Pietro Di Santo

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 Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient-Level, International, Collaborative, Multi-Center Analysis

Background The adoption of the transradial (TR) approach over the traditional transfemoral (TF) approach has been hampered by concerns of increased radiation exposure—a subject of considerable debate within the field. We performed a patient‐level, multi‐center analysis to definitively address the impact of TR access on radiation exposure. Methods and Results Overall, 10 centers were included from 6 countries—Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of TR versus TF access using measured dose‐area product (DAP). To account for local variations in equipment and exposure, standardized TR:TF DAP ratios were constructed per center with procedures separated by coronary angiography (CA) and percutaneous coronary intervention (PCI). Among 57 326 procedures, we demonstrated increased radiation exposure with the TR versus TF approach, particularly in the CA cohort across all centers (weighted‐average ratios: CA, 1.15; PCI, 1.05). However, this was mitigated by increasing TR experience in the PCI cohort across all centers (r=−0.8; P=0.005). Over time, as a center transitioned to increasing TR experience (r=0.9; P=0.001), a concomitant decrease in radiation exposure occurred (r=−0.8; P=0.006). Ultimately, when a centers balance of TR to TF procedures approaches 50%, the resultant radiation exposure was equivalent. Conclusions The TR approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the TR and TF approaches are used with equal frequency—a guiding principle for centers adopting the TR approach.

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.

Association Between Self‐Reported Potentially Modifiable Cardiac Risk Factors and Perceived Need to Improve Physical Health: A Population‐Based Study

Background An individuals perceived need to improve their physical health (PNIPH) is an essential precursor to adopting healthy behaviors. Nine potentially modifiable risk factors (PMRFs) for myocardial infarction collectively account for ≥90% of the population attributable risk. Though widely recognized, their impact on individuals’ health perceptions is unclear. Methods and Results Residents from 6 provinces were administered a module on changes to improve health as part of the 2011–2012 Canadian Community Health Survey, yielding relevant data for 8 of the 9 PMRFs sought. The potential effects of PMRFs individually and cumulatively on PNIPH were examined using modified Poisson regression. In total, 45 443 respondents were included, representing 11 006 123 individuals and corresponding to 96.8% of the adult population of the sampled provinces. The sum of PMRFs was positively associated with PNIPH (adjusted prevalence ratio, 1.08; 95% CI, 1.07–1.09 per additional PMRF) with 82.3% of individuals with ≥5 PMRFs reporting this perception. Smoking, obesity, and low physical activity were most strongly associated with PNIPH, whereas hypertension and diabetes mellitus exhibited no association with this outcome after adjusting for potential confounders. Barriers to adopting healthy behaviors were reported by 55.9% of individuals endorsing PNIPH. Conclusions The cumulative burden of PMRFs is positively associated with PNIPH; however, individual PMRFs differentially contribute to this perception. Among those at highest cardiac risk, ≈1 in 5 denied PNIPH. A better understanding of factors underlying health perceptions and behaviors is needed to capitalize on cardiovascular preventive efforts.

Role of plasminogen activator inhibitor-1 in coronary pathophysiology

The standard of care for obstructive atherosclerotic coronary disease is revascularization, predominantly achieved via percutaneous placement of a stent with concurrent medical therapy. Advancements in percutaneous coronary intervention (PCI) have dramatically improved outcomes. However, major complications from PCI due to target lesion failure continue to occur at rates between 5 and 10% in the first twelve months following intervention limiting its therapeutic efficacy. Plasminogen activator inhibitor-1 (PAI-1) is a protein of interest for both arterial remodeling and thrombotic risk as it regulates cell migration and vascular thrombosis. Elevated PAI-1 antigen levels have been identified as a potential biomarker for coronary artery disease and metabolic syndrome while being modulated by a number of atherosclerotic risk factors. Although linked by some studies as a marker of disease severity and prognosis, it remains to be understood whether it is also a mediator and/or therapeutic target of vascular disease. In this review, we discuss the current understanding of PAI-1 in vascular disease and its potential role in in-stent restenosis and stent thrombosis.

Optimal Mean Arterial Pressure in Comatose Survivors of Out-of-hospital Cardiac Arrest: An Analysis of Area Below Blood Pressure Thresholds

AIM OF THE STUDY To determine the optimal mean arterial pressure (MAP) during the early-to-intermediate phase care of comatose survivors of out-of-hospital cardiac arrest (OHCA). METHODS We identified consecutive comatose survivors of OHCA with an initial shockable rhythm. Using blood pressure-over-time plots, we calculated the area below pre-specified MAP thresholds (ABT; mmHg*hours) during the first 96 h of admission. We used incremental MAP thresholds ranging between 65 and 85 mmHg. Logistic regression analyses were used to examine the association between ABT and clinical outcomes for each MAP threshold and to adjust for age, duration of cardiac arrest, and bystander CPR. The primary outcome was severe neurological dysfunction as defined by a cerebral performance category (CPC) ≥3. RESULTS We identified 122 consecutive OHCA patients meeting inclusion criteria. The rate of the primary outcome was 33%. There was a significant association between ABT and the rate of the primary outcome when MAP thresholds of 60 (p = 0.01), 65 (p < 0.01), 70 (p < 0.01), 75 (p < 0.01), and 80 mmHg (p < 0.01) were used. This association was lost once a MAP threshold of 85 mmHg was reached (p = 0.63). In the adjusted analysis, the association between ABT and the primary outcome was no longer present when the MAP threshold reached 75 mmHg. CONCLUSIONS In comatose survivors of OHCA with an initial shockable rhythm, higher ABT is associated with increased rates of severe neurological dysfunction when MAP thresholds <75 mmHg are used. The current findings support the hypothesis that higher MAP targets (≥75 mmHg) may be indicated in this patient population.

Photoplethysmography using a smartphone application for assessment of ulnar artery patency: a randomized clinical trial

BACKGROUND: Radial artery access is commonly performed for coronary angiography and invasive hemodynamic monitoring. Despite limitations in diagnostic accuracy, the modified Allen test (manual occlusion of radial and ulnar arteries followed by release of the latter and assessment of palmar blush) is used routinely to evaluate the collateral circulation to the hand and, therefore, to determine patient eligibility for radial artery access. We sought to evaluate whether a smartphone application may provide a superior alternative to the modified Allen test. METHODS: We compared the modified Allen test with a smartphone heart rate–monitoring application (photoplethysmography readings detected using a smartphone camera lens placed on the patient’s index finger) in patients undergoing a planned cardiac catheterization. Test order was randomly assigned in a 1:1 fashion. All patients then underwent conventional plethysmography of the index finger, followed by Doppler ultrasonography of the radial and ulnar arteries (the diagnostic standard). The primary outcome was diagnostic accuracy of the heart rate–monitoring application. RESULTS: Among 438 patients who were included in the study, we found that the heart rate–monitoring application had a superior diagnostic accuracy compared with the modified Allen test (91.8% v. 81.7%, p = 0.002), attributable to its greater specificity (93.0% v. 82.8%, p = 0.001). We also found that this application had greater diagnostic accuracy for assessment of radial or ulnar artery patency in the ipsilateral and contralateral wrist (94.0% v. 84.0%, p < 0.001). INTERPRETATION: A smartphone application used at the bedside was diagnostically superior to traditional physical examination for confirming ulnar patency before radial artery access. This study highlights the potential for smartphone-based diagnostics to aid in clinical decision-making at the patient’s bedside. Trial registration: Clinicaltrials.gov, no. NCT02519491.

Evaluation of Cobalt and Chromium Levels Following Implantation of Cobalt Chromium Coronary Stents: A Pilot Study

BACKGROUND Large increases in myocardial trace elements may adversely affect metabolism and become detrimental to cardiac function. Percutaneous coronary intervention (PCI) allows for the revascularisation of obstructive coronary artery disease using drug-eluting stents. These stents are comprised of a metallic stent backbone covered in an engineered polymer which delivers a drug over a prescribed period to the vessel wall. Given the potential implications of trace metal accumulation within the myocardium, our goal is to determine if metallic coronary stents are able to cause detectable elevations in serum cobalt and/or chromium levels. METHODS This study was a single centre, observational, pilot study with 20 patients who underwent planned PCI with implantation of a cobalt chromium drug eluting stent. Serum blood samples were drawn at baseline prior to PCI, 4hours post-stent deployment and at the time of routine follow-up after PCI. All blood samples were analysed for cobalt and chromium concentrations. The primary outcome of this study was the difference in serum cobalt and chromium levels at routine clinical follow-up. RESULTS The mean follow up was 64.1±17.3 days. There was no difference in serum cobalt levels when comparing baseline and routine clinical follow up (3.32±2.14nmol/L vs. 3.14±1.00nmol/L, p=0.99) nor in chromium levels (4.24±2.31nmol/L vs. 2.82±1.22 nmol/L, p=0.11). There was also no difference between baseline and 4hours post-PCI serum concentrations. CONCLUSIONS Percutaneous coronary intervention with cobalt chromium coronary stents does not appear to cause an elevation in these trace element serum concentrations.