Regulation of the HIF switch in human endothelial and cancer cells.

Hypoxia-inducible factors (HIFs) are transcription factors that reprogram the transcriptome for cells to survive hypoxic insults and oxidative stress. They are important during embryonic development and reprogram the cells to utilize glycolysis when the oxygen levels are extremely low. This metabolic change facilitates normal cell survival as well as cancer cell survival. The key feature in survival is the transition between acute hypoxia and chronic hypoxia, and this is regulated by the transition between HIF-1 expression and HIF-2/HIF-3 expression. This transition is observed in many human cancers and endothelial cells and referred to as the HIF Switch. Here we discuss the mechanisms involved in the HIF Switch in human endothelial and cancer cells which include mRNA and protein levels of the alpha chains of the HIFs. A major continuing effort in this field is directed towards determining the differences between normal and tumor cell utilization of this important pathway, and how this could lead to potential therapeutic approaches.

National recommendations to standardise acute kidney injury detection and alerting.

BACKGROUND: National Health Service England issued a Patient Safety Alert in 2014 mandating all acute Trusts in England to implement Acute Kidney Injury (AKI) warning stage results and to do so using a standardised algorithm. In 2021, the Renal and Pathology Getting It Right First Time (GIRFT) teams found significant variation in AKI reporting across the UK. A survey was designed to capture information on the entire AKI detection and alerting process to investigate the potential sources of this unwarranted variation. METHODS: In August 2021, an online survey consisting of 54 questions was made available to all UK laboratories. The questions covered creatinine assays, laboratory information management systems (LIMS), the AKI algorithm and AKI reporting. RESULTS: We received 101 responses from laboratories. Data were reviewed for England only - 91 laboratories. Findings included that 72% used enzymatic creatinine. In addition, 7 manufacturer-analytical platforms, 15 different LIMS and a wide range of creatinine reference ranges were in use. In 68% of laboratories, the AKI algorithm was installed by the LIMS provider. Marked variation was found in the minimum age of AKI reporting with only 18% starting at the recommended 1 month/28-days. Some 89% phoned all new AKI2s and AKI3s, as per AKI guidance while 76% provided comments/hyperlinks in reports. CONCLUSIONS: The national survey has identified laboratory practices that potentially contribute to unwarranted variation in the reporting of AKI in the England. This has formed the basis for improvement work to remedy the situation, including national recommendations, included within this article.

Serum lipoprotein(a) and bioprosthetic aortic valve degeneration.

AIMS: Bioprosthetic aortic valve degeneration demonstrates pathological similarities to aortic stenosis. Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for incident aortic stenosis and disease progression. The aim of this study is to investigate whether serum Lp(a) concentrations are associated with bioprosthetic aortic valve degeneration. METHODS AND RESULTS: In a post hoc analysis of a prospective multimodality imaging study (NCT02304276), serum Lp(a) concentrations, echocardiography, contrast-enhanced computed tomography (CT) angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) were assessed in patients with bioprosthetic aortic valves. Patients were also followed up for 2 years with serial echocardiography. Serum Lp(a) concentrations [median 19.9 (8.4-76.4) mg/dL] were available in 97 participants (mean age 75 ± 7 years, 54% men). There were no baseline differences across the tertiles of serum Lp(a) concentrations for disease severity assessed by echocardiography [median peak aortic valve velocity: highest tertile 2.5 (2.3-2.9) m/s vs. lower tertiles 2.7 (2.4-3.0) m/s, P = 0.204], or valve degeneration on CT angiography (highest tertile n = 8 vs. lower tertiles n = 12, P = 0.552) and 18F-NaF PET (median tissue-to-background ratio: highest tertile 1.13 (1.05-1.41) vs. lower tertiles 1.17 (1.06-1.53), P = 0.889]. After 2 years of follow-up, there were no differences in annualized change in bioprosthetic hemodynamic progression [change in peak aortic valve velocity: highest tertile [0.0 (-0.1-0.2) m/s/year vs. lower tertiles 0.1 (0.0-0.2) m/s/year, P = 0.528] or the development of structural valve degeneration. CONCLUSION: Serum lipoprotein(a) concentrations do not appear to be a major determinant or mediator of bioprosthetic aortic valve degeneration.

Emerging molecular imaging targets and tools for myocardial fibrosis detection.

Myocardial fibrosis is the heart's common healing response to injury. While initially seeking to optimize the strength of diseased tissue, fibrosis can become maladaptive, producing stiff poorly functioning and pro-arrhythmic myocardium. Different patterns of fibrosis are associated with different myocardial disease states, but the presence and quantity of fibrosis largely confer adverse prognosis. Current imaging techniques can assess the extent and pattern of myocardial scarring, but lack specificity and detect the presence of established fibrosis when the window to modify this process may have ended. For the first time, novel molecular imaging methods, including gallium-68 (68Ga)-fibroblast activation protein inhibitor positron emission tomography (68Ga-FAPI PET), may permit highly specific imaging of fibrosis activity. These approaches may facilitate earlier fibrosis detection, differentiation of active vs. end-stage disease, and assessment of both disease progression and treatment-response thereby improving patient care and clinical outcomes.

Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart.

AIM: Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration. METHODS AND RESULTS: We carried out a comprehensive meta-analysis of integrated single-cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularization. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1, and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularization. CONCLUSION: We present a high-resolution single-cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development.

Native Aortic Valve Disease Progression and Bioprosthetic Valve Degeneration in Patients With Transcatheter Aortic Valve Implantation.

BACKGROUND: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR). METHODS: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol. RESULTS: In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P<0.001) and SAVR (r=0.7, P<0.001). On multivariable analysis, 18F-NaF uptake was the only predictor of peak velocity progression (P<0.001). CONCLUSIONS: In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276.

Acute Kidney Injury in Primary Care: A Review of Patient Follow-Up, Mortality, and Hospital Admissions following the Introduction of an AKI Alert System.

BACKGROUND/AIMS: In February 2017, our laboratory implemented an electronic AKI flagging system for primary care using the NHS England AKI detection algorithm. Our study investigated the impact on patient follow-up, hospital admission, length of stay, and mortality. METHODS: Primary care results March 2017-February 2018 with an AKI test code were downloaded from the pathology computer. RESULTS: Over 12 months, 1,784 AKI episodes were identified; 81.3% AKI1, 11.3%, AKI2, and 7.5% AKI3. A repeat creatinine was requested within 14 days on 55% AKI1s, 84% AKI2s, and 86% AKI3s. Primary care took the repeat sample in 73.2% AKI1s and 56.7% AKI2s and acute hospital locations for 47.4% AKI3s. Median time to hospital admission was 34 days for AKI1, 6 for AKI2, and 1 for AKI3 (p < 0.05). Length of stay was found to be 1, 2, and 4 days for AKI 1/2/3, respectively (p < 0.05). The 90-day mortality for admitted patients was 15, 18, and 21% for AKI 1/2/3, respectively (p = 0.180). The 90-day mortality for the non-admitted patients was 4, 9, and 50% for AKI 1/2/3, respectively (p < 0.05). AKI patient outcome data pre versus post the start of the AKI flag system were compared. A statistically significant reduction was found in the median length of stay for AKI1 and AKI3 and in mortality for AKI1 and AKI3 patients and for all AKIs as a whole. A further analysis was performed to take into account the difference in pre- and post-alert populations. Mortality overall was significantly improved (p < 0.001), and length of stay was reduced in AKI3 patients (p = 0.048). DISCUSSION/CONCLUSION: Our study demonstrates that an electronic AKI warning alert system for primary care appears to be associated with a beneficial impact on patient management and outcome.

Society of Thoracic Surgeons Risk Score and EuroSCORE-2 Appropriately Assess 30-Day Postoperative Mortality in the STICH Trial and a Contemporary Cohort of Patients With Left Ventricular Dysfunction Undergoing Surgical Revascularization.

BACKGROUND: The STICH trial (Surgical Treatment for Ischemic Heart Failure) demonstrated a survival benefit of coronary artery bypass grafting in patients with ischemic cardiomyopathy and left ventricular dysfunction. The Society of Thoracic Surgeons (STS) risk score and the EuroSCORE-2 (ES2) are used for risk assessment in cardiac surgery, with little information available about their accuracy in patients with left ventricular dysfunction. We assessed the ability of the STS score and ES2 to evaluate 30-day postoperative mortality risk in STICH and a contemporary cohort (CC) of patients with a left ventricle ejection fraction ≤35% undergoing coronary artery bypass grafting outside of a trial setting. METHODS AND RESULTS: The STS and ES2 scores were calculated for 814 STICH patients and 1246 consecutive patients in a CC. There were marked variations in 30-day postoperative mortality risk from 1 patient to another. The STS scores consistently calculated lower risk scores than ES2 (1.5 versus 2.9 for the CC and 0.9 versus 2.4 for the STICH cohort), and underestimated postoperative mortality risk. The STS and ES2 scores had moderately good C statistics: CC (0.727, 95% CI: 0.650-0.803 for STS, and 0.707, 95% CI: 0.620-0.795 for ES2); STICH (0.744, 95% CI: 0.677-0.812, for STS and 0.736, 95% CI: 0.665-0.808 for ES2). Despite the CC patients having higher STS and ES2 scores than STICH patients, mortality (3.5%) was lower than that of STICH (4.8%), suggesting a possible decrease in postoperative mortality over the past decade. CONCLUSIONS: The 30-day postoperative mortality risk of coronary artery bypass grafting in patients with left ventricular dysfunction varies markedly. Both the STS and ES2 score are effective in evaluating risk, although the STS score tend to underestimate risk. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Management of Type 1 Diabetes With a Very Low-Carbohydrate Diet.

OBJECTIVES: To evaluate glycemic control among children and adults with type 1 diabetes mellitus (T1DM) who consume a very low-carbohydrate diet (VLCD). METHODS: We conducted an online survey of an international social media group for people with T1DM who follow a VLCD. Respondents included adults and parents of children with T1DM. We assessed current hemoglobin A1c (HbA1c) (primary measure), change in HbA1c after the self-reported beginning of the VLCD, total daily insulin dose, and adverse events. We obtained confirmatory data from diabetes care providers and medical records. RESULTS: Of 316 respondents, 131 (42%) were parents of children with T1DM, and 57% were of female sex. Suggestive evidence of T1DM (based on a 3-tier scoring system in which researchers took into consideration age and weight at diagnosis, pancreatic autoimmunity, insulin requirement, and clinical presentation) was obtained for 273 (86%) respondents. The mean age at diagnosis was 16 ± 14 years, the duration of diabetes was 11 ± 13 years, and the time following a VLCD was 2.2 ± 3.9 years. Participants had a mean daily carbohydrate intake of 36 ± 15 g. Reported mean HbA1c was 5.67% ± 0.66%. Only 7 (2%) respondents reported diabetes-related hospitalizations in the past year, including 4 (1%) for ketoacidosis and 2 (1%) for hypoglycemia. CONCLUSIONS: Exceptional glycemic control of T1DM with low rates of adverse events was reported by a community of children and adults who consume a VLCD. The generalizability of these findings requires further studies, including high-quality randomized controlled trials.

Clinical Inertia in a Randomized Trial of Telemedicine-Based Chronic Disease Management: Lessons Learned.

BACKGROUND: Treatment nonadherence and clinical inertia perpetuate poor cardiovascular disease (CVD) risk factor control. Telemedicine interventions may counter both treatment nonadherence and clinical inertia. INTRODUCTION: We explored why a telemedicine intervention designed to reduce treatment nonadherence and clinical inertia did not improve CVD risk factor control, despite enhancing treatment adherence versus usual care. METHODS: In this analysis of a randomized trial, we studied recipients of the 12-month telemedicine intervention. This intervention comprised two nurse-administered components: (1) monthly self-management education targeting improved treatment adherence; and (2) quarterly medication management facilitation designed to support treatment intensification by primary care (thereby reducing clinical inertia). For each medication management facilitation encounter, we ascertained whether patients met treatment goals, and if not, whether primary care recommended treatment intensification following the encounter. We assessed disease control associated with encounters, where intensification was/was not recommended. RESULTS: We examined 455 encounters across 182 intervention recipients (100% African Americans with type 2 diabetes). Even after accounting for valid reasons for deferring intensification (e.g., treatment nonadherence), intensification was not recommended in 67.5% of encounters in which hemoglobin A1c was above goal, 72.5% in which systolic blood pressure was above goal, and 73.9% in which low-density lipoprotein cholesterol was above goal. In each disease state, treatment intensification was more likely with poorer control. CONCLUSIONS: Despite enhancing treatment adherence, this intervention was unsuccessful in countering clinical inertia, likely explaining its lack of effect on CVD risk factors. We identify several lessons learned that may benefit investigators and healthcare systems.

The Cornish experience of the ASSIST-CKD project.

Introduction The ASSIST-CKD project is a national quality improvement programme, aiming to decrease the number of patients presenting late to renal services by enabling laboratories to review up to five years of estimated glomerular filtration rate results graphically and report deteriorating patients to their general practitioner. Aim To assess the impact of the project on the laboratory, and of patient reporting on general practitioner management and the local renal service. Method Each week two searches were performed (Search A: maximum age 65 years, maximum eGFR 50 ml/min/1.73 m2 and Search B: Age 66-120 years, maximum eGFR 40 ml/min/1.73 m2) on patients with an estimated glomerular filtration rate requested by their general practitioner within the previous seven days. Patients showing deterioration in estimated glomerular filtration rate had a printed graph sent to their general practitioner. Feedback on the graphs and their impact on patient management were obtained from the general practitioners via a questionnaire. Results A median of 37 patients/week were listed for review for Search A, with 32% reported; and Search B a median of 227 patients/week listed, 32% reported. General practitioner surgery questionnaires (29) showed the reports were well received. Of general practitioners responding to the questionnaire, 67% had reviewed a patient earlier than intended, 54% had reviewed local guidance, 48% had emailed the renal team and 48% had referred a patient on receipt of a graph; 34% had shown a graph to their patients, of whom 70% found that useful. Conclusion There is some evidence that ASSIST-CKD reporting has enhanced patient care; however, further long-term assessment is still required.

Jump starting shared medical appointments for diabetes with weight management: Rationale and design of a randomized controlled trial.

BACKGROUND: Rates of glycemic control remain suboptimal nationwide. Medication intensification for diabetes can have undesirable side effects (weight gain, hypoglycemia), which offset the benefits of glycemic control. A Shared Medical Appointment (SMA) intervention for diabetes that emphasizes weight management could improve glycemic outcomes and reduce weight while simultaneously lowering diabetes medication needs, resulting in less hypoglycemia and better quality of life. We describe the rationale and design for a study evaluating a novel SMA intervention for diabetes that primarily emphasizes low-carbohydrate diet-focused weight management. METHODS: Jump Starting Shared Medical Appointments for Diabetes with Weight Management (Jump Start) is a randomized, controlled trial that is allocating overweight Veterans (body mass index≥27kg/m2) with type 2 diabetes into two arms: 1) a traditional SMA group focusing on medication management and self-management counseling; or 2) an SMA group that combines low-carbohydrate diet-focused weight management (WM/SMA) with medication management. Hemoglobin A1c reduction at 48weeks is the primary outcome. Secondary outcomes include hypoglycemic events, diabetes medication use, weight, medication adherence, diabetes-related quality of life, and cost-effectiveness. We hypothesize that WM/SMA will be non-inferior to standard SMA for glycemic control, and will reduce hypoglycemia, diabetes medication use, and weight relative to standard SMA, while also improving quality of life and costs. CONCLUSIONS: Jump Start targets two common problems that are closely related but infrequently managed together: diabetes and obesity. By focusing on diet and weight loss as the primary means to control diabetes, this intervention may improve several meaningful patient-centered outcomes related to diabetes.

Assessing electronic health record phenotypes against gold-standard diagnostic criteria for diabetes mellitus.

OBJECTIVE: We assessed the sensitivity and specificity of 8 electronic health record (EHR)-based phenotypes for diabetes mellitus against gold-standard American Diabetes Association (ADA) diagnostic criteria via chart review by clinical experts. MATERIALS AND METHODS: We identified EHR-based diabetes phenotype definitions that were developed for various purposes by a variety of users, including academic medical centers, Medicare, the New York City Health Department, and pharmacy benefit managers. We applied these definitions to a sample of 173 503 patients with records in the Duke Health System Enterprise Data Warehouse and at least 1 visit over a 5-year period (2007-2011). Of these patients, 22 679 (13%) met the criteria of 1 or more of the selected diabetes phenotype definitions. A statistically balanced sample of these patients was selected for chart review by clinical experts to determine the presence or absence of type 2 diabetes in the sample. RESULTS: The sensitivity (62-94%) and specificity (95-99%) of EHR-based type 2 diabetes phenotypes (compared with the gold standard ADA criteria via chart review) varied depending on the component criteria and timing of observations and measurements. DISCUSSION AND CONCLUSIONS: Researchers using EHR-based phenotype definitions should clearly specify the characteristics that comprise the definition, variations of ADA criteria, and how different phenotype definitions and components impact the patient populations retrieved and the intended application. Careful attention to phenotype definitions is critical if the promise of leveraging EHR data to improve individual and population health is to be fulfilled.

One Year's Observational Study of Acute Kidney Injury Incidence in Primary Care; Frequency of Follow-Up Serum Creatinine and Mortality Risk.

BACKGROUND/AIMS: Publications on acute kidney injury (AKI) have concentrated on the inpatient population. We wanted to determine the extent of AKI in the community, its follow-up and patient impact. METHOD: Primary Care creatinine results for May 2012-April 2013 from Cornwall, United Kingdom, were screened for AKI. RESULTS: Over 12 months, 991 AKI episodes were identified (0.4% of all Primary Care creatinine requests); 51% were AKI1, 29% AKI2 and 10% AKI3. Of these, 51% AKI1s, 72% AKI2s and 77% AKI3s had a repeat creatinine requested within 14 days as per National Institute for Health and Care Excellence (NICE) guidelines. Admissions (May 2012-July 2013) were identified on 46% AKI1s, 58% AKI2s and 65% AKI3s (p < 0.05). The median time from AKI identification to hospital admission was 33 days for AKI1, 12 days for AKI2 and 1 day for AKI3 (p < 0.05); with a median length of stay of 2, 4 and 7 days, respectively (p < 0.05). The 90-day mortality from AKI identification for the admitted patients was 12% AKI1s, 20% AKI2s and 27% AKI3s (p < 0.05) vs. 11, 21 and 65% (p < 0.05) for those that were not admitted. There was no significant difference in mortality for admitted patients vs. non-admitted patients, except for the AKI3s. CONCLUSION: AKI is associated with increased admission and mortality rates; although a large proportion of patients had repeat creatinine testing within 14 days, there was still a significant number with delayed follow-up. Education within Primary Care is required on how to prevent, identify, follow-up and manage AKI.

Managing hyperglycemia and diabetes in patients receiving enteral feedings: A health system approach.

Evidence of poor outcomes in hospitalized patients with hyperglycemia has led to new and revised guidelines for inpatient management of diabetes. As providers become more aware of the need for better blood glucose control, they are finding limited guidance in the management of patients receiving enteral nutrition. To address the lack of guidelines in this population, Duke University Health System has developed a consistent practice for managing such patients. Here, we present our practice strategies for insulin use in patients receiving enteral nutrition. Essential factors include assessing the patients' history of diabetes, hyperglycemia, or hypoglycemia and timing and type of feedings. Insulin practices are then designed to address these issues keeping in mind patient safety in the event of abrupt cessation of nutrition. The outcome of the process is a consistent and safe method for glucose control with enteral nutrition.