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Implications of a vasodilatory human monoclonal autoantibody in postural hypotension.

ABSTRACT: Functional autoantibodies to the autonomic receptors are increasingly recognized in the pathophysiology of cardiovascular diseases. To date, no human activating monoclonal autoantibodies to these receptors have been available. In this study, we describe for the first time a ?2-adrenergic receptor (?2AR)-activating monoclonal autoantibody (C5F2) produced from the lymphocytes of a patient with idiopathic postural hypotension. C5F2, an IgG3 isotype, recognizes an epitope in the N terminus of the second extracellular loop (ECL2) of ?2AR. Surface plasmon resonance analysis revealed high binding affinity for the ?2AR ECL2 peptide. Immunoblotting and immunofluorescence demonstrated specific binding to ?2AR in H9c2 cardiomyocytes, CHO cells expressing human ?2AR, and rat aorta. C5F2 stimulated cyclic AMP production in ?2AR-transfected CHO cells and induced potent dilation of isolated rat cremaster arterioles, both of which were specifically blocked by the ?2AR-selective antagonist ICI-118551 and by the ?2AR ECL2 peptide. This monoclonal antibody demonstrated sufficient activity to produce postural hypotension in its host. Its availability provides a unique opportunity to identify previously unrecognized causes and new pharmacological management of postural hypotension and other cardiovascular diseases.

SUBMITTER: Li H

PROVIDER: S-EPMC3798543 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Implications of a vasodilatory human monoclonal autoantibody in postural hypotension.

Li Hongliang H Zuccolo Jonathan J Kem David C DC Zillner Caitlin C Lee Jiyeon J Smith Kenneth K James Judith A JA Cunningham Madeleine W MW Yu Xichun X

The Journal of biological chemistry 20130916 42

Functional autoantibodies to the autonomic receptors are increasingly recognized in the pathophysiology of cardiovascular diseases. To date, no human activating monoclonal autoantibodies to these receptors have been available. In this study, we describe for the first time a β2-adrenergic receptor (β2AR)-activating monoclonal autoantibody (C5F2) produced from the lymphocytes of a patient with idiopathic postural hypotension. C5F2, an IgG3 isotype, recognizes an epitope in the N terminus of the se ...[more]

PMID: 24043632

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Project description:ObjectivesBalancing the risks of hypotension and vasopressor-associated adverse effects is a daily challenge in ICUs. We conducted a systematic review with meta-analysis to examine the effect of lower versus higher exposure to vasopressor therapy on mortality among adult ICU patients with vasodilatory hypotension.Data sourcesWe searched Ovid Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from inception to October 15, 2021.Study selectionWe included randomized controlled trials of lower versus higher exposure to vasopressor therapy in adult ICU patients with vasodilatory hypotension without language or publication status limits.Data extractionThe primary outcome was 90-day all-cause mortality, with seven prespecified subgroups. Secondary outcomes included shorter- and longer-term mortality, use of life-sustaining therapies, vasopressor-related complications, neurologic outcome, and quality of life at longest reported follow-up. We conducted random-effects meta-analyses to calculate summary effect measures across individual studies (risk ratio [RR] for dichotomous variables, mean difference for continuous variables, both with 95% CIs). The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation. We registered this review on the International Prospective Register of Systematic Reviews (CRD42021224434).Data synthesisOf 3,403 records retrieved, 68 full-text articles were reviewed and three eligible studies included. Lower exposure to vasopressors probably lowers 90-day mortality but this is based on moderate-certainty evidence, lowered for imprecision (RR, 0.94; 95% CI, 0.87-1.02). There was no credible subgroup effect. Lower vasopressor exposure may also decrease the risk of supraventricular arrhythmia (odds ratio, 0.55; 95% CI, 0.36-0.86; low certainty).ConclusionsIn patients with vasodilatory hypotension who are started on vasopressors, moderate-certainty evidence from three randomized trials showed that lower vasopressor exposure probably lowers mortality. However, additional trial data are needed to reach an optimal information size to detect a clinically important 10% relative reduction in mortality with this approach.

Project description:ImportanceVasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.ObjectiveTo determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.Design, setting, and participantsA multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.InterventionsPatients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).Main outcome and measuresThe primary clinical outcome was all-cause mortality at 90 days.ResultsOf 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).Conclusions and relevanceAmong patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.Trial registrationisrctn.org Identifier: ISRCTN10580502.

Project description:ObjectivesFalls are a common problem in older people. Postural hypotension contributes to falls but is often asymptomatic. In the absence of symptoms, postural hypotension is only infrequently checked for in clinical practice. We undertook this study to derive, validate and explore the prospective associations of a prediction tool to identify people likely to have unrecognised postural hypotension.Design and settingCross-sectional and prospective multivariable cohort analysis.Participants1317 participants of the Invecchiare in Chianti study, a population-based cohort representative of the older Italian population.Primary outcome measuresPredictive value of score to suggest presence of postural hypotension.MethodsSubjects were randomised 1:1 to derivation or validation cohorts. Within the derivation cohort, univariable associations for candidate predictors of postural hypotension were tested. Variables with p<0.1 entered multivariable linear regression models. Factors retaining multivariable significance were incorporated into unweighted and weighted Detecting Risk Of Postural hypotension (DROP) scores. These scores were tested in the validation cohort against prediction of postural hypotension, cognitive decline and mortality over 9 years of follow-up.ResultsPostural hypotension was present in 203 (15.4%) of participants. Factors predicting postural hypotension were: digoxin use, Parkinson's disease, hypertension, stroke or cardiovascular disease and an interarm systolic blood pressure difference. Area under the curve was consistent at 0.65 for all models, with significant ORs of 1.8 to 2.4 per unit increase in score for predicting postural hypotension. For a DROP score ?1, five cases need to be tested to identify one with postural hypotension.Increasing DROP scores predicted mortality (OR 1.8 to 2.8 per unit rise) and increasing rates of decline of Mini Mental State Examination score (analysis of variance p<0.001) over 9 years of follow-up.ConclusionsThe DROP score provides a simple method to identify people likely to have postural hypotension and increased risks to health who require further evaluation.

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Implications of a vasodilatory human monoclonal autoantibody in postural hypotension.

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Implications of a vasodilatory human monoclonal autoantibody in postural hypotension.

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