management.

Adenosine vs Regadenoson Pharmacologic Stress Differs in Women with Suspected Coronary Microvascular Dysfunction: A Report from the Women’s Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) Study

Background: Stress cardiac magnetic resonance (CMR) imaging with myocardial perfusion reserve index (MPRI) measurement has emerged as a noninvasive method for assessing coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease (CAD). Pharmacologic stress with adenosine or regadenoson is typically used with comparable coronary vasodilation, but higher unadjusted MPRI has been reported with regadenoson in healthy men. This difference has not been assessed in symptomatic or healthy women. Methods: In a prospective cohort study, 139 symptomatic women with suspected CMD and no obstructive CAD underwent stress CMR and invasive coronary flow reserve (CFR) testing. Adenosine was the default vasodilator (n=99), while regadenoson was used if history of asthma or prior adenosine intolerance (n=40). Stress CMR was also performed in 40 age-matched healthy controls using adenosine (n=20) and regadenoson (n=20). Unpaired t-tests and analysis of covariance were performed to compare MPRI with adenosine and regadenoson in the symptomatic women and healthy controls. Results: Compared to regadenoson cases, adenosine cases had lower invasive CFR (2.64±0.62 vs 2.94±0.68, p=0.01) and pharmacologic heart rate change (28±16 vs 38±15 bpm, p=0.0008). Unadjusted MPRI was lower in the adenosine compared to regadenoson cases (1.73±0.38 vs 2.27±0.59, p<0.0001). When adjusted for heart rate, rate-pressure-product, and invasive CFR, MPRI remained lower in the adenosine cases (p<0.0001). Invasive CFR to adenosine correlated with adenosine MPRI (r 0.17, p=0.02) but not regadenoson MPRI (r -0.14, p=0.19). There was no significant difference in MPRI in the controls who received adenosine vs regadenoson (2.27±0.33 vs 2.38±0.44, p=0.36). Conclusion: In women undergoing stress CMR for suspected CMD, those who received adenosine had lower MPRI than those who received regadenoson. However, there were no differences in MPRI in the healthy controls. These findings suggest there may be physiologic differences in adenosine and regadenoson response in the coronary microcirculation of symptomatic women.