Citations

LINKED CONTENTThis article is linked to Nørgård et al and Nørgård & Friedman papers. To view these articles, visit https://doi.org/10.1111/apt.15956 and https://doi.org/10.1111/apt.16024https://doi.org/10.1111/apt.16024

LINKED CONTENTThis article is linked to Kreijne et al paper. To view this article, visit https://doi.org/10.1111/apt.17555

Background: Diastolic dysfunction (DD) is frequently present in patients with hypertrophic cardiomyopathy (HCM) due to abnormal left ventricular (LV) relaxation, wall hypertrophy, increased LV filling pressures and myocardial disarray and fibrosis, even though ejection fraction (EF) remains preserved until late stages. Our aim was to investigate in a large cohort whether contemporary markers of DD and increased filling pressures are associated with outcomes in these patients. Methods: We screened consecutive patients with HCM who had transthoracic echocardiography and no significant valvular heart disease. The associations of septal/lateral e’ velocity, E/e’, left atrial volume index (LAVi), and tricuspid regurgitant velocity (TR) with all-cause mortality were tested. A diastolic score (DS) was also calculated (1 point for each abnormality in e’, E/e’, TR, LAVi). Results: 1,496 patients with HCM were studied (mean age 52±15 yrs; 61% men; LV EF 69±7%; Table). Diastolic abnormalities were highly prevalent in these patients ( Table ). In the subset without septal reduction therapy (SRT; n=900), at a median followup of 9 years (IQR 7-11 yrs; n=78 deaths), increased E/e’ and DS were strongly associated with mortality (log-rank P <.0001 for both; Figure ). However, E/e’ did not remain significant in multivariable models after adjustment for known cardiac risk factors or other significant confounders ( Table ). In contrast, DS >2 remained independently associated with ~2-fold higher mortality risk (adjusted HR 1.91 [1.14-3.20, P =.01]; n=693; Table). In patients who underwent SRT (n=596), these associations showed the same trend but attenuated. Conclusion: In HCM patients who did not require SRT, the severity of DD was associated with mortality, independent of cardiac pump function or known cardiac risk factors. The composite score was more powerful than E/e’. Further studies are needed to fully understand the impact of DD in these patients with and without SRT.

Abstract Background and Aims Inflammation is an established contributor to accelerated atherosclerosis, which is highly prevalent in people with chronic kidney disease (CKD) and even more so in those treated with peritoneal dialysis (PD). We therefore hypothesised that PD-induced systemic inflammation is essential in the development of atherosclerosis. To study this we developed a novel mouse model of CKD and PD accelerated atherosclerosis. Method We performed a 5/6ths nephrectomy in ApoE deficient “black 6” mice, fed these mice a high-cholesterol diet (HCD), and intraperitoneally administered 3.86% Physioneal daily for 67 days. There were three groups of mice: control (HCD-only), CKD+HCD, and CKD+HCD+PD, with relevant shams. Tissues were harvested twelve weeks after the nephrectomy. Assessments of residual kidney function, atherosclerotic plaque pathology and immunology, and systemic immune responses were performed. Results Atherosclerotic plaque size in the aortic arch was larger in the PD group compared to the control, increasing from 83,779 μm2 ±18,430 to 109,973 μm2 ±25,602 (p = 0.0349), whilst plaque size was unchanged in the CKD group. In contrast, both the CKD and PD groups displayed altered plaque stability. There was less collagen in the plaque vs control, decreasing from 43.54% ±10.65 to 29.71% ±9.43 and 29.73% ±10.18 respectively. Additionally, fibrous cap thickness decreased in both groups vs control. The plaques from only the PD group showed infiltration by T-cells compared to control, with no changes in macrophage content in either the CKD or PD group. In the spleen in the CKD and PD groups, naïve CD4 cells increased and effector CD4 cells decreased compared to control, with the latter change also occurring in the circulation. Central memory CD4 cells, terminally differentiated Th1 cells, Th17 cells, and ‘vascular homing’ cells all increased in the PD group compared to control mice. These homing cells also increased in circulation. The PD group showed decreases in the spleen of regulatory T-cells, effector Th1 cells, and effector CD8 cells. Notably, all of these changes were absent from the mesenteric lymph node. There was a large drop in monocytes in the spleen and a loss of immature and mature dendritic cells in the PD group. Conclusion Combining CKD, a high-cholesterol diet, and exposure to PD fluids in ApoE−/-mice successfully generated a new model for cardiovascular disease in human PD patients. This new model is in a widespread and well-understood mouse line representative of human atherosclerosis. Here we demonstrate the pronounced effects of CKD and PD on the innate and adaptive immune response which increases atherosclerotic burden and leads to larger more vulnerable plaques

Background Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity. Methods We retrospectively characterized hematologic toxicities associated with CRS seen on a phase 1 study of anti-CD22 CAR T-cells for children and young adults with relapsed/refractory CD22+ hematologic malignancies. Additional analyses included correlation of hematologic toxicities with neurotoxicity and exploring effects of hemophagocytic lymphohistiocytosis-like toxicities (HLH) on bone marrow recovery and cytopenias. Coagulopathy was defined as evidence of bleeding or abnormal coagulation parameters. Hematologic toxicities were graded by Common Terminology Criteria for Adverse Events V.4.0. Results Across 53 patients receiving CD22 CAR T-cells who experienced CRS, 43 (81.1%) patients achieved complete remission. Eighteen (34.0%) patients experienced coagulopathy, of whom 16 had clinical manifestations of mild bleeding (typically mucosal bleeding) which generally subsided following CRS resolution. Three had manifestations of thrombotic microangiopathy. Patients with coagulopathy had higher peak ferritin, D-dimer, prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), tissue factor, prothrombin fragment F1+2 and soluble vascular cell adhesion molecule-1 (s-VCAM-1). Despite a relatively higher incidence of HLH-like toxicities and endothelial activation, overall neurotoxicity was generally less severe than reported with CD19 CAR T-cells, prompting additional analysis to explore CD22 expression in the central nervous system (CNS). Single-cell analysis revealed that in contrast to CD19 expression, CD22 is not on oligodendrocyte precursor cells or on neurovascular cells but is seen on mature oligodendrocytes. Lastly, among those attaining CR, grade 3–4 neutropenia and thrombocytopenia were seen in 65% of patients at D28. Conclusion With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted. Trial registration number NCT02315612 .

Abstract The overall goal of the annual Transdisciplinary Research in Energetics and Cancer (TREC) Training Workshop is to provide transdisciplinary training for scientists in energetics and cancer and clinical care. The 2022 Workshop included 27 early-to-mid career investigators (trainees) pursuing diverse TREC research areas in basic, clinical, and population sciences. The 2022 trainees participated in a gallery walk, an interactive qualitative program evaluation method, to summarize key takeaways related to program objectives. Writing groups were formed and collaborated on this summary of the 5 key takeaways from the TREC Workshop. The 2022 TREC Workshop provided a targeted and unique networking opportunity that facilitated meaningful collaborative work addressing research and clinical needs in energetics and cancer. This report summarizes the 2022 TREC Workshop’s key takeaways and future directions for innovative transdisciplinary energetics and cancer research.

Abstract Functional testing with stress echocardiography is based on the detection of regional wall motion abnormality with two-dimensional echocardiography and is embedded in clinical guidelines. Yet, it under-uses the unique versatility of the technique, ideally suited to describe the different functional abnormalities underlying the same wall motion response during stress. Five parameters converge conceptually and methodologically in the state-of-the-art ABCDE protocol, assessing multiple vulnerabilities of the ischemic patient. The five steps of the ABCDE protocol are (1) step A: regional wall motion; (2) step B: B-lines by lung ultrasound assessing extravascular lung water; (3) step C: left ventricular contractile reserve by volumetric two-dimensional echocardiography; (4) step D: coronary flow velocity reserve in mid-distal left anterior descending coronary with pulsed-wave Doppler; and (5) step E: assessment of heart rate reserve with a one-lead electrocardiogram. ABCDE stress echo offers insight into five functional reserves: epicardial flow (A); diastolic (B), contractile (C), coronary microcirculatory (D), and chronotropic reserve (E). The new format is more comprehensive and allows better functional characterization, risk stratification, and personalized tailoring of therapy. ABCDE protocol is an ‘ecumenic’ and ‘omnivorous’ functional test, suitable for all stresses and all patients also beyond coronary artery disease. It fits the need for sustainability of the current era in healthcare, since it requires universally available technology, and is low-cost, radiation-free, and nearly carbon-neutral.

Abstract: Athletes of all ages may be affected by medical and mental health issues. Sports medicine physicians should be familiar with common conditions that may affect the well-being of athletes, such as attention-deficit/hyperactivity disorder (ADHD). ADHD behaviors have the potential to affect a person's ability to concentrate. It is likely that social and cognitive therapies combined with pharmacotherapy will be the most effective way to treat ADHD in athletes. Medications used for ADHD, especially stimulant types, are known to improve alertness, reaction time, anaerobic performance, and endurance, which would potentially improve athletic performance. Furthermore, stimulant medications may enable student athletes with ADHD to focus on academic studies for longer periods of time, beyond usual levels of fatigue, important for those who may be exhausted after practices and games. The purported performance enhancement effects and potential adverse effects of stimulant medications have prompted many sports governing bodies to ban prescription stimulants or establish strict rules for their use. Athletes taking physician-prescribed stimulants to treat ADHD need to provide the appropriate documentation for approval before competition or risk punitive measures. Physicians should strive to provide a high quality of care to athletes with ADHD through early diagnosis, appropriate and careful multidisciplinary treatment, and complete and timely documentation to facilitate continued sports participation.

Abstract Aims Tricuspid valve regurgitation (TR) is a common valvular disease associated with increased mortality. There is a need for tools to assess the interaction between the pulmonary artery (PA) circulation and the right ventricle in patients with TR and to investigate their association with outcomes. The pulmonary artery pulsatility index (PAPi) has emerged as a haemodynamic risk predictor in left heart disease and pulmonary hypertension (PH). Whether PAPi discriminates risk in unselected patients with greater than or equal to moderate TR is unknown. Methods and results In 5079 patients with greater than or equal to moderate TR (regardless of aetiology) and PA systolic and diastolic pressures measured on their first echocardiogram, we compared all-cause mortality at 5 years based on the presence or absence of PH and PAPi levels. A total of 2741 (54%) patients had PH. The median PAPi was 3.0 (IQR 1.9, 4.4). Both the presence of PH and decreasing levels of PAPi were associated with larger right ventricles, worse right ventricular systolic function, higher NT-pro BNP levels, greater degrees of right heart failure, and worse survival. In a subset of patients who had an echo and right heart catheterization within 24 h, the correlation of non-invasive to invasive PA pressures and PAPi levels was very good (r = 0.76). Conclusion In patients with greater than or equal to moderate TR with and without PH, lower PAPi is associated with right ventricular dysfunction, right heart failure, and worse survival. Incorporating PA pressure and PAPi may help stratify disease severity in patients with greater than or equal to moderate TR regardless of aetiology.