Citations

Abstract Aims We aimed to determine the effect of increasing body weight upon right ventricular (RV) volumes, energetics, systolic function, and stress responses using cardiovascular magnetic resonance (CMR). Methods and results We first determined the effects of World Health Organization class III obesity [body mass index (BMI) > 40 kg/m2, n = 54] vs. healthy weight (BMI < 25 kg/m2, n = 49) upon RV volumes, energetics and systolic function using CMR. In less severe obesity (BMI 35 ± 5 kg/m2, n = 18) and healthy weight controls (BMI 21 ± 1 kg/m2, n = 9), we next performed CMR before and during dobutamine to evaluate RV stress response. A subgroup undergoing bariatric surgery (n = 37) were rescanned at median 1 year to determine the effects of weight loss. When compared with healthy weight, class III obesity was associated with adverse RV remodelling (17% RV end-diastolic volume increase, P < 0.0001), impaired cardiac energetics (19% phosphocreatine to adenosine triphosphate ratio reduction, P < 0.001), and reduction in RV ejection fraction (by 3%, P = 0.01), which was related to impaired energetics (R = 0.3, P = 0.04). Participants with less severe obesity had impaired RV diastolic filling at rest and blunted RV systolic and diastolic responses to dobutamine compared with healthy weight. Surgical weight loss (34 ± 15 kg weight loss) was associated with improvement in RV end-diastolic volume (by 8%, P = 0.006) and systolic function (by 2%, P = 0.03). Conclusion Increasing body weight is associated with significant alterations in RV volumes, energetic, systolic function, and stress responses. Adverse RV modelling is mitigated with weight loss. Randomized trials are needed to determine whether intentional weight loss improves symptoms and outcomes in patients with obesity and heart failure.

Abstract The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

Background and Aims Sirtuin 1 (SIRT1) is a complex NAD+‐dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1‐induced destabilization of primary cilia in cholangiocarcinoma (CCA). Approach and Results A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)‐mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD ‐producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1‐overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α‐tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma‐associated oncogene 1, phosphorylated extracellular signal‐regulated kinase, and IL‐6) expression. Conclusions In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

PURPOSECholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort.METHODSThis is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020.RESULTSOur group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038).CONCLUSIONFGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.

ABSTRACT Endometriosis is a rare cause of large bowel obstruction and has been infrequently reported in patients with inflammatory bowel disease. We present an unusual case of a young woman with ulcerative colitis, who presented with a large bowel obstruction with colonic stricture and peripancreatic mass concerning for malignancy. The evaluation revealed endometriosis, and her large bowel obstruction was successfully managed with leuprolide and colonic stenting.

INTRODUCTION: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. METHODS: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. RESULTS: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP ( P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations ( P < 4.885 × 10 −23 ). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling ( HTR2A , DRD3 , NPY , and BDNF ), hypothalamic-pituitary-adrenal axis ( NR3C1 and FKBP5 ), and cell-cell interaction ( CTNND2 and THBS2 ). DISCUSSION: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.

Background: The package insert for apixaban recommends against its use for stroke prevention in patients with atrial fibrillation (AF) with prosthetic heart valves. There are no published data on the use of apixaban in patients with AF with bioprosthetic valves. This analysis provides preliminary exploratory data on the safety and efficacy of apixaban in these patients. Methods: The ARISTOTLE trial randomized patients with AF to apixaban versus warfarin, and patients with a history of bioprosthetic valve replacement were eligible for inclusion in the trial. In this secondary analysis, baseline characteristics of patients with bioprosthetic valves were compared between apixaban and warfarin patients using Wilcoxon tests for continuous variables and chi-square tests for categorical variables. Unadjusted endpoints were compared between randomized treatments using a Cox regression model. With data collection on these valve patients ongoing, this interim report represents 82 of 260 patients with a history of valve surgery from ARISTOTLE. Results: Among 82 patients with bioprosthetic valves, 41 patients each were in the apixaban and warfarin arms. The patients had a median age of 78 years (vs. 70 years in overall trial), 18% had prior stroke (vs. 19% in overall trial), and 41% had concomitant aspirin use (vs. 31% in overall trial). Other than a higher rate of hypertension in the warfarin arm (98% vs. 81%, p=0.03), there were no statistically significant differences in baseline characteristics between the two groups. There were few events in patients with bioprosthetic valves. There were 2 stroke events, and there were no statistically significant differences between the apixaban and warfarin groups for major bleeding, stroke/systemic embolism, all-cause death, or cardiovascular death (Table). Conclusions: Among the small number of patients in ARISTOTLE with bioprosthetic valves, there were few events with similar event rates in both the apixaban and warfarin groups.

Background: The presence of frailty increases the risk of long-term mortality for a myriad of reasons, but its association with cardiac-specific mortality among the elderly undergoing percutaneous coronary intervention (PCI) is unknown. We sought to determine the relationship between frailty and cause-specific (cardiac versus non-cardiac) mortality among elderly patients undergoing PCI. Methods: A prospective cohort of elderly (>65 years) patients undergoing PCI at Mayo Clinic between October 2005 and September 2008 were tested for frailty using the Fried criteria. Vital status was prospectively monitored including evaluation of death certificates, telephone interviews and review of autopsy/medical records. Results: Frailty data was obtained in 428 (84%) of 508 elderly patients (median age 74.2 years [SD 6.4, range 65-100]; 59% male). Of these, 92 (21%) patients were frail while 231 (54%) had intermediate frailty and 105(25%) were not frail. Frail patients were older than intermediate and non-frail patients (77.6 vs 74.3 vs 71.0 years; p<0.001) and had more comorbidities (mean Charlson index 4.6 vs 3.9 vs 2.8; p<0.001). There were 113 deaths (26% of cohort) during 5.1 median years of follow-up, of which 77 (68%) were classified as non-cardiac and 36 (32%) which were classified as cardiac. Frailty at baseline was associated with poor overall survival compared to non-frail patients (HR 6.1, 95% CI 3.2, 11.6; p<0.001). The estimated effect of frailty was nearly 3 times greater for cardiac mortality (HR 13.1, 95% CI 3.0, 57.0; p=0.001) than non-cardiac mortality (HR 4.6, 95% CI 2.2, 9.7; p<0.001). These findings remained significant following multivariable adjustment. Conclusions: Frailty is common among elderly patients undergoing PCI and is associated with poor overall survival and both cardiac and non-cardiac causes of death.

Background: Transthoracic echocardiography is the mainstay of cardiac imaging and is highly dependent upon cardiac sonographers for whom image acquisition can be physically demanding and associated with musculoskeletal pain. Prior studies are limited by the absence of adequate control groups and a lack of adjustment for potential confounders. Objectives: The purpose of this study was to determine the prevalence and impact of work-related musculoskeletal pain in cardiac sonographers as compared to a large control group of non-invasive healthcare professionals with similar demographics. Methods: An electronic survey was administered to Mayo Clinic employees identified by human resources at six major patient care facilities in four different states. Results: There were 2682 employees within the departments of cardiology and radiology who were contacted and 1532 (57%) completed the survey. After exclusion of those who wear protective lead aprons, 517 employees comprised the control group and 66 cardiac sonographers made up the study group. Cardiac sonographers and the control group were similar in age, sex, BMI, length of employment and history of prior musculoskeletal pain. Cardiac sonographers reported work-related musculoskeletal pain more frequently than the control group (88% vs 40%; p<0.001). This association persisted after multivariable adjustment for age, sex, body mass index, length of current employment and history of pre-existing musculoskeletal pain (OR 11.6; (95% CI 5.32, 25.5); p<0.001). Cardiac sonographers were more likely to seek medical care for their work-related pain (55% vs 21%; p<0.001) and to have missed work due to pain (35% vs 12%, p<0.001). Conclusions: In this multi-site case control study, cardiac sonographers experienced significantly more work-related pain and missed more work due to pain than a large control group of non-invasive healthcare professionals with similar demographics.

Background: Cellular adhesion molecules (CAM) have a central role in the accumulation of circulating leukocytes at sites of vascular injury, infection and/ inflammation, and have been associated with the development of atherosclerotic plaque and coronary artery disease in mature adults. Objective: To test the hypothesis that higher overall circulating CAM levels in young adults predict cardiovascular disease (CVD) events over the next 18 years. Method: We measured several circulating CAM molecules (ICAM-1, P-selectin, E-selectin and VCAM) in the Coronary Artery Risk Development in Young Adults (CARDIA) study at exam year 7 (1992-93, black and white men and women, CVD-free, mean age 32, range 25-37 years, n=2428) and monitored incident CVD events (n=70, including coronary heart disease, stroke, and heart failure, adjudicated based on medical records) through exam year 25, mean age of 50 years. We ranked each CAM in quintiles (coded 0-4) and summed the ranks across CAMs into an index to examine the association with incident CVD with Cox regression models. Results: Unadjusted cumulative CVD event rates were 1.6% (sum of CAM quartile ranks 0-8: 22 events in 1353 participants), 2.3% (sum of ranks 9-12: 29/813), and 7.3% (sum of ranks 13-16: 19/262). In proportional hazards regression analysis adjusted for year 7 age, sex, race, clinic, education, smoking, diet, physical activity, body mass index, blood pressure, blood lipids, and blood glucose, sum of ranks 13-16 were associated with a higher risk of CVD compared to the referent (rank sum 0-8) (See Table). Conclusion: High levels of circulating CAMs at an early stage of adulthood (mean age 32, range 25-37 years) were associated with an increased risk of incident CVD events. CAMs may be an early biomarker for development of subclinical CVD, even in CVD-free young adults with low atherosclerosis burden and decades prior to the development of clinical CVD.