Impaired Functional Capacity Research Articles

Functional capacity and its associated factors in older adults in the rural area in Brazil

Background & Aim: Aging leads to bodily changes and impairment of functional capacity in older adults. The objective was to analyze the association between socio-demographic and health data, cognitive impairment, and risk of sarcopenia with functional capacity in older adults enrolled in the Family Health Strategies in the rural area of the municipality of Picos, Piauí, Brazil.
 Methods & Materials: This is a quantitative and cross-sectional study that was developed with 320 older adults attending the Family Health Strategies located in the rural area of Picos, Piauí, Brazil. The participants were people 60 years old, registered in the Family Health Strategies, and living in a rural area. Data was collected in the older adults’ homes using the following instruments: Demographic profile, Self-reported illnesses, Mini-Mental State Examination, Barthel Index, Lawton and Brody Scale, and SARC-F.
 Results: It was found that 70% had cognitive impairment, 53.8% were at risk of sarcopenia, with a mean of 93.72 (SD=11.84) points for basic activities daily living, and 77.8% with partial dependence for instrumental activities daily living with a mean of 16.79 (SD=3.79) points. In the multivariate multiple regression, it was identified that there was an association between Basic Activities of Daily Living and Instrumental Activities of Daily Living with age (p<0.001), number of children (p=0,025), education (p=0.003), monthly income (p=0.018), number of diseases (p<0.001), sarcopenia (p<0.001) and cognitive status (p<0.001).
 Conclusion: A high prevalence of functional disability was identified in elderly people living in the rural area of ​​Picos, Piauí, Brazil. Therefore, it is important to pay attention to factors associated with dependence on daily activities.

Abnormal workload-indexed blood pressure response to exercise in patients at risk of or with overt heart failure

Abstract Background Conflicting evidence exists regarding the functional and prognostic significance of hypertensive response to exercise (HRE), commonly defined as peak systolic blood pressure (SBP) >210 mmHg in males and >190 mmHg in females. No study yet has explored the impact of sex-specific, workload-indexed HRE in patients at different stages of the heart failure (HF) spectrum, as defined by the American College of Cardiology/American Heart Association HF staging system. Purpose We evaluated the SBP/Workload slope during exercise across the HF spectrum and investigated the hemodynamic, functional and prognostic correlates of HRE. Methods Fifty-eight healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C) were enrolled; among the latter, 143 had preserved (HFpEF) and 226 reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. For each patient, we recorded at least two BP measurements during exercise: the first within the first minute of exercise and the last at peak effort. The SBP/Workload slope was calculated as the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each ACC/AHA HF Stage, we divided patients according to SBP/Workload slope tertiles; HRE was defined as the highest sex-specific SBP/Workload slope tertile. A composite of all-cause mortality and hospitalization for cardiovascular reasons was chosen as the primary outcome. Results The median SBP/Workload slope was 0.53 (interquartile range 0.36-0.72) mmHg/W and was steeper in women than in men in all subgroups (p<0.0001). After adjusting for age and sex, SBP/Workload slope was significantly higher in Stages A-B (0.61, 0.47-0.75 mmHg/W) and HFpEF (0.63, 0.42-0.86 mmHg/W) compared to controls (0.43, 0.35-0.57 mmHg/W) and HFrEF (0.47, 0.30-0.63 mmHg/W, Figure 1). In all subgroups, patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction (Table). After a median follow-up of 16 months, HRE was an independent predictor of adverse outcomes (Hazard Ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak absolute SBP values did not. Kaplan-Meier analysis confirmed a worse survival probability for patients with HRE in Stages A-B and HFpEF but not in HFrEF. After adjusting for confounding factors, the patients with the highest SBP/Workload slope had a 47% higher risk of the primary outcome than subjects in the lowest tertile (Figure 2). Conclusions Across the HF spectrum, patients with HRE, as evaluated by the SBP/Workload slope, present with peculiar pathophysiological features and impaired functional capacity. This is especially true for those in Stages A-B and patients with HFpEF. In these subgroups, HRE may portend an increased risk of adverse cardiovascular outcomes.SBP/workload slopesKaplan-Meier curves and Hazard Ratios

Changes in physical performance after Fontan operation: a follow-up study

Abstract Background Maximal oxygen consumption (peak VO2) is markedly compromised in patients with Fontan circulation compared to healthy subjects. In addition to the natural aging process, adaptive mechanisms inherent to univentricular physiology may further contribute to a decline in peak VO2 over time. These patients may have limitations in their ability to engage in physical activity, which may exacerbate the decline in peak VO2. This study aims to quantify the impairment of functional capacity over time in patients in the late postoperative period of Fontan operation and the relationship with a sedentary lifestyle. Method We studied 46 patients, 57% female, with a median age of 28 (24 - 35) years and 17 (15 - 21) years after Fontan surgery. Maximum and submaximal variables were analyzed from two standardized cardiopulmonary exercise tests (CPET) on a treadmill and performed with a range of five (4 - 9) years between them. All patients' physical activity levels were ranked using the short version of the International Physical Activity Questionnaire (IPAQ), comparing the functional capacity between active and sedentary patients. Clinical and surgical data were extracted from medical records. We performed a descriptive analysis of the demographic, clinical, and surgical data and a comparative analysis between the variables of the first and second CPET. The annual change was calculated by dividing the differences between the last and first tests by the time interval between them. Maximal variables were analyzed only for patients who achieved a maximum test (respiratory exchange ratio was equal to or greater than ≥ 1.1, heart rate > 85% of the predicted, and signs of intense effort. Results Among the 46 patients in the study, 40 performed maximum CPET. The characteristics of patients are shown in Table 1. There was an annual decrease in peak VO2 of 0.42 (1.17- -0.71) mL/kg/min and 0.72 (-2.14 - 0.71) % of predicted VO2. Impaired submaximal parameters occurred in all patients. There was an increased number of sedentary subjects on the second test compared with the first (p=0.009) (Table 2). Comparing the functional capacity of inactive patients with active, we found lower values in peak VO2: 23.1 (20.8-25.1) vs. 35.1 (32.0-35.4) mL/kg/min (p<0.001) and in a percentage of predicted 62 (59-67) vs. 84 (76-97) % (p=0.012). When analyzing the ejection fraction of the systemic ventricle by most recent echocardiogram and brain natriuretic peptide (BNP) plasmatic level, these variables were not significantly changed. Conclusion Functional capacity decreased over time in the studied population, represented mainly by a significant annual loss in peak VO2 and the predicted age values. Reduced functional capacity was observed in the inactive patients compared with active. No change in ventricular function was identified, as well as in BNP plasmatic level over time.Table_1Table_2

Significantly elevated hepatic extracellular volume in adult patients with a Fontan circulation and its correlation with impaired functional capacity.

Fontan-associated liver disease is a major concern in patients who have undergone the procedure. Regular imaging of the liver is currently recommended for Fontan patients, but not other congenital heart diseases. The extracellular volume (ECV) of the liver obtained during CMR scanning and studies can show the high liver ECV in Fontan patients. However, the correlation between the liver ECV and the functional capacity of Fontan patients has not yet been reported. This study aimed to compare the liver ECV between Fontan patients and other congenital heart diseases with significant pulmonic regurgitation (PR) or tricuspid regurgitation (TR), and to evaluate the correlation between the liver ECV in adult Fontan patients and their functional capacity as well as clinical characteristics. Retrospective analysis of cardiovascular magnetic resonance imaging from patients with history of Fontan surgery between 2017 and 2021 were conducted. The clinical characteristics and liver ECV were evaluated and compared between patients and control group. Functional capacity was evaluated using a 6-min walk distance (6MWD). The correlation between the liver ECV and functional capacity was analyzed. 35 patients were enrolled in the study, including 13 Fontan patients, 12 Ebstein's anomaly or repaired tetralogy of Fallot (rTOF) patients with significant PR or TR, and 10 patients for the control group. The liver ECV were significantly higher in Fontan patients compared with Ebstein's anomaly/rTOF and the control group (41.% in Fontan group, 33.9% in Ebstein's anomaly/rTOF, and 31.7% in control group with p = 0.01 and 0.0008 in Fontan vs. Ebstein's anomaly/rTOF and Fontan vs. control group, respectively). In Fontan patients, there was a significant correlation between the liver ECV and the liver blood biochemistry with r = 0.879, p = 0.01 for AST/ALT ratio and r = 0.65, p = 0.005 for AST. The liver ECV was inversely correlated with the six-minute walk distance (r = -0.55, p = 0.02). The liver ECV in patients who had undergone Fontan operation showed a significantly elevated and has significantly inversed correlation with their functional capacity. These findings indicated that the liver ECV may be a potentialmarker for adverse clinical outcomes. However, due to small size population, further prospective study with larger number of patients may validate this findings.

Proprioception and Mechanoreceptors in Osteoarthritis: A Systematic Literature Review.

Osteoarthritis (OA) is one of the most common chronic diseases in the world. It is frequently accompanied by high levels of persistent pain, as well as substantial impairments in function and functional capacity. This review aims to systematically analyze the changes in proprioception and related mechanoreceptors in OA patients. Studies from September 2013 to September 2023 were identified by conducting searches on the PubMed, Web of Science, and Scopus electronic databases following the PRISMA statement. One reviewer independently assessed and screened the literature, extracted the data, and graded the studies. The body of evidence underwent an evaluation and grading process using the ROBINS-I tool, which was specifically designed to assess the risk of bias in non-randomized studies of interventions. Results were summarized using descriptive methods. A search through 37 studies yielded 14 clinical studies that were ultimately included. The primary focus of the studies was on the knee joint, particularly the posterior cruciate ligament (PCL). The studies found that PCL in OA patients had impaired proprioceptive accuracy, possibly due to changes in mechanoreceptors (Ruffini, Pacini, and Golgi Mazzoni corpuscles). This suggests that dysfunctional articular mechanoreceptors, especially in severe cases of OA, may contribute to reduced proprioception. Dynamic stabilometry also identified significant proprioceptive deficits in patients with knee articular cartilage lesions, underscoring the impact of such lesions on knee proprioception. Literature data have shown that proprioceptive accuracy may play an important role in OA, particularly in the knee PCL and cartilage. However, the role of proprioception and related mechanoreceptors needs to be further clarified. Future studies focusing on the relationship between proprioception, OA disease, and symptoms, considering age and gender differences, and exploring OA joints other than the knee should be conducted to improve clinical and surgical outcomes in cases where proprioception and mechanoreceptors are impaired in OA patients.

Three-dimensional echocardiography for the evaluation of hypertrophic cardiomyopathy patients: relation to symptoms and exercise capacity

Patients with hypertrophic cardiomyopathy may exhibit impaired functional capacity, associated with increased morbidity and mortality. Systolic function is one of the determinants of functional capacity. Early identification of systolic disfunction may identify patients at risk for adverse outcomes. Myocardial deformation parameters, derived from three-dimensional (3D) speckle-tracking echocardiography (3DSTE) are useful tools to assess left ventricular systolic function, and are often abnormal before a decline in ejection fraction is seen. The aim of this study was to evaluate the correlation between myocardial deformation parameters obtained by 3DSTE and functional capacity in patients with hypertrophic cardiomyopathy. Seventy-four hypertrophic cardiomyopathy adult patients were prospectively evaluated. All patients underwent a dedicated 2D and 3D echocardiographic examination and cardiopulmonary exercise testing (CPET). Values of 3D global radial (GRS), longitudinal (3DGLS) and circumferential strain (GCS) were overall reduced in our population: 99% (n = 73) of the patients had reduced GLS, 82% (n = 61) had reduced GRS and all patients had reduced GCS obtain by 3DSTE. Average peak VO2 was 21.01 (6.08) ml/Kg/min; 58% (n = 39) of the patients showed reduced exercise tolerance (predicted peak VO2 < 80%). The average VE/VCO2 slope was 29.0 (5.3) and 16% (n = 11) of the patients had impaired ventilatory efficiency (VE/VCO2 > 34). In multivariable analysis, 3D GLS (β1 = 0.10, 95%CI: 0.03;0.23, p = 0.014), age (β1 = -0.15, 95%CI: -0.23; -0.05, p = 0.002) and female gender (β1 = -5.10, 95%CI: -7.7; -2.6, p < 0.01) were independently associated with peak VO2. No association was found between left ventricle ejection fraction obtain and peak VO2 (r = 0.161, p = 0.5). Impaired myocardial deformation parameters evaluated by 3DSTE were associated with worse functional capacity assessed by peak VO2.

Evaluation of quality of life, sleep, and sleepiness in dental students during active learning and remote emergency learning

Objective: This study aimed to evaluate the quality of life (QoL), quality of sleep, and sleepiness index in undergraduate dentistry students between their active learning (AL) and emergency remote learning (ERL) due to social distancing imposed during the COVID-19 pandemic. Methods: Information was collected using the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36-BR), Epworth Sleepiness Scale (ESS-BR), and Pittsburgh Sleep Quality Index (PSQI-BR) questionnaires administered before and during the COVID-19 pandemic. A comparison regarding the type of education, demographic factors, academic performance, PSQI-BR, ESS-BR, and SF-36-BR between the groups was performed, considering a significance level of 0.05. Results: A total of 55 students were from AL, while 45 students were from ERL. The sample consisted of 74 women and 26 men aged 21–30 years. The academic coefficient of these students ranged from 7 to 8 points (AL= 38.2% and ERL= 57.8%). In addition, a large proportion of the students reported having no failures (AL=60% and ERL= 66.7%). Regarding QoL, the students presented a greater impairment in functional capacity (p = 0.01), followed by limitations in social aspects, general health perception, body pain, and vitality. According to the ESS-BR scores (p = 0.04), the students presented a lower quality of sleep. Conclusion: Dentistry students had the worst QoL panoramas and poor relative sleep quality before and during the COVID-19 pandemic. Furthermore, QoL instruments were reliable for quantifying health-related QoL in AL and ERL.

Cardiopulmonary exercise testing criteria for advanced therapies in patients with heart failure.

Many cardiology associations endorse the role of the cardiopulmonary exercise test (CPET) to define the severity of impairment of functional capacity in individuals with heart failure with reduced ejection fraction (HFrEF) and when evaluating the need for advanced therapies for these patients. The focus of the CPET within the cardiology community has been on peak volume of oxygen uptake (VO2). However, several CPET variables are associated with outcomes in individuals with and without chronic disease and can inform clinical decisions in individuals with HFrEF. In this manuscript, we will review the normal cardiopulmonary response to a graded exercise test and review current guideline recommendations relative to CPET in patients with HFrEF.

Cardiopulmonary Performance Among Heart Failure Patients Before and After Left Ventricular Assist Device Implantation

BackgroundPatients with heart failure with reduced ejection fraction (HFrEF) have persistent impairments in functional capacity after continuous-flow left ventricular assist device (CF-LVAD) implantation. ObjectivesThis study aims to characterize longitudinal changes in exercise hemodynamics and functional capacity among patients with HFrEF before and after CF-LVAD implantation. MethodsTen patients underwent 3 invasive cardiopulmonary exercise tests on upright cycle ergometry with pulmonary artery catheterization: 1) Visit 1 before CF-LVAD implantation; 2) Visit 2 after device implantation with CF-LVAD pump speed held constant at baseline speed; and 3) Visit 3 with increases in pump speed during exercise (median: 1,050 rpm [IQR: 750-1,150 rpm] and 220 rpm [IQR: 120-220 rpm] for HeartMate 3 and HeartWare VAD, respectively). Hemodynamics and direct Fick cardiac output were monitored using pulmonary artery catheterization. Gas exchange metrics were determined using indirect calorimetry. ResultsMaximal oxygen uptake (Visits 1, 2, and 3: 10.8 ± 2.5 mL/kg/min, 10.7 ± 2.2 mL/kg/min, and 11.5 ± 1.7 mL/kg/min; P = 0.92) did not improve after device implantation. Mean pulmonary arterial and pulmonary capillary wedge pressures increased significantly during submaximal and peak exercise on preimplantation testing (P < 0.01 for rest vs peak exercise) and remained elevated, with minimal change on Visits 2 and 3 regardless of whether pump speed was fixed or increased. ConclusionsAmong patients with HFrEF, cardiovascular hemodynamics and exercise capacity were similar after CF-LVAD implantation, regardless of whether patients exercised at fixed or adjusted pump speeds during exercise. Further research is needed to determine methods by which LVADs may alleviate the HFrEF syndrome after device implantation. (Effect of mechanIcal circulatoRy support ON exercise capacity aMong pAtieNts with heart failure [IRONMAN]; NCT03078972)

Life engagement in people living with schizophrenia: predictors and correlates of patient life engagement in a large sample of people living in the community.

Life engagement represents a holistic concept that encompasses outcomes reflecting life-fulfilment, well-being and participation in valued and meaningful activities, which is recently gaining attention and scientific interest. Despite its conceptual importance and its relevance, life engagement represents a largely unexplored domain in schizophrenia. The aims of the present study were to independently assess correlates and predictors of patient life engagement in a large and well-characterized sample of schizophrenia patients. To assess the impact of different demographic, clinical, cognitive and functional parameters on life engagement in a large sample of patients with schizophrenia, data from the social cognition psychometric evaluation project were analyzed. Overall schizophrenia and depressive symptom severity, premorbid IQ, neurocognitive performance, social cognition performance both in the emotion processing and theory of mind domains, functional capacity, social skills performance and real-world functioning in different areas all emerged as correlates of patient life engagement. Greater symptom severity and greater impairment in real-world interpersonal relationships, social skills, functional capacity and work outcomes emerged as individual predictors of greater limitations in life engagement. Life engagement in people living with schizophrenia represents a holistic and complex construct, with several different clinical, cognitive and functional correlates. These features represent potential treatment targets to improve the clinical condition and also facilitate the process of recovery and the overall well-being of people living with schizophrenia.

Associations between symptoms and functional capacity in patients after COVID-19 infection and community controls.

Post-acute sequelae of COVID-19 (PASC or 'long COVID') reflect ongoing symptoms, but these are non-specific and common in the wider community. Few reports of PASC have been compared with a control group. To compare symptoms and objective impairment of functional capacity in patients with previous COVID-19 infection with uninfected community controls. In this community-based, cross-sectional study of functional capacity, 562 patients from Western Melbourne who had recovered from COVID-19 infections in 2021 and 2022 were compared with controls from the same community and tested for functional capacity pre-COVID-19. Functional impairment (<85% of the predicted response) was assessed using the Duke Activity Status Index (DASI) and 6-min walk distance (6MWD) test. A subgroup underwent cardiopulmonary exercise testing before and after exercise training. Of 562 respondents (age 54 ± 12 years, 69% women), 389 were symptomatic. Functional impairment (<85% predicted metabolic equivalent of tasks) was documented by DASI in 149 participants (27%), and abnormal 6MWD (<85% predicted) was observed in 14% of the symptomatic participants. Despite fewer risk factors and younger age, patients with COVID-19 had lower functional capacity by 6MWD (P < 0.001) and more depression (P < 0.001) than controls. In a pilot group of seven participants (age 58 ± 12 years, two women, VO2 18.9 ± 5.7 mL/kg/min), repeat testing after exercise training showed a 20% increase in peak workload. Although most participants (69%) had symptoms consistent with long COVID, significant subjective functional impairment was documented in 27% and objective functional impairment in 14%. An exercise training programme might be beneficial for appropriately selected patients.

Old Age and Frailty in Deceased Organ Transplantation and Allocation-A Plea for Geriatric Assessment and Prehabilitation.

Due to demographic ageing and medical progress, the number and proportion of older organ donors and recipients is increasing. At the same time, the medical and ethical significance of ageing and old age for organ transplantation needs clarification. Advanced age is associated with the frailty syndrome that has a negative impact on the success of organ transplantation. However, there is emerging evidence that frailty can be modified by suitable prehabilitation measures. Against this backdrop, we argue that decision making about access to the transplant waiting list and the allocation of donor organs should integrate geriatric expertise in order to assess and manage frailty and impairments in functional capacity. Prehabilitation should be implemented as a new strategy for pre-operative conditioning of older risk patients' functional capacity. From an ethical point of view, advanced chronological age per se should not preclude the indication for organ transplantation and the allocation of donor organs.

Effect of Light-Intensity Cycle Ergometer Aerobic Exercise on 2-Min Walking Test Distance and Maximum Oxygen Uptake in Myasthenia Gravis Patients: A Randomized Controlled Trial

Introduction: Fatigue and impaired functional capacity are more likely to be observed with myasthenia gravis (MG). MG prevalence in the Indonesian population is still limited. MG can benefit from participating in aerobic exercise without causing a decline in function, but relatively few exercise training studies have been conducted in this group of patients. This study analyzed how light-intensity cycle ergometer aerobic exercise influences functional and aerobic capacity in MG. Methods: An 8-week randomized controlled trial using a light-intensity cycle ergometer for aerobic exercise three times a week was carried out on adult patients with MG Foundation of America Class I-IIa, and adult patients. Eighteen MG patients were randomly assigned to the intervention or control group (standard exercise training). Two-min walking tests (2MWTs) distance and maximum oxygen uptake (VO2Max) were measured before and after the 8-week intervention. VO2Max was calculated from the 2MWT formula. A t-test was used to compare 2MWT distance and VO2Max within and between groups with a significance level of P &lt; 0.05. Results: Light intensity cycle ergometer aerobic exercise significantly improved the functional and aerobic capacity in the intervention group at 8 weeks (2MWT distance P = 0.001 and VO2Max P = 0.001) but not in the control group (P = 0.523 and P = 0.575, respectively). Substantial changes were also found between groups in both 2MWT distances (P = 0.002; effect size = 1.75) and VO2Max (P = 0.001; effect size = 1.81) pre- and post-test. Conclusion: Eight weeks of light-intensity cycle ergometer aerobic exercise improves the functional and aerobic capacity of adult MG patients.

1238-P: The Face of Diabetic Cardiomyopathy—Baseline Characteristics from the ARISE-HF Trial

Background: Diabetic Cardiomyopathy (DbCM) is a severe complication of diabetes and a cause of heart failure (HF) occurring in the absence of other causes of cardiac dysfunction. Methods and Results: ARISE-HF (NCT04083339) is a global Phase 3 randomized study evaluating the safety and efficacy of a novel highly selective aldose reductase inhibitor (AT-001) versus placebo to improve exercise capacity in individuals with DbCM (defined by elevated cardiac biomarkers or structural/functional cardiac abnormalities along with impaired exercise capacity). Table 1 details the 684 study participants with DbCM in the study: 50% female, with a mean age 67.5 years. Glycemic control at enrollment was excellent (HbA1c of 6.99%). At baseline, the median NT-proBNP was 71 ng/L and hs-cTnT was 9 ng/L. Among echocardiographic abnormalities evaluated at enrollment, the most common were abnormal global longitudinal strain and impaired diastolic relaxation. Daily physical activity was low (mean PASE score of 154.3 + 89.6). Significant impairment in cardiac functional capacity was present at enrollment with a peak VO2 of 15.7 + 3.8 ml/kg/min. Conclusion: The ARISE-HF trial is an ongoing phase 3 clinical trial evaluating the safety and efficacy of aldose reductase inhibition on exercise capacity in patients with DbCM. The baseline analysis of the study cohort provides a unique characterization of individuals with DbCM. Disclosure J.Butler: Consultant; Abbott,, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer,, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma,, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sequana Medical, Vifor, Speaker's Bureau; Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Janssen. F.Zannad: Advisory Panel; BMS, Novo Nordisk, Pfizer Inc., Servier Laboratories, Other Relationship; Applied Therapeutics Inc., Bayer Inc., Boehringer Ingelheim and Eli Lilly Alliance, Merck &amp; Co., Inc., Novartis. J.L.Januzzi: Consultant; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., AstraZeneca, Research Support; Applied Therapeutics Inc., Abbott, Roche Diagnostics, Novartis, Innolife Co., Ltd. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. J.Ezekowitz: Advisory Panel; Applied Therapeutics Inc. N.E.Ibrahim: None. C.S.Lam: Other Relationship; Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research &amp; Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai. R.Perfetti: None. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. W.Tang: Consultant; Sequana Medical NV, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics LLC, Renovacor, Boston Scientific Corporation, Kiniksa Pharmaceuticals Inc, WhiteSwell Inc, CardiaTec Biosciences Inc, Other Relationship; American Board of Internal Medicine, Springer Nature, Research Support; National Heart, Lung, and Blood Institute. A.Urbinati: None.

Investigation into aberrant B cell repertoire in myeloma on humoral immunity and patient survival.

8016 Background: B cells are critical to inhibiting tumor progression, as they generate tumor-reactive antibodies; promote anti-tumor killing capacity of NK cells and phagocytosis of macrophages/DCs; and enrich priming of T cells against the tumor. Multiple myeloma (MM) is a B-cell-derived malignancy, and its survival is partly driven by a deficiency in the immune response. Yet, the abnormalities of the B-cell-mediated humoral responses in MM are ill defined. Methods: We investigated B cell composition in bone marrow (BM) from patients with newly diagnosed MM (NDMM, N = 170), relapsed refractory MM (RRMM, N = 140) and healthy donors (HD, N = 21) by multi-color flow cytometry. Results: We observed that B1b cells was significantly reduced by 45% (p = 0.004) in NDMM patients compared to HD. B1b cells are important in generating long-lasting protective antibodies, particularly against vaccines, in a T cell independent fashion. Similarly, B2 cells, which can produce all antibody types, were significantly reduced in the periphery of NDMM and RRMM patients. Within the B2 cell population, germinal center (GC) matured B cells were significantly reduced in both BM and periphery of MM patients, as shown by significantly higher expression of Fas receptor. Because of deficiencies in the GC-maturation of these B cells, their ability to switch from IgM to IgG was also significantly decreased. On the other hand, the population of regulatory B cells (Bregs) were significantly elevated by 2.3-fold (p &lt; 0.05) in the BM and periphery of NDMM and periphery of RRMM patients. However, the ability of Breg cells to produce suppressive cytokines, like IL-10, was significantly reduced (p = 0.03), indicating impaired suppressive functional capacity. We investigated whether this dysregulated B cell homeostasis impacts myeloma patient survival following treatment. We found that a higher proportion of Bregs and a lower percent of B1a in BM and periphery prior to treatment was associated with favorable progression-free survival (PFS) in both NDMM and RRMM patients. We hypothesized that reduction of B2 cells and their inability to have GC-based maturation could impair antibody generation against acute infections and tumor neoantigens. Therefore, we evaluated MM patients’ ability to produce antibodies against hepatitis B surface antigen-based vaccination. We observed that only 31% of MM patients (N = 32) respond to the vaccine compared to 90% of HD. Furthermore, MM patients’ antibody titers were significantly lower ( &lt; 120 IU/L) compared to &gt; 5000IU/L in HD. Conclusions: All together, these results show that in MM patients, vaccine-responsive populations of B cells are reduced, with fewer mature B cells with limited repertoires in GC to fight against acute infections, and with a high number of dysregulated regulatory B cells. These results indicate that compromised B cell functionality in MM patients could impact therapeutic outcome.

MORPHOLOGICAL CHANGES OF RATS’ CEREBRAL CORTEX UNDER CONDITIONS OF DMH-INDUCED EXPERIMENTAL CARCINOGENESIS

Abstract. The progression of the endogenous intoxication syndrome accompanies the development of any neoplasm. The infl uence of toxic products leads to signifi cant disruptions in homeostasis, which seriously aff ects the central nervous system, specifi cally the cortex of the large hemispheres. Therefore, the purpose of our study was to establish changes in the morphological reorganization of the cortex of the large hemispheres of rats with DMG-induced adenocarcinoma in situ. The study used 85 mature white male rats. All animals were divided into 2 groups: I – 35 intact animals and II – 50 animals with DMG-induced colon adenocarcinoma.Histological slides of the brain were prepared by the generally accepted methodology. The drugs were studied using a MICROmed SEO SCAN light microscope and photo- documented using a Vision CCD Camera. The histological organization of the cerebral cortex of intact animals had typical histoarchitectonics. In the fi rst three stages of the experiment, moderate changes in the morphological organization of the cortex were detected compared to the control group. The fourth stage of DMG-induced carcinogenesis modeling was characterized by the manifestation of morphological changes, a decrease in the number of normochromic, an increase in hypo- and hyperchromic neurocytes, and the appearance of cell alteration signs. Typical for this period also was the progression of hemodynamic disorders: venous hyperemia, stasis, aggregation of erythrocytes («sludge»), and an increase in perivascular and pericellular edema. At the 5th and 6th stages of the experiment, a violation of the cytoarchitectonics of the cortex was revealed. Destructive changes in neurocytes increased. Betz cells were in a state of tigrolysis, sometimes in total one. A decrease in the Nissl substance in neurons confi rmed their impaired functional capacity. Increased permeability of capillary walls led to severe pericellular edema of neurocytes. Intracellular edema was also detected in most neurocytes. The 7th stage of the induced carcinogenesis was characterized by the presence of severe destructive changes in neurons: an increase in the number of hypo-, hyperchromic, sharply hypo-, and sharply hyperchromic neurocytes, a fragmentation of neurocyte neuroplasm, most of Betz cells in a state of total tigrolysis, a decrease in the content of Nissl substance in them, up to its complete absence. Blood capillaries had a deformed wall and signifi cantly enlarged perivascular spaces. Consequently, the study established the development and dynamics of alterative changes in the neurocytes of the cerebral cortex caused by DMG-induced carcinogenesis. These disorders were characterized by alteration of neurocytes and progressive microcirculation disorders. All identifi ed morphological changes in the brains of aff ected animals prove their dependence on the duration of carcinogen exposure.&#x0D;

Functional and prognostic impact of hypertensive response to exercise across the heart failure spectrum

Abstract Funding Acknowledgements Type of funding sources: None. Background Conflicting data exist regarding the prognostic significance of hypertensive response to exercise (HRE), commonly defined according to absolute peak systolic blood pressure (SBP) values. Limited evidence is available regarding the impact of workload-indexed HRE in patients at different stages of the heart failure (HF) spectrum as defined by the American College of Cardiology/American Heart Association HF staging system. Purpose We evaluated the SBP/Workload slope during exercise across the HF spectrum and investigated the haemodynamic, functional and prognostic correlates of HRE. Methods We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C); among the latter, 143 had preserved (HFpEF) and 226 reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. For each patient, we recorded the first (i.e., within the first minute of exercise) and last (i.e., at peak effort) BP measurement during the ramp protocol. The SBP/Workload slope (Figure 1) was calculated as the ratio of the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles; HRE was defined as the highest sex-specific SBP/Workload slope tertile in each HF stage. The primary outcome was a composite of all-cause mortality and hospitalization for cardiovascular reasons. Results Median SBP/Workload slope was 0.53 mmHg/W, interquartile range 0.36-0.72 mmHg/W; the slope was 39% steeper in women than in men (p&amp;lt;0.0001). After adjusting for age and sex, SBP/Workload slope in controls (0.43, 0.35-0.57 mmHg/W) was similar to HFrEF (0.47, 0.30-0.63 mmHg/W) but significantly lower than Stages A-B (0.61, 0.47-0.75 mmHg/W) and HFpEF (0.63, 0.42-0.86 mmHg/W). In all HF stages, patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (Hazard Ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p=0.005) and HFpEF (p&amp;lt;0.001), but not HFrEF. After adjusting for age, sex, body mass index, rest and peak SBP, rest and peak cardiac output, and rest and peak left ventricular ejection fraction, patients with the highest SBP/Workload slope had a 47% higher risk of the primary outcome than subjects in the lowest tertile (Figure 2). Conclusion HRE, as evaluated by the SBP/Workload slope, is associated with distinct pathophysiological features and impaired functional capacity across the HF spectrum, especially in Stages A-B and in patients with HFpEF. Patients with HRE in these subgroups may be at increased risk of adverse cardiovascular outcomes.

P69 SHORT–TERM EFFECT OF DAPAGLIFLOZIN ON LEFT VENTRICULAR LONGITUDINAL FUNCTION IN PATIENTS WITH HEART FAILURE WITH REDUCED LEFT VENTRICULAR EJECTION FRACTION

Abstract Background It is known that sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to confer important clinical benefits in patients with congestive heart failure (HF). Several evidences show SGLT2 influence the longitudinal systolic function of the left ventricle after medium and long term follow–up (FUP) in patients with HF. The aim of this study is to demonstrate how dapagliflozin can modify the global longitudinal strain (GLS) in a population of patients with systolic congestive heart failure (HFrEF) evaluating possible correlations with the basal functional capacity. Methods Clinical and echocardiographic data were retrospectively analyzed in 60 HFrEF patients treated with dapagliflozin, within a dedicated outpatient HF clinic. Pre–treatment data were correlated with to clinical and instrumental FUP date that was generally performed after two months of treatment. The clinical and instrumental data consisted of the NYHA functional class, the left ventricular ejection fraction (LVEF) and the GLS. Results There was no significant change between baseline and FUP date on LVEF (25.2 ± 9.9% vs 25.6 ± 9.6% p.s.), while GLS showed significant improvement (13.1 ± 3.7% vs 14.3 ± 3.1% p &amp;lt; 0.03). GLS improvement in HFrEF patients with more impaired functional class (NYHA III/IV) was more significant from 10.9 ± 3.4% to 13.1 ± 2.2% (p &amp;lt; 0.01), compared to that in HFeEF patients with less compromised functional class (NYHA I–II) from 13.6 ± 2.4% to 14.1 ± 2.1% (p 0.07). Conclusions Dapagliflozin was associated with short term improvement in longitudinal left ventricular myocardial function in patients with chronic congestive systolic heart failure. This improvement is more evident in patients who start from a more impaired functional capacity than in clinically more stable patients.

ITK inhibition improves the response to immune checkpoint blockade in solid tumors

Abstract Cytotoxic CD8+ T cell (CTL) exhaustion is driven by persistent T cell receptor (TCR) stimulation in chronic infections and tumors. The exhausted state of T cells is characterized by impaired effector function and proliferative capacity, upregulation of multiple inhibitory receptors and altered transcriptional profiles. The phenotypic and epigenetic changes of these cells hinder effective antitumor immunity and immunotherapy. Therefore, reinvigorating exhausted T cells may provide significant clinical benefits to patients with cancer. Our approach is to reduce chronic TCR stimulation by inhibiting IL2-inducible T-cell kinase (ITK), a pivotal component of TCR signaling. In our study, we found that intermittent ITK inhibitor treatment significantly improved ICB response in three immune checkpoint blockade (ICB) -resistant solid tumors (melanoma, mesothelioma or pancreatic cancer) in vivo. In vitro, we demonstrated that specific ITK inhibitor and ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK) and ITK, directly reversed the exhaustion-related phenotypes in exhausted CTLs. The changes included enhanced cytokine production, decreased inhibitory receptor expression and changes in transcription factors. Subsequently, RNA-seq data revealed that exhaustion-related transcriptional profile of in vitro CTLs is reduced by ibrutinib treatment. Ibrutinib mediated reversal of CTL exhaustion was BTK independent. To conclude, our study demonstrates that ITK inhibition can be used to directly ameliorate CTLs exhaustion and overcomes immune checkpoint blockade resistance in solid tumors. This work was supported by the department of Immunology, KWF Grant 128371 (PDK), in part from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779295 (PDK), and by the China Scholarship Council for funding PhD fellowships (No. 201506160120 for MZ and 201906210055 for LL).

Impaired pathogen-specific CD4 +T cell functionality in patients with CLL

Abstract Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and remains an incurable disease. Many patients with CLL are affected by non-malignant complications, including infectious diseases, as witnessed during the past years, with very high COVID-19 mortality rates. Accumulating data indicate that T cells might become exhausted in patients with CLL, which might be a contributing factor to poor control of pathogenic infections. Here we developed flow cytometry protocols to combine activation-induced molecule (AIM) assessment and functional read-outs to understand if bacteria- and virus-specific CD4 +T cell responses are impaired in patients with CLL. PBMCs were collected from indolent CLL patients (n=23) and age and gender-matched blood donors (n=17) to assess CD4 +T cell dysfunction against pathogenic bacteria (S. Pneumonia, H. Influenzae, M. Catarrhalis, K. Pneumoniae) and viruses (CMV, EBV, IAV). We show that the frequency of CD4 +T cell responses against most assessed bacterial species was of lower frequencies in CLL patients compared to matched control groups. Both bacteria- and virus-specific CD4 +T cells experienced, in general, signs of functional exhaustion, including diminished capacity to produce IFN-γ, TNF, IL-2, IL-17, and/or IL-21, during indolent CLL. Functional exhaustion was not coupled to increased expression of inhibitory receptors but instead reduced stem-like phenotypes of CD4 +T cells. These data indicate that untreated CLL is coupled to impaired functional capacity of bacteria and virus-specific CD4 +T cells, which might lead to poor pathogen control. Swedish Cancer Foundation(Cancerfonden)