Is microvascular dysfunction a systemic disorder with common biomarkers found in the heart, brain, and kidneys? - A scoping review.

Although microvascular dysfunction (MVD) has been well characterized in individual organs as different disease entities, clinical evidence is mounting in support of an underlying systemic process. To address this hypothesis, we systematically searched PubMed and Medline for studies in adults published between 2014 and 2019 that measured blood biomarkers of MVD in three vital organs i.e. brain, heart, and the kidney. Of the 9706 unique articles 321 met the criteria, reporting 49 biomarkers of which 16 were common to the three organs. Endothelial dysfunction, inflammation including reactive oxidation, immune activation, and coagulation were the commonly recognized pathways. Triglyceride, C-reactive protein, Cystatin C, homocysteine, uric acid, IL-6, NT-proBNP, thrombomodulin, von Willebrand Factor, and uric acid were increased in MVD of all three organs. In contrast, vitamin D was decreased. Adiponectin, asymmetric dimethylarginine, total cholesterol, high-density and low-density cholesterol were found to be variably increased or decreased in studies. We review the pathways underlying MVD in the three organs and summarize evidence supporting its systemic nature. This scoping review informs clinicians and researchers in the multi-system manifestation of MVD. Future work should focus on longitudinal investigations to evaluate the multi-system involvement of this disease.

Use of peripheral arterial tonometry in detection of abnormal coronary flow reserve.

BACKGROUND: We assessed the utility of EndoPAT, a device that measures reactive hyperemia index (RHI) as a clinical screening tool for identifying low coronary flow reserve (CFR). Distinguishing normal from low CFR aids assessment for coronary microvascular dysfunction (CMD) or large vessel coronary artery disease (CAD). METHODS: From June 2014-May 2019, in a convenience sample, we measured RHI in adults undergoing clinically indicated cardiac Rubidium-82 positron emission tomography/computed tomography (PET/CT) at a single center. Exclusion criteria were inability to consent, lack of English proficiency, and physical limitation. We defined low RHI as <1.67 and low CFR as <2.5. Distribution of RHI was skewed so we used its natural logarithm (LnRHI) to calculate Pearson correlation and area under the curve (AUC). RESULTS: Of 265 patients with PET/CT, we enrolled 131, and 100 had adequate data. Patients had a mean age of 61 years (SD = 12), 46% were female, 29% non-white. Thirty-six patients had low RHI, and 60 had depressed CFR. LnRHI did not distinguish patients with low from normal CFR (AUC = 0.53; 95% Cl, 0.41-0.64) and did not correlate with CFR (r = -0.021, p = 0.83). Low RHI did not distinguish patients with traditional CAD risk factors, presence of calcification, or perfusion defect (p > 0.05). Conversely, mean augmentation index, a measure of arterial stiffness, was higher with low RHI (p = 0.005) but not CFR (p = 0.625). RHI was lower in patients we identified as CMD (low CFR, no perfusion defect and calcium score of 0) (1.88 versus 2.21, p = 0.35) although we were underpowered (n = 12) to meet statistical significance. CONCLUSIONS: Peripheral RHI is insufficient as a clinical screening tool for low CFR as measured by cardiac PET/CT. Differences in vascular pathology assessed by each method may explain this finding.

Utility of discovery approach using proteomics to create a biomarker profile for coronary microvascular dysfunction.

INTRODUCTION: Coronary microvascular dysfunction (CMD) is a complex disease, difficult to diagnose and often requires advanced imaging. We used mass spectrometry (MS) using discovery approach to search for serum proteins as potential biomarkers in these patients. METHODS: We used serum samples from 10 patients with CMD and 10 with normal coronary flow reserve (CFR) admitted to an observation unit where acute myocardial infarction was excluded. We identified CMD using 82Rb positron emission tomography/computed tomography as CFR <2 in response to regadenoson, in the absence of coronary calcification or regional perfusion defects. We used MS to identify potential protein biomarkers that were differentially expressed in cases and controls. RESULTS: Baseline characteristics were not different between cases and controls, except for beta-blocker use and which was higher in cases, and mean (SD) CFR which was lower in cases [1.19 (0.23) and 2.78 (0.78) in cases and controls respectively; p < 0.01]. We identified 5345 peptides corresponding to 209 proteins, and identified 197 proteins by peptides with suitable properties to infer relative quantitation values. While the calculated values for some proteins (e.g. vascular cell adhesion molecule-1, apolipoprotein C and Von Willebrand Factor) indicate fold-differences between groups, these are most likely a result of high values in only 1-2 patients and are not statistically significant. CONCLUSION: Mass spectrometry using discovery approach may not be an adequate method for quantitative assessment of serum proteins in CMD patients. Future MS studies should evaluate other approaches including tissue samples or serial measurements.

The association of non-prescription drug use preceding out-of-hospital cardiac arrest and clinical outcomes.

BACKGROUND: Clinicians may make prognostication decisions for out-of-hospital cardiac arrest (OHCA) using historical details pertaining to non-prescription drug use. However, differences in outcomes between OHCAs with evidence of non-prescription drug use, compared to other OHCAs, have not been well described. METHODS: We included emergency medical service-treated OHCA in the British Columbia Cardiac Arrest Registry (January/2019-June/2023). We classified cases as "non-prescription drug-associated cardiac arrests" (DA-OHCA) if there was evidence of non-prescription drug use preceding the OHCA, including witness accounts of use within 24 h or paraphernalia at the scene. We fit logistic regression models to investigate the association between DA-OHCA (vs. other cases) and favourable neurological outcome (Cerebral Performance Category [CPC] 1-2) and survival at hospital discharge, and return of spontaneous circulation (ROSC). RESULTS: Of 18,426 OHCA, 2,171 (12%) were classified as DA-OHCA. DA-OHCA tended to be younger, unwitnessed, occur during the evening or night, and present with a non-shockable rhythm, compared to other OHCA. DA-OHCA (221 [10%]) had a greater proportion (difference 1.8%; 95% CI 0.49-3.2) with favourable neurological outcomes compared to other OHCA (1,365 [8.4%]). Adjusted models did not identify an association of DA-OHCA with favourable neurological outcome (OR 1.08, 95% CI 0.87-1.33) or survival to hospital discharge (OR 1.13, 95% CI 0.93-1.38), but did demonstrate an association with ROSC (OR 1.13, 95% CI 1.004-1.27). CONCLUSION: In unadjusted models, DA-OHCA was associated with an improved odds of survival and favourable neurological outcomes at hospital discharge, compared to other OHCA. However, we did not detect an association in adjusted analyses.

Clinical Profile and Sex-Specific Recovery With Cardiac Rehabilitation After Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Cardiac rehabilitation (CR) improves major adverse cardiac outcomes in patients recovering from myocardial infarction. CR influences outcomes through attenuation of cardiac risk factors, lifestyle changes, and biological effects on endothelial function. The clinical profile and sex-specific outcomes with CR after coronary artery bypass grafting (CABG) is less well defined. METHODS: This retrospective cohort study of consecutive patients undergoing elective or urgent CABG was performed between 2014 and 2016 at a single site. Patients requiring concomitant procedures were excluded. Patients received referral to a 12-week, 36-session CR program standardized through the health care system and tracked via electronic health records. Clinical data and complications during hospitalization were abstracted from Society of Thoracic Surgeons (STS) registry and matched with 12-months outcomes from electronic health records. Primary composite outcomes were mortality and STS-defined complications within 12 months after CABG. Kaplan-Meier plots for mortality were generated from conditional 6-month survival data. FINDINGS: Of 756 patients undergoing CABG, 420 met the eligibility criteria (mean age, 66 years). Women (18%) had a similar cardiac risk profile to men except for a higher hemoglobin A1c level and lower hematocrit before surgery. Women had similar extent of revascularization to men but had higher rates of intraoperative (30% vs 8%; p < 0.001) and postoperative blood transfusions (43% vs 29%; p = 0.014) compared with men. Only 66% of women qualified for direct discharge to home compared with 85% of men (p = 0.0003). Twelve-month mortality was 1.3% and 2%, respectively (p > 0.05). Half of the cohort got referred for CR, and 32% of men and 23% of women underwent CR. Twelve-month composite outcomes did not differ by referral to cardiac rehabilitation (odds ratio = 0.77; 95% CI, 0.36-1.64) or engagement with CR (odds ratio = 0.67; 95% CI -0.05 to 0.086), adjusting for age, sex, body mass index, and diabetes. Kaplan-Meier analysis found no significant difference in survival between those who did and did not undergo CR. Men experienced increases in metabolic equivalents (38%, P = 0.014), grip strength (11%, P < 0.0001), and sense of physical well-being (40.9%, P < 0.0001), whereas women experienced increases in aerobic exercise duration (15.5%, P = 0.02) and a trend in improved sense for physical well-being (93.3%, P = 0.06). IMPLICATIONS: Sex differences exist with CR after CABG. Future studies should confirm these findings in larger cohorts and corroborate the effect on endothelial function and other biological markers.

The Geriatric Emergency Care Applied Research (GEAR) network approach: a protocol to advance stakeholder consensus and research priorities in geriatrics and dementia care in the emergency department.

INTRODUCTION: Increasingly, older adults are turning to emergency departments (EDs) to address healthcare needs. To achieve these research demands, infrastructure is needed to both generate evidence of intervention impact and advance the development of implementation science, pragmatic trials evaluation and dissemination of findings from studies addressing the emergency care needs of older adults. The Geriatric Emergency Care Applied Research Network (https://gearnetwork.org) has been created in response to these scientific needs-to build a transdisciplinary infrastructure to support the research that will optimise emergency care for older adults and persons living with dementia. METHODS AND ANALYSIS: In this paper, we describe our approach to developing the GEAR Network infrastructure, the scoping reviews to identify research and clinical gaps and its use of consensus-driven research priorities with a transdisciplinary taskforce of stakeholders that includes patients and care partners. We describe how priority topic areas are ascertained, the process of conducting scoping reviews with integrated academic librarians performing standardised searches and providing quality control on reviews, input and support from the taskforce and conducting a large-scale consensus workshop to prioritise future research topics. The GEAR Network approach provides a framework and systematic approach to develop a research agenda and support research in geriatric emergency care. ETHICS AND DISSEMINATION: This is a systematic review of previously conducted research; accordingly, it does not constitute human subjects research needing ethics review. These reviews will be prepared as manuscripts and submitted for publication to peer-reviewed journals, and the results will be presented at conferences.Open Science Framework registered DOI: 10.17605/OSF.IO/6QRYX, 10.17605/OSF.IO/AKVZ8, 10.17605/OSF.IO/EPVR5, 10.17605/OSF.IO/VXPRS.

Rationale for withholding professional resuscitation in emergency medical system-attended out-of-hospital cardiac arrest.

BACKGROUND: Half of out-of-hospital cardiac arrests (OHCA) are deemed inappropriate for resuscitation by emergency medical services (EMS). We investigated patient characteristics and reasons for non-treatment of OHCAs, and determined the proportion involving illicit drug use. METHODS: We reviewed consecutive EMS-untreated OHCA from the British Columbia Cardiac Arrest Registry (2019-2020). We abstracted patient characteristics and categorized reasons for EMS non-treatment: (1) prolonged interval from the OHCA to EMS arrival ("non-recent OHCA") with or without signs of "obvious death"; (2) do-not-resuscitate (DNR) order; (3) terminal disease; (4) verbal directive; and (5) unspecified. We abstracted clinical details regarding a history of, or evidence at the scene of, illicit drug use. RESULTS: Of 13 331 cases, 5959 (45%) were not treated by EMS. The median age was 67 (IQR 54-81) and 1903 (32%) were female. EMS withheld resuscitation due to: non-recent OHCA, with and without signs of "obvious death" in 4749 (80%) and 108 (1.8%), respectively; DNR order in 952 (16%); terminal disease in 77 (1.3%); family directive in 41 (0.69%); and unspecified in 32 (0.54%). Overall and among those with non-recent OHCA, 695/5959 (12%) and 691/4857 (14%) had either a history of or evidence of recent illicit drug use, respectively. CONCLUSION: A prolonged interval from the OHCA until EMS assessment was the predominant reason for withholding treatment. Innovative solutions to decrease this interval may increase the proportion of OHCA that are treated by EMS and overall outcomes. Targeted interventions for illicit-drug use-related OHCAs may add additional benefit.

Detecting Cognitive Impairment and Dementia in the Emergency Department: A Scoping Review.

OBJECTIVES: To identify research and practice gaps to establish future research priorities to advance the detection of cognitive impairment and dementia in the emergency department (ED). DESIGN: Literature review and consensus-based rankings by a transdisciplinary, stakeholder task force of experts, persons living with dementia, and care partners. SETTING AND PARTICIPANTS: Scoping reviews focused on adult ED patients. METHODS: Two systematic scoping reviews of 7 medical research databases focusing on best tools and approaches for detecting cognitive impairment and dementia in the ED in terms of (1) most accurate and (2) most pragmatic to implement. The results were screened, reviewed, and abstracted for relevant information and presented at the stakeholder consensus conference for discussion and ranked prioritization. RESULTS: We identified a total of 1464 publications and included 45 to review for accurate tools and approaches for detecting cognitive impairment and dementia. Twenty-seven different assessments and instruments have been studied in the ED setting to evaluate cognitive impairment and dementia, with many focusing on sensitivity and specificity of instruments to screen for cognitive impairment. For pragmatic tools, we identified a total of 2166 publications and included 66 in the review. Most extensively studied tools included the Ottawa 3DY and Six-Item Screener (SIS). The SIS was the shortest to administer (1 minute). Instruments with the highest negative predictive value were the SIS (vs MMSE) and the 4 A's Test (vs expert diagnosis). The GEAR 2.0 Advancing Dementia Care Consensus conference ranked research priorities that included the need for more approaches to recognize more effectively and efficiently persons who may be at risk for cognitive impairment and dementia, while balancing the importance of equitable screening, purpose, and consequences of differentiating various forms of cognitive impairment. CONCLUSIONS AND IMPLICATIONS: The scoping review and consensus process identified gaps in clinical care that should be prioritized for research efforts to detect cognitive impairment and dementia in the ED setting. These gaps will be addressed as future GEAR 2.0 research funding priorities.

Pulmonary Hypertension in Intensive Care Units: An Updated Review.

Pulmonary hypertension (PH) is a condition associated with high morbidity and mortality. Patients with PH who require critical care usually have severe right ventricular (RV) dysfunction. Although different groups of PH have different etiologies, pulmonary vascular dysfunction is common in these groups. PH can lead to increased pulmonary artery pressure, which can ultimately cause RV failure. Clinicians should be familiar with the presentations of this disease and diagnostic tools. The contributing factors, if present (e.g., sepsis), and coexisting conditions (e.g., arrhythmias) should be identified and addressed accordingly. The preload should be optimized by fluid administration, diuretics, and dialysis, if necessary. On the other hand, the RV afterload should be reduced to improve the RV function with pulmonary vasodilators, such as prostacyclins, inhaled nitric oxide, and phosphodiesterase type 5 inhibitors, especially in group 1 PH. Inotropes are also used to improve RV contractility, and if inadequate, use of ventricular assist devices and extracorporeal life support should be considered in suitable candidates. Moreover, vasopressors should be used to maintain systemic blood pressure, albeit cautiously, as they increase the RV afterload. Measures should be also taken to ensure adequate oxygenation. However, mechanical ventilation is avoided in RV failure. In this study, we reviewed the pathophysiology, manifestations, diagnosis, monitoring, and management strategies of PH, especially in intensive care units.

Long-Term Effectiveness of a Lifestyle Intervention: A Pragmatic Community Trial to Prevent Metabolic Syndrome.

INTRODUCTION: The purpose of this study is to evaluate the long-term effectiveness of a community-based lifestyle education on primary prevention of metabolic syndrome in a middle-income country. STUDY DESIGN: This study followed 3,180 individuals free of metabolic syndrome who were under the coverage of three health centers in Tehran from 1999 until 2015. They were undergoing triennial examinations resulting in four re-exams. People in one of three areas received interventions consisting of family-, school-, and community-based educational programs, including a face-to-face educational session at baseline. Data were analyzed considering the incidence of metabolic syndrome at each re-exam and also repeated-measure analysis including all re-exams together. Weighting was considered to correct selection bias because of loss to follow-up. Data were analyzed in 2017. RESULTS: After 3 years, 149 of 852 participants in the intervention and 471 of 2,328 people in control area developed metabolic syndrome at first re-exam resulting in a RR of 0.78 (95% CI=0.67, 0.92). The difference between groups remained unchanged up to the 6-year follow-up (RR=0.79, 95% CI=0.66, 0.93, at second re-exam), but disappeared during the third and fourth re-exams (RR=1.04, 95% CI=0.91, 1.18 and RR=1.03, 95% CI=0.91, 1.16, respectively). Marginal models for longitudinal data showed a significant interaction between intervention and time of re-exams. Further analyses showed that the effect of the intervention might have been rooted in improvement of lipid profile and glucose level. CONCLUSIONS: In a middle-income country, face-to-face educational sessions followed by a long-term maintenance community-level educational program could reduce the risk of metabolic syndrome for up to 6 years. A booster face-to-face session is recommended to retain this preventive effect. TRIAL REGISTRATION: This study is registered at Iran Registry for Clinical Trials (http://irct.ir) IRCT138705301058N1.

Usefulness of pulmonary artery diameter in diagnosing pulmonary hypertension in patients admitted to tuberculosis intensive care unit.

OBJECTIVE/BACKGROUND: Pulmonary hypertension (PH) can be a complication of patients with severe pulmonary tuberculosis (TB). We aimed to study the correlation between pulmonary artery (PA) diameter (PAD) as measured by computed tomography (CT) and mean PA pressure (mPAP) as measured by echocardiography. We also aimed to determine the accuracy of PAD in diagnosing PH in patients with pulmonary TB. METHODS: We retrospectively investigated the correlation between PAD measured using CT and mPAP measured using echocardiography in 132 patients with TB and PH, and 68 patients with TB but without PH, admitted to the TB intensive care unit at Masih Daneshvari Hospital in Tehran, Iran. We used logistic regression analysis to determine the relationships between PAD, PA diameter to ascending aorta (AA) ratio, and area of PA to area of AA ratio with mPAP. Using receiver operating characteristic analysis, we examined the utility of the PAD in predicting PH (mPAP ⩾25mmHg). RESULTS: PAD had a significant correlation with mPAP (p<0.005 and r=0.47). Also, PA:AA ratio and area of PA to area of AA ratio had significant correlation with mPAP (r=0.48 and r=0.47, respectively; p<0.001). The threshold of 29mm for PAD was determined using ROC. This index had a sensitivity of 0.55, specificity of 70.2 and area under curve of 0.66. CONCLUSION: Although PAD and PA:AA ratio are useful in assessing of presence of PH, we conclude that these CT parameters are not sufficient for ruling in or ruling out PH in this group of patients.