Percutaneous endovascular management of Angio-Seal related vascular occlusion.

BACKGROUND: The use of vascular closure devices (VCDs) to achieve quick and safe hemostasis after femoral arterial access is widely accepted. Major complications include bleeding and occlusion of the femoral artery due to device failure, which often necessitates vascular intervention. This manuscript details our peripheral percutaneous endovascular interventional (PEI) approach for the management of femoral artery occlusion resulting from Angio-Seal (Terumo, Somerset, New Jersey, USA) VCD deployment. METHODS: Consecutive patients who developed occlusive complications after Angio-Seal deployment underwent PEI to overcome specific complications. Patients' clinical and procedural characteristics, along with their short- and long-term follow-up data, were analyzed. RESULTS: The study cohort included 40 patients who experienced Angio-Seal occlusive complications between July 2013 and September 2023. The mean age of the patients was 74 ± 10 years and 55% were female. All the patients were treated with PEI, with an overall procedural success rate of 100%. The primary approach for PEI was directional atherectomy, which was used in 35 cases (88%), followed by balloon, while a cutting balloon was used in 5 patients (13%). Stenting served as the definitive therapy in only 7 patients (18%). No procedural complications or conversions to surgery were observed. During a median follow-up of 244 (IQR = 100-707) days, none of the patients required re-intervention related to Angio-Seal occlusion and salvage intervention. CONCLUSION: In the management of Angi-Seal VCD-related femoral artery occlusion, the adjunctive use of directional atherectomy followed by balloon angioplasty was effective and safe, allowing re-establishment of flow with excellent long-term outcomes.

The impact of ventricular remodeling on quality-of-life outcomes after Transcatheter aortic valve replacement.

BACKGROUND: Among patients with aortic stenosis, ventricular remodeling by hypertrophy can limit the augmentation of flow with exertion, even after valve intervention. However, the effect of hypertrophy on quality of life (QoL) improvement has not been studied. We aimed to determine the effect of ventricular hypertrophy on QoL outcomes after transcatheter aortic valve replacement (TAVR). METHODS: All patients undergoing TAVR from 2011 to 2021 at our institution were included. Groups were divided into none/mild ventricular hypertrophy (non-remodeled, NR) and moderate/severe left ventricular hypertrophy (VH) according to guideline-recommended cut-offs for left ventricular (LV) wall thickness. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was utilized to assess QoL; primary outcome was KCCQ change <5 from baseline to 30 days and 1 year. RESULTS: We analyzed 679 patients (NR: N = 389, VH: N = 290). Groups differed by septal thickness (1.12 cm vs. 1.44 cm, p < 0.001), posterior wall thickness (1.08 cm vs. 1.33 cm, p < 0.001), and LV internal diastolic diameter (4.34 cm vs. 4.19 cm, p = 0.006). The primary outcome was similar between NR and VH at 30 days (31.6 % vs. 28.6 %, p = 0.449) and 1 year (27.7 % vs. 21.5 %, p = 0.217). NR and VH experienced similar proportions of worsening, no change, or small, moderate, and large improvements in KCCQ score. Both groups experienced similar domain score changes and New York Heart Association class improvement. A subgroup analysis of VH patients did not reveal interaction with cavity size or stroke volume. CONCLUSION: Patients with significant ventricular remodeling by hypertrophy and aortic stenosis have similar QoL changes after intervention compared to patients without significant remodeling.

ISCCM Position Statement on the Management of Invasive Fungal Infections in the Intensive Care Unit.

Rationale: Invasive fungal infections (IFI) in the intensive care unit (ICU) are an emerging problem owing to the use of broad-spectrum antibiotics, immunosuppressive agents, and frequency of indwelling catheters. Timely diagnosis which is imperative to improve outcomes can be challenging. This position statement is aimed at understanding risk factors, providing a rational diagnostic approach, and guiding clinicians to optimize antifungal therapy. Objectives: To update evidence on epidemiology, risk factors, diagnostic approach, antifungal initiation strategy, therapeutic interventions including site-specific infections and role of therapeutic drug monitoring in IFI in ICU and focus on some practice points relevant to these domains. Methodology: A committee comprising critical care specialists across the country was formed and specific aspects of fungal infections and antifungal treatment were assigned to each member. They extensively reviewed the literature including the electronic databases and the international guidelines and cross-references. The information was shared and discussed over several meetings and position statements were framed to ensure their reliability and relevance in critical practice. The draft document was prepared after obtaining inputs and consensus from all the members and was reviewed by an expert in this field. Results: The existing evidence on the management of IFI was updated and practice points were prepared under each subheading to enable critical care practitioners to streamline diagnosis and treatment strategies for patients in the ICU with additional detail on site-specific infections therapeutic drug monitoring. Conclusion: This position statement attempts to address the management of IFI in immunocompetent and non-neutropenic ICU patients. The practice points should guide in optimization of the management of critically ill patients with suspected or proven fungal infections. How to cite this article: Bhattacharya PK, Chakrabarti A, Sinha S, Pande R, Gupta S, Kumar AAK, et al. ISCCM Position Statement on the Management of Invasive Fungal Infections in the Intensive Care Unit. Indian J Crit Care Med 2024;28(S2):S20-S41.

Inflammation-induced epigenetic imprinting regulates intestinal stem cells.

It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5+ ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.

Bacteroides ovatus alleviates dysbiotic microbiota-induced graft-versus-host disease.

Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects of Bacteroides ovatus were linked to its ability to metabolize dietary polysaccharides into monosaccharides, which suppressed the mucus-degrading capabilities of colonic mucus degraders such as Bacteroides thetaiotaomicron and Akkermansia muciniphila, thus reducing GVHD-related mortality. Collectively, these findings reveal the importance of microbiota in aLGI-GVHD and therapeutic potential of B. ovatus.

Two-year follow-up of transcatheter aortic valve replacement in low-risk patients with symptomatic severe bicuspid aortic valve stenosis.

BACKGROUND: In 2019, the US Food and Drug Administration (FDA) approved transcatheter aortic valve replacement (TAVR) for low-risk patients with symptomatic severe tricuspid aortic stenosis. However, bicuspid aortic valve (BAV) patients were included only in single-arm registries of pivotal low-risk TAVR trials, resulting in limited data for this subgroup. METHODS: The LRT (Low Risk TAVR) trial was an investigator-initiated, prospective, multicenter study and the first FDA-approved investigational device exemption trial to evaluate the feasibility of TAVR with balloon-expandable or self-expanding valves in low-risk patients with symptomatic severe BAV stenosis. This analysis reports 2-year follow-up, assessing the primary outcome of all-cause mortality and evaluating clinical outcomes. RESULTS: From 2016 to 2019, a total of 72 low-risk patients diagnosed with symptomatic, severe BAV stenosis underwent TAVR across six centers. Six patients were lost to follow-up. At 2-year follow-up, mortality was 1.5% (1 of 66 patients). Among the remaining 65 patients, four experienced nondisabling strokes (6.2%), while 2 (3.1%) developed infective endocarditis. No new permanent pacemakers were required beyond the 30-day follow-up, and no patients, including those with endocarditis, needed aortic valve re-intervention. At the 2-year echocardiography follow-up (n = 65), 27.8% of BAV patients showed mild aortic regurgitation, with none exhibiting moderate or severe regurgitation. The mean aortic gradient was 12.1 ± 4.1 mmHg, and the mean valve area was 1.7 ± 0.5 cm². CONCLUSION: The 2-year follow-up confirms commendable clinical outcomes of TAVR in patients with bicuspid aortic stenosis, establishing its evident safety.

Cerebrovascular events after transcatheter aortic valve implantation.

Periprocedural stroke after transcatheter aortic valve implantation (TAVI) remains a significant issue, which is associated with high morbidity, and is increasingly important as intervention shifts to younger and lower-risk populations. Over the last decade of clinical experience with TAVI, the incidence of periprocedural stroke has stayed largely unchanged, although it is prone to underreporting due to variation in ascertainment methods. The aetiology of stroke in TAVI patients is multifactorial, and changing risk profiles, differing study populations, and frequent device iterations have made it difficult to discern consistent risk factors. The objective of this review is to analyse and clarify the contemporary published literature on the epidemiology and mechanisms of neurological events in TAVI patients and evaluate potential preventive measures. This summary aims to improve patient risk assessment and refine case selection for cerebral embolic protection devices, while also providing a foundation for designing future trials focused on stroke prevention.

High-risk percutaneous coronary intervention with or without mechanical circulatory support: Will Impella show superiority in the PROTECT IV randomized trial?

BACKGROUND: PROTECT IV is a current enrolling randomized controlled trial evaluating high-risk percutaneous coronary intervention (HR-PCI) with prophylactic Impella versus no Impella to reduce the composite primary endpoint of all-cause death, stroke, myocardial infarction (MI), or cardiovascular hospitalization. In a PROTECT IV-like cohort of patients who underwent HR-PCI without Impella, we aimed to report the rate of major adverse events to determine whether the trial is adequately powered. METHODS AND RESULTS: A total of 700 patients meeting similar inclusion/exclusion criteria of PROTECT IV who underwent HR-PCI without Impella at a single tertiary center from 2008 to 2022 were included in the analysis. The composite rates of all-cause death, MI, target lesion revascularization, and target vessel revascularization at 1, 2, and 3 years were estimated using the Kaplan-Meier method, and the results were used to calculate the sample size under the constant hazard ratio assumption and expected number of events to be observed used in planning PROTECT IV. The primary endpoint occurred in 30.8 % of patients at 2 years. PROTECT IV assumes a hazard ratio of 0.75 using a multivariate Cox regression, which, under a 5 % level and 90 % power, yields 516 events. This implies a 2-year primary outcome rate of 50 % for the non-Impella arm. CONCLUSION: Therefore, PROTECT IV estimates that a sample size of 1252 patients is required for Impella to be declared superior to the non-Impella group. Using our observed 2-year outcome of 30.8 %, we estimate that PROTECT IV requires 1966 patients, demonstrating that PROTECT IV is probably underpowered.

Bioprosthetic Aortic Valve Thrombosis: Definitions, Clinical Impact, and Management: A State-of-the-Art Review.

Bioprosthetic aortic valve thrombosis is frequently detected after transcatheter and surgical aortic valve replacement due to advances in cardiac computed tomography angiography technology and standardized surveillance protocols in low-surgical-risk transcatheter aortic valve replacement trials. However, evidence is limited concerning whether subclinical leaflet thrombosis leads to clinical adverse events or premature structural valve deterioration. Furthermore, there may be net harm in the form of bleeding from aggressive antithrombotic treatment in patients with subclinical leaflet thrombosis. This review will discuss the incidence, mechanisms, diagnosis, and optimal management of bioprosthetic aortic valve thrombosis after transcatheter aortic valve replacement and bioprosthetic surgical aortic valve replacement.

Impella Versus Non-Impella for Nonemergent High-Risk Percutaneous Coronary Intervention.

The benefit of mechanical circulatory support with Impella (Abiomed, Inc., Danvers, Massachusetts) for high-risk percutaneous coronary intervention (HR-PCI) is uncertain. PROTECT III registry data showed improved outcomes with Impella compared with historical data (PROTECT II) but lack a direct comparison with the HR-PCI cohort without Impella support. We retrospectively identified patients meeting the PROTECT III inclusion criteria for HR-PCI and compared this group (non-Impella cohort [NonIMP]) with the outcomes data from the PROTECT III registry (Impella cohort). Baseline differences were balanced using inverse propensity weighting. The coprimary outcome was major adverse cardiac events (MACE) in-hospital and at 90 days. A total of 283 patients at great risk did not receive Impella support; 200 patients had 90-day event ascertainment and were included in the inverse propensity weighting analysis and compared with 504 patients in the Impella cohort group. After calibration, few residual differences remained between groups. The primary outcome was not different in-hospital (3.0% vs 4.8%, p = 0.403) but less in NonIMP at 90 days (7.5% vs 13.8%, p = 0.033). Periprocedural vascular complications, bleeding, and transfusion rate did not differ between groups; however, acute kidney injury occurred more frequently in the NonIMP group (10.5% vs 5.4%, p = 0.023). In conclusion, under identical HR-PCI inclusion criteria for Impella use in PROTECT III, an institutional non-Impella-supported HR-PCI cohort showed similar MACE in-hospital but fewer MACE at 90 days, whereas there was no signal for periprocedural harm with Impella use. These results do not support routine usage of Impella for patients with HR-PCI.

Temporal trends with the Evolut family of self-expanding transcatheter heart valves: A single-center experience.

BACKGROUND: The Evolut self-expanding valve (SEV) systems (Medtronic), were designed to accommodate varying valve sizes and reduce paravalvular leak (PVL) while maintaining a low delivery profile. These systems have evolved between product generations, alongside valve deployment techniques changing over time. AIMS: This study aimed to examine whether these changes impacted clinical outcomes. METHODS: EPROMPT is a prospective, investigator-initiated, postmarketing registry of consecutive patients undergoing transfemoral transcatheter aortic valve replacement (TAVR) using the Evolut PRO/PRO+ SEV system. A total of 300 patients were divided into three consecutive cohorts of 100 patients according to implantation date (January to October 2018, November 2018 to July 2020, and August 2020 to November 2021). Procedural and clinical outcomes over these time periods were compared. RESULTS: Valve Academic Research Consortium (VARC)-2 device implantation success improved over time (70.0% vs. 78.0% vs. 88.8%, p = 0.01), with a similar trend for VARC-3 device success (94.7% vs. 81.7% vs. 96.8%, p < 0.001). PVL (all degrees) frequency was likewise reduced over time (31.0% vs. 17.0% vs. 19.2%, p = 0.04). Furthermore, a trend was noticed toward shorter procedure times and shorter length of stay. However, postprocedural pacemaker implantation rates did not significantly differ (15.2% vs. 21.1% vs. 14.0%, p = 0.43). CONCLUSION: During a 3-year period, we demonstrated better TAVR outcomes with newer SEV iterations, alongside changes in implantation techniques, which might result in better procedural and clinical outcomes. However, we did not see a significant change in peri-procedural pacemaker rates for SEV.

Impact of Significant Hemoglobin Drop Without Bleeding in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: Hemoglobin (Hgb) drop without bleeding is common among patients undergoing transcatheter aortic valve replacement; however, the clinical implications of significant Hgb drop have not been fully evaluated. METHODS AND RESULTS: Consecutive patients undergoing transcatheter aortic valve replacement at our institution from 2011 to 2021 were retrospectively reviewed. Three groups were assessed: no Hgb drop and no bleed (NoD-NoB [reference group]), Hgb drop with bleed, and Hgb drop and no bleed (D-NoB). Hgb drop was defined as ≥3 g/dL decrease from pre- to post-transcatheter aortic valve replacement. Outcomes of interest were in-hospital death and 1-year all-cause mortality. A total of 1851 cases with complete Hgb data were included: NoD-NoB: n=1579 (85.3%); D-NoB: n=49 (2.6%); Hgb drop with bleed: n=223 (12.6%). Compared with NoD-NoB, the D-NoB group was older (81.1 versus 78.9 years of age) with higher preprocedure Hgb (12.9 versus 11.7 g/dL). In-hospital death rate was higher among patients with D-NoB versus NoD-NoB (4.5% versus 0.8%, P<0.001) and similar to Hgb drop with bleed (4.5% versus 4.1%, P=0.999). Predictors of in-hospital death were D-NoB (odds ratio [OR], 3.45 [95% CI, 1.32-8.69]) and transfusion (OR, 10.6 [95% CI, 4.25-28.2]). Landmark survival analysis found that D-NoB experienced 1-year mortality rate comparable to NoD-NoB, whereas Hgb drop with bleed had higher midterm mortality (hazard ratio [HR], 3.2 [95% CI, 1.83-5.73]), and transfusion continued to impact mortality (HR, 2.5 [95% CI, 1.79-3.63]). CONCLUSIONS: Hgb drop without bleeding is common among patients undergoing transcatheter aortic valve replacement and may represent a higher risk of periprocedural death. Blood transfusion increases short- and midterm mortality risk in patients with and without bleeding, supporting a restrictive transfusion strategy.

Markedly elevated high-sensitivity troponin and in-hospital mortality after cardiac surgery.

BACKGROUND: High-sensitivity troponin (hsTnI) is correlated with cardiac mortality; however, studies on the relationship of markedly elevated hsTnI with in-hospital mortality after cardiac surgery are sparse. Therefore, we aimed to define this relationship in order to help guide in-hospital, acute management of post-surgical patients. METHODS: We retrospectively analyzed all cardiac surgeries completed at our institution between January 2020 and June 2022 in which a peak hsTnI was noted to be >35× upper limit of normal (ULN = 34 ng/L). The primary outcome was in-hospital death. Subgroup analysis was performed to assess differences between coronary artery bypass grafting (CABG) and other cardiac surgeries. RESULTS: A total of 1382 cases met inclusion criteria. The patients' mean age was 64.8 years and 68.2 % were male. Median peak hsTnI after surgery was 4202 ng/L (interquartile ratio: 2427-7654). Univariate analysis of troponin level with mortality found that for every 1000 ng/L increase in hsTnI, odds of in-hospital death increased by 3.8 % (odds ratio [OR]: 1.038; 95 % confidence interval [CI] 1.027-1.050; p < 0.0001). In a multivariate model, troponin (OR 1.02; 95 % CI 1.01-1.04; p = 0.004) maintained a significant association with in-hospital death. CABG was associated with a lower risk of in-hospital death for any given hsTnI level up to 60,000 ng/L compared to other cardiac surgeries. CONCLUSION: Increasing hsTnI level is associated with increasing probability of in-hospital mortality and, therefore, serves as an additional, objective measure of risk to help guide in-hospital clinical management.

Antibiotic-associated neutropenia is marked by depletion of intestinal Lachnospiraceae in pediatric patients.

Hematologic side effects are associated with prolonged antibiotic exposure in up to 34% of patients. Neutropenia, reported in 10-15% of patients, increases the risk of sepsis and death. Murine studies have established a link between the intestinal microbiota and normal hematopoiesis. We sought to identify predisposing factors, presence of microbiota-derived metabolites, and changes in intestinal microbiota composition in otherwise healthy pediatric patients who developed neutropenia after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics and at the time of neutropenia. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and type of infection or type of antibiotic used; however intensive care unit admission and length of therapy were associated with neutropenia. Reduced intestinal microbiome richness and decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism and fatty acid metabolism that are known to be produced by Lachnospiraceae . Our study confirms a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis. As the microbiome is a key determinant of stem cell transplant and immunotherapy outcomes, these findings are likely to be of broad significance. Key Points: Neutropenia occurred in 17% of patients receiving prolonged antibiotic therapy.We found no association between neutropenia and type of infection or class of antibiotic used. Development of neutropenia after prolonged antibiotic treatment was associated with decreased prevalence of Lachnospiraceae and Lachnospiraceae metabolites such as citrulline.

Recruitment and Retention of Hematopoietic Cell Transplantation and Cellular Therapy Physicians: A Report from the ASTCT Talent Acquisition Task Force.

A shortage of transplant and cellular therapy (TCT) physicians is expected given the expansion of TCT indications and the scope of practice of TCT programs in recent years. American Society of Transplantation and Cellular Therapy (ASTCT) conducted a survey of early career transplant physicians and trainees to assess the factors that prompted them to pursue to career in TCT. This was a cross-sectional survey conducted via emails sent to the ASTCT membership. Fifty-nine respondents completed the survey. The vast majority of respondents decided to pursue a career in TCT during their hematology/oncology fellowship (41%), followed by during residency (25%) or medical school (18%), and a majority of them had some exposure to TCT in their clinical training already. The most common reason for choosing to specialize in TCT was interest in the clinical practice of TCT (81%) closely followed by the scientific allure of the field (75%). Most respondents were extremely committed to remaining in this field of practice. We found that those in the field report high levels of satisfaction despite factors that would otherwise predispose them to burnout. A systematic and sustained effort to promote trainee engagement that could result in improved recruitment and retention in the field of TCT is needed. Professional societies in partnership with educational institutions could conduct outreach and help attract trainees from diverse backgrounds.

Frequency of ventriculography during left heart catheterization for radial vs. femoral access.

BACKGROUND: Radial artery access has been used for left heart catheterization (LHC) and percutaneous coronary intervention (PCI) for over 30 years. This method has gained popularity among operators due to superficial vessel anatomy, allowing for easy accessibility and compressibility, resulting in effective hemostasis. METHODS: We conducted a retrospective analysis of patients who underwent PCI due to ST-elevation myocardial infarction (STEMI), non-ST-elevation acute coronary syndrome (NSTE-ACS), and chest pain (stable angina) from November 2013 to February 2023. RESULTS: We analyzed validated registries and found 7714 PCIs. Of these, 1230 were STEMI patients, 5585 were NSTE-ACS patients, and 899 were stable angina patients, forming the basis of our final analysis. In STEMI patients, there was a trend toward a higher rate of ventriculography with femoral access compared to radial access (53.4 % vs. 47.5 %, p = 0.06), which was also observed in NSTE-ACS patients (34.2 % vs. 31.8 %, p = 0.07). The use of central venous access was more common with femoral access in all three diagnoses, with significantly higher rates seen in STEMI patients (36.2 % vs. 7.6 %, p < 0.001), NSTE-ACS patients (19.3 % vs. 2.8 %, p < 0.001), and chest pain patients (26.4 % vs. 2.7 %, p < 0.001). CONCLUSIONS: The analysis revealed that operators may perform fewer ventriculography and RHC procedures when using radial access as compared to femoral access. While there is discrepancy in performing left ventriculography and RHC when using a radial artery, it is essential to emphasize that routinely performing ventriculography and hemodynamic assessment has not proven to impact outcomes, despite their contributions to proper decision-making and treatment.

From chest pain to coronary functional testing: Clinical and economic impact of coronary microvascular dysfunction.

BACKGROUND: Coronary functional testing to formally diagnose coronary microvascular dysfunction (CMD) reduces cardiovascular events and alleviates angina. This study aims to investigate the extensive and complex journey that patients with CMD undergo, from the onset of chest pain to eventual diagnosis. METHODS: Data from the Coronary Microvascular Disease Registry (CMDR) were analyzed, including information on the date of first documentation of chest pain, number of non-invasive and invasive tests the patient underwent, emergency department visits, and hospitalizations. In addition, we estimated the total cost per patient. A total of 61 patients with CMD diagnosis were included in this analysis. RESULTS: Most patients in our cohort were older than 50 years of age. The median time from initial chest pain symptoms to diagnosis was 0.62 (interquartile range [IQR]: 0.06-2.96) years. During this period, patients visited the emergency department a median of 1.0 (IQR: 0.0-2.0) times. Diagnostic tests included 3.0 (IQR: 2.0-6.0) electrocardiograms, 3.0 (IQR: 0.0-6.0) high-sensitivity troponin tests, and 1.0 (IQR: 1.0-2.0) echocardiograms. Prior to diagnosis of CMD, 13 (21.3 %) patients had left heart catheterization without coronary functional testing. Non-invasive testing for ischemia was conducted in 43 (70.5 %) patients. Alternative non-cardiac diagnoses were given to 11 (18.0 %) patients during the diagnostic process, with referrals made to gastroenterology for 16 (26.2 %) and pulmonology for 10 (16.4 %) patients. The cost was almost $2000/patient. CONCLUSION: Timely identification of CMD offers promising opportunities for prompt symptom alleviation, accompanied by reduced visits to the emergency department, cardiovascular testing, invasive medical procedures, and consequently reduced healthcare expenses.

Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models.

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.