Juan J. Russo

Methodological Rigor in Preclinical Cardiovascular Studies: Targets to Enhance Reproducibility and Promote Research Translation

Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.

Methodological Rigor in Preclinical Cardiovascular Studies

Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.

Sex Bias Is Increasingly Prevalent in Preclinical Cardiovascular Research: Implications for Translational Medicine and Health Equity for Women

Ensuring that women are adequately represented in clinical trials is recognized as essential for sex equity in health. However, the use of female animal models and sex-based reporting have not been equally enforced in preclinical stages of research, which often precede and inform clinical trials. In 2014, the National Institutes of Health announced that it would require that sex be considered as a biological variable in applications for preclinical research funding,1 yet a reluctance to include female animal models in preclinical experiments persists. Inappropriately inferring experimental findings to both sexes when a single sex is studied or when sex is not specified has the potential to disadvantage women by skewing our understanding of disease processes toward male-predominant patterns and by reducing the likelihood of female-specific therapeutics advancing to the clinical realm. We therefore systematically examined all preclinical cardiovascular studies published in American Heart Association journals with archives spanning at least 10 years ( Circulation , Circulation Research , Hypertension , Stroke , and Arteriosclerosis, Thrombosis, and Vascular Biology [ ATVB ]) for evidence of sex …

Impact of mean arterial pressure on clinical outcomes in comatose survivors of out-of-hospital cardiac arrest: Insights from the University of Ottawa Heart Institute Regional Cardiac Arrest Registry (CAPITAL-CARe)

AIM OF THE STUDY We sought to assess the relationship between mean arterial pressure (MAP) and clinical outcomes in comatose survivors of out-of-hospital cardiac arrest (OHCA). METHODS We identified consecutive comatose survivors of OHCA with an initial shockable rhythm treated with targeted temperature management. We examined clinical outcomes in relation to mean MAP (measured hourly) during the first 96h of hospitalization. Co-primary outcomes were the rates of death and severe neurological dysfunction at discharge. RESULTS In 122 patients meeting inclusion criteria, death occurred in 29 (24%) and severe neurological dysfunction in 39 (32%). Higher mean MAPs were associated with lower odds of death (OR 0.55 per 5mmHg increase; 95%CI 0.38-0.79; p=0.002) and severe neurological dysfunction (OR 0.66 per 5mmHg increase; 95%CI 0.48-0.90; p=0.01). After adjustment for differences in patient, index event, and treatment characteristics, higher mean MAPs remained associated with lower odds of death (OR 0.60 per 5mmHg increase; 95%CI 0.40-0.89; p=0.01) but not severe neurological dysfunction (OR 0.73 per 5mmHg increase; 95%CI 0.51-1.03; p=0.07). The relationship between mean MAP and the odds of death (p-interaction=0.03) and severe neurological dysfunction (p-interaction=0.03) was attenuated by increased patient age. CONCLUSION In comatose survivors of OHCA treated with target temperature management, a higher mean MAP during the first 96h of admission is associated with increased survival. The association between mean MAP and clinical outcomes appears to be attenuated by increased age.

Progenitor Cells for Arterial Repair: Incremental Advancements towards Therapeutic Reality

Coronary revascularization remains the standard treatment for obstructive coronary artery disease and can be accomplished by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. Considerable advances have rendered PCI the most common form of revascularization and improved clinical outcomes. However, numerous challenges to modern PCI remain, namely, in-stent restenosis and stent thrombosis, underscoring the importance of understanding the vessel wall response to injury to identify targets for intervention. Among recent promising discoveries, endothelial progenitor cells (EPCs) have garnered considerable interest given an increasing appreciation of their role in vascular homeostasis and their ability to promote vascular repair after stent placement. Circulating EPC numbers have been inversely correlated with cardiovascular risk, while administration of EPCs in humans has demonstrated improved clinical outcomes. Despite these encouraging results, however, advancing EPCs as a therapeutic modality has been hampered by a fundamental roadblock: what constitutes an EPC? We review current definitions and sources of EPCs as well as the proposed mechanisms of EPC-mediated vascular repair. Additionally, we discuss the current state of EPCs as therapeutic agents, focusing on endogenous augmentation and transplantation.

Hyperglycaemia in comatose survivors of out-of-hospital cardiac arrest

Background: The optimal blood glucose target during the early hospitalisation of comatose survivors of out-of-hospital cardiac arrest (OHCA) has not been established. Methods: In a retrospective cohort study, we examined clinical outcomes in relation to mean blood glucose during the first 96 hours of hospital admission in comatose survivors of OHCA with an initial shockable rhythm. Mean blood glucose was assessed as a continuous (primary analysis) and categorical variable: <6 mmol/L, 6 to <8 mmol/L and ⩾8 mmol/L. Co-primary outcomes were the rates of death during the index hospitalisation and severe neurological dysfunction at discharge. We used multivariable logistic regression analyses to adjust for baseline differences in patient and index event characteristics. Results: Among 122 eligible patients, death and severe neurological dysfunction occurred in 29 (24%) and 40 (33%) patients, respectively. Higher mean blood glucose levels during the first 96 hours of admission were associated with increased odds of death (odds ratio (OR): 1.50; 95% confidence interval (CI): 1.17–1.92; p = 0.001) and severe neurological dysfunction (OR: 1.42; 95% CI: 1.11–1.80; p = 0.004). The associations between mean blood glucose and the odds of death (OR: 1.35; 95% CI: 1.04–1.76; p = 0.02) and severe neurological dysfunction (OR: 1.28; 95% CI: 1.00–1.64; p = 0.05) persisted after adjusting for age, time from cardiac arrest to return of spontaneous circulation (ROSC) and vasoactive agent use. There was no interaction between age, time from cardiac arrest to ROSC or a history of diabetes mellitus and the relationship between mean blood glucose and co-primary outcomes. Conclusions: In comatose survivors of OHCA with initial shockable rhythms, higher mean blood glucose levels during the first 96 hours of admission are associated with increased rates of death and severe neurological dysfunction.

Time to Treatment: Focus on Transfer in ST-Elevation Myocardial Infarction

In the modern ST-elevation myocardial infarction (STEMI) system, the use of electrocardiogram by emergency medical services (EMS) personnel and the option to bypass emergency departments on route to a PCI-capable hospital is of particular importance. Through training and a standardized referral process, EMS personnel can now accurately diagnose and refer STEMI patients directly to the catheterization laboratory of a percutaneous coronary intervention-capable hospital. Regional STEMI models have been implemented successfully across North America, resulting in palpable reductions in door-to-balloon time, morbidity, and mortality.

How common is isolated cardiac sarcoidosis? Extra-cardiac and cardiac findings on clinical examination and whole-body 18F–fluorodeoxyglucose positron emission tomography

BACKGROUND Sarcoidosis is a systemic inflammatory disease which can involve nearly any organ. Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The reported prevalence of isolated cardiac sarcoidosis (CS) varies widely with reported rates of 27-54%. The explanation for this variability is likely multi-factorial but perhaps mostly related to the diagnostic method(s) for assessing extra-cardiac involvement. The primary aim of this study was to assess the rate of isolated CS in a homogeneous, prospectively recruited cohort of patients with clinically manifest CS, using whole body FDG PET-CT imaging as a gold standard. A secondary aim was to describe the extent and distribution of extra-cardiac sarcoidosis at the time of first presentation of clinically manifest CS. METHODS Patients were prospectively recruited at the time of first presentation with cardiac symptoms. All patients underwent whole-body and cardiac 18F-FDG PET-CT. All patients were examined for presence of skin sarcoidosis and were assessed by an ophthalmologist. RESULTS 31 patients were included (mean age 56±8years, 17 female, 100% Caucasian). Patients had limited extra-cardiac involvement (mean of 2.2 organs) however using the most precise definition, only 1/31 (3.2%) patients had isolated CS. There were marked differences in right ventricular (RV) and atrial involvement between patients presenting with CS as first presentation compared to patients presenting initially with extra-cardiac disease. CONCLUSIONS Most patients had limited extra-cardiac involvement at the time of presentation of manifest CS however, isolated CS, using the proposed gold standard, was only observed in one patient.

Predicting Acute Kidney Injury following Transcatheter Aortic Valve Replacement

PURPOSE Acute kidney injury occurs in up to a quarter of patients following transcatheter aortic valve replacement (TAVR) and has been associated with increased short and long-term mortality rates. A variety of patient characteristics predictive of post-TAVR acute kidney injury (AKI) have been identified, however discrepancies among studies exist almost uniformly. We investigated the hypothesis that the change in glomerular filtration rate (ΔGFR) in response to contrast administered during pre-TAVR coronary angiography is predictive of ΔGFR post-TAVR. METHODS The study comprised 195 patients who underwent TAVR at a single center between August 2008 and June 2015 and were prospectively included in the CAPITAL TAVR registry. Multiple linear regression analysis was conducted to estimate the effect of independent variables on the change in renal function post-TAVR. RESULTS There was no relationship identified between the ΔGFR post-angiogram and the ΔGFR post-TAVR (r=0.043, P=0.582). Multiple linear regression analysis revealed that a significant amount of the change in renal function post-TAVR can be explained by the patients baseline creatinine (beta coefficient, -0.310, P.

In-hospital outcomes of STEMI patients on warfarin undergoing primary PCI

We sought to describe the safety and efficacy outcomes of patients on warfarin presenting with ST‐elevation myocardial infarction (STEMI).