Six minute walk test in Italian children with cystic fibrosis aged 6 and 11

Six Minute Walk Test (6MWT) is a field exercise test widely used in clinical practice, both in adults and in pediatric patients. The primary aim of the study is to evaluate the physical performance of the subjects and compare them with the predicted Italian values. The secondary aim is to verify the possible relationship between the 6MWT distance (6MWD) and the clinical variables of the sample. Italian children between 6-11 years affected by CF were recruited from 9 regional centres for CF. Short questionnaire assessments about their health state and physical activity routine was administered. Anthropometric characteristics were measured before the test and, peripheral oxygen saturation (SpO2), heart and respiratory rate were measured before and after a 6-minute walk test. The tests were performed according to the American Thoracic Society (ATS) guidelines. 6MWD was compared with the predicted distance calculated by the reference equation for healthy subjects of the same age.A total of 132 children were recruited (70 male) and completed the assessment. The mean (±SD) for 6MWD was 557.4(±69.9), male = 551.4(±80.0), female = 560.4(±63.3), however the predicted distance mean was 605m. A total of 101(76.5%) subjects practice regular physical activity. A total of 31(23%) had a FEV1 lower than their Lower Limits of Normal (LLN). Functional performance on the 6MWT was poorer among the CF patients than among the predicted distance estimated with Italian values. The correlation with the amount of physical activity and 6MWD has been verified.

The Efficacy of a Commercial Physical Activity Monitor in Longitudinal Tracking of Pulmonary Hypertension Patients

Patients with pulmonary arterial hypertension (PAH) have quality of life (QoL) limitations, decreased exercise capacity, and poor prognosis if left untreated. Standard exercise testing is routinely performed for the evaluation of patients with PAH but may be limited in its ability to monitor activity levels in daily living. We evaluated the validity of the commercial Fitbit Charge HR as a tool to assess real time exercise capacity as compared to standard exercise testing in patients with PAH. Ambulatory pediatric and adult PAH patients were enrolled and given a Fitbit with instructions to continuously wear during waking hours. Subjects underwent a 6-minute walk test (6MWT), cardiopulmonary exercise test (CPET) and an SF-36 QoL survey on the day of enrollment and follow-up. Twenty-seven ambulatory subjects with PH were enrolled and 21 had sufficient data for analyses (median age 25, range 13-59, 14 F) were enrolled. Daily steps measured by the Fitbit had a positive correlation with 6MWT distance (r = 0.72, p = 0.03) and an inverse correlation with WHO functional class. On the QoL survey, 77% reported improvement in energy/fatigue (p = 0.055). At follow up there was a strong correlation between Fitbit steps and role limitations due to physical problems (r = 0.88, p = 0.020) and weaker correlations with less related QoL markers. These findings suggest activity monitors may have potential as a simple/novel method of assessing longitudinal exercise capacity and activity levels in PAH patients. Further study in larger cohorts of patients is warranted to determine the best accelerometric correlates with outcomes.

Birtamimab in Patients with Mayo Stage IV AL Amyloidosis: Rationale for Confirmatory Affirm-AL Phase 3 Study Design

Background: Light chain (AL) amyloidosis is a rare, progressive, and typically fatal hematologic disorder caused by plasma cells that produce misfolded AL protein, resulting in deposits of amyloid in tissues and organs that cause organ dysfunction and failure. Birtamimab is an investigational monoclonal antibody designed to neutralize circulating soluble amyloid and deposited insoluble amyloid, thus promoting the phagocytic clearance of amyloid deposits. In 2018, the global phase 3 VITAL study in newly diagnosed, treatment-naïve patients was terminated based on a futility analysis of the composite primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization >90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835, 95% CI 0.5799, 1.2011; p=0.330). Post hoc analysis of ACM over 9 months revealed a pronounced survival benefit (HR=0.413, 95% CI 0.191, 0.895; p=0.025; Figure) in a subgroup of patients at high risk for early mortality (Mayo stage IV). At 9 months, the proportions of surviving patients were 74% and 49% in the birtamimab + SOC and placebo + SOC groups, respectively. Post hoc analyses of secondary endpoints in this subgroup also supported clinical and functional benefits of birtamimab + SOC, with clinically meaningful improvements observed in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance (both nominal p<0.05) at 9 months. Across all birtamimab clinical trials, no drug-related deaths, dose-limiting toxicities, or major risks were identified. Aims: To evaluate the efficacy and safety of birtamimab + SOC versus placebo + SOC in Mayo stage IV patients with AL amyloidosis by assessing time to ACM over 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study will enroll up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will receive either 24 mg/kg intravenous birtamimab or placebo every 28 days (both arms will also receive SOC, defined as concomitant chemotherapy with a first-line bortezomib-containing regimen). Patients will be randomly assigned 2:1 to birtamimab or placebo and will be stratified at randomization based on their 6MWT distance (<300 meters vs ≥300 meters). The primary efficacy endpoint of AFFIRM-AL is time to ACM using a log-rank test. Secondary endpoints are change from baseline to month 9 in SF-36v2 and 6MWT distance. Safety endpoints include adverse events, clinical laboratory observations, and immunogenicity analyses. An interim efficacy analysis is planned when ~50% of the events have occurred. Results: Given the >50% relative risk reduction for ACM observed in the post hoc analysis of VITAL for the AL amyloidosis subpopulation of patients with Mayo stage IV disease, the phase 3 AFFIRM-AL study is designed to confirm this effect of birtamimab under a Special Protocol Assessment agreement with the US FDA. Conclusion/Summary: Effective treatments to improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo stage IV disease is approximately 6-9 months. Birtamimab is the only investigational therapeutic in which a survival benefit has been observed, in a post hoc subgroup analysis of VITAL in patients with AL amyloidosis with advanced cardiac involvement. AFFIRM-AL is expected to initiate in mid-2021. (NCT04973137) Figure 1 Figure 1. Disclosures Gertz: Alnylam, Amgen, Annexon, Appellis, Celgene, Ionis/Akcea, Janssen, Medscape, Physicians Education Resource, Prothena, Research to Practice: Other: personal fees; Spectrum: Other: personal fees, Research Funding; AbbVie: Other: personal fees for Data Safety Monitoring board; Teva, Johnson and Johnson, Medscape, DAVA oncology: Other: speaker fees; Pharmacyclics, Proclara: Other: Advisory Board; i3Health: Other: development of educational materials; Springer Publishing: Patents & Royalties. Tripuraneni: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001). Kinney: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001).

Results of the Diaphragmatic Plication Database: 10 Years' Experience

Background Unilateral diaphragmatic paralysis or paresis (UDP) in adults is an often overlooked disease which relevantly impairs the patient's lung function and quality of life. Particularly in idiopathic UDP, there is no evidence for conservative therapy and only little evidence for surgical therapy. Methods The method involves retrospective single-center analysis of patients with UDP persistent for at least 1 year who were operated by diaphragmatic resection, plication, and augmentation with a polypropylene mesh. The patients were tested for lung and diaphragmatic function, six-minute walk test (6MWT), and blood gas analysis before, 3 and 12 months after surgery. Results In total, 85 patients received surgery for UDP. The most frequent reasons for UDP were idiopathic (67%), iatrogenic (mainly cardiac and cervical spine surgery; 24%), and trauma (9%). The mean operation time was 84 ± 24 minutes, the length of hospital stay 8.4 ± 3.9 days, chest tubes were removed after 11.7 ± 4.1 days. Overall morbidity was 42%, mortality 0%. Forced expiratory volume in one second (FEV1) in supine position improved by 12.4% absolute, vital capacity by 11.8% absolute, and sniff nasal inspiratory pressure by 1.4 kPa 12 months after surgery (p <0.001 each). Total lung capacity increased by 6.8% absolute at 12 months (p = 0.001) The 6MWT distance improved by 45.9 m at 3 months and 50.9 m at 12 months (p = 0.001, each). Conclusion Surgical therapy for UDP is highly effective in the long term. The superiority over conservative treatments needs to be evaluated prospectively with standardized physiotherapeutic protocols. FEV1 in supine position and 6MWT are easy to perform tests and represent statistically and patient-relevant outcomes.

Acute effect of oxygen therapy on exercise tolerance and dyspnea perception in ILD patients

Ambulatory oxygen therapy (AOT) is commonly prescribed in Interstitial Lung Disease (ILD) patients, with the aim of reducing dyspnea and increasing exercise tolerance. Despite its frequent use and a reasonable physiological rationale, there is a lack of evidence supporting the effect of AOT on improving dyspnea during exercise. Moreover, dyspnea encompasses distinct sensory (intensity, quality) and affective (anxiety, fear) components with different underlying neurophysiological mechanisms. The aim of this study was to evaluate the effect of oxygen supplementation on exercise tolerance and dyspnea in ILD patients with exercise induced hypoxia (EIH). Forty-seven ILD patients performed a six minute walk test (6MWT) on room air (RA) and with oxygen supplementation (Ox). The 6MWT distance (6MWD) was significantly greater with oxygen supplementation (RA: 242±143 m vs Ox: 345±106 m p<0,01). With oxygen supplementation, the overall dyspnea and anxiety significantly decreased both at rest (1,1±1,4 Borg Unit (BU) vs 0,4±0,9BU , p.<0.01, and 1,1±1,6BU vs 0,5±1,3 BU, p.<0.05, respectively) and at the end of exercise (5,1±2,6 BU vs 3,7±2,5 BU, p.<0.001 and 3,4 ±2,9 vs 2,5 ±2,8, p.<0.01, respectively) despite a greater walked distance. In ILD patients with EIH, oxygen supplementation increases the exercise tolerance and reduces overall dyspnea perception and the anxiety component of breathlessness.

Improving risk stratifcation of pulmonary hypertension patients

Background According to the 2016 ESC/ERS Guidelines on Pulmonary Hypertension (PH), the right atrial area (RAA) and the presence ofa pericardial effusion (PE) are the two main echocardiographic prognostic markers in PH patients (pts). Aim To assess the predictive ability of these two parameters. Methods Pts with PH were prospectively studied and several clinical/demographic/echocardiographic were retrieved as well as data from six-minute walk test (6MWT) and brain natriuretic peptide (BNP). All-cause mortality was analyzed by PE, RAA and other echocardiographic parameters for positive (PPV) and negative predictive value (NPV) to detect if the current guideline recommended cut-offs can precisely stratify risk in this setting. A survival analysis was performed to evaluate risk stratification (RS) provided by several different cut-offs. Results A total of 51 PH pts (mean age 54±46 years, 33.3% male, baseline BNP of 342.4±439.9pg/mL, mean 6MWT distance of 360.3±109.2 meters and baseline pulmonary artery systolic pressure of 78±26mmHg), of which 64.7% had Group I PH (GI) and 35.3% presented chronic thromboembolic pulmonary hypertension. There were no significant differences between these two groups, however pts in GI were significantly younger (p=0.001), achieved a lower 6MWT distance (p=0.038) and had worse values of right ventricular strain (p=0.040). 27 pts (52.9%) died during a mean follow-up of 52 months, with no differences between groups (p=0.756). The presence of a PE had a low NPV and PPV for the primary endpoint (45.0% and 45.5%, respectively), as well as the guideline recommended cut-offs for RAA (18cm2: NPV- 50.0% and PPV– 55.2%; 26cm2: NPV- 51.3% and PPV– 66.7%). A Pulsed Doppler Tei index (TIp) cut-off of 0.40 had a higher NPV (70.8%) and PPV (74.1%). By Kaplan-Meieran alysis, neither the presence of PE (log rank p=0.508) nor the recommended RAA cut-offs provided accurate risk discrimination (log rank p&gt;0.05 for all). Pts below a TIp cut-off of 0.40 presented a significantly lower survival during follow-up (log rank p=0.002) Conclusion The currently recommended echocardiographic prognostic markers cannot precisely discriminate risk in PH pts. Markers of Right Ventricular Dysfunction may improve RS in this population. FUNDunding Acknowledgement Type of funding sources: None.

Improvement of exercise tests and reduction of heart failure biomarkers in short term follow up after comprehensive rehabilitation program of patients with implanted LVAD

Background There is increasing recognition of the importance of rehabilitating patients after LVAD implantation. The novel method of comprehensive rehabilitation starting directly after LVAD implantation was designed for our LVAD patients population. Aim of the study The study aimed to determine, if novel rehabilitation program improves functional and biochemical parameters in patients after recent LVAD implantation. Study group 37 recent LVAD (22 Heart Mate III, 15 HeartWare) recipients (19–67, mean 58.7 years, 35 men) participated in specially designed rehabilitation program. The program included 4–5 weeks of sationary rehabilitation: supervised endurance training on cycloergometer (5 times per week), resistance training, general fitness exercises with elements of equivalent and coordination exercises (every day). It was followed by individual exercises performed at home. At the beginning and at the end of rehabilitation program the patients performed 6 minute walking test (6MWT), cardiopulmonary exercise test (CPET). Following prognostic biomarkers of heart failure: NT-proBNP, galectin-3 and ST2 were also measured. Results See table 1. Increase of 6MWT distance, higher maximal workload, peak VO2 and upward shift of anaerobic threshold in CPET were observed in all patients. Significant reductions of NTproBNP, ST2 and galectin-3 levels were observed. There were no major adverse events during rehabilitation. Conclusions Comprehensive novel rehabilitation in LVAD recipients is safe and results in significant improvement of functional tests and biomarkers of heart failure. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Center for Research and Development: National grant - STRATEGMED II,

Impaired health status is independently associated with persistently elevated NT-proBNP levels despite medical therapy for heart failure with reduced ejection fraction

Background Impaired health status as measured by standardized tools such as Kansas City Cardiomyopathy Questionnaire (KCCQ), Duke Activity Status Index (DASI) and six-minute walk test (6MWT) has been shown to predict hospitalization and mortality in patients with chronic heart failure. However, prognostic implications of these measurements in response to guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF) remained to be elucidated. Purpose We hypothesized that impaired health status were predictive of persistently elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) after 6 and 12 months of therapeutic optimization in HFrEF. Methods Data on the GUIDE-IT trial that included protocolized HFrEF drug titration were analyzed. Patients who did not have NT-proBNP at 12 months were excluded. KCCQ overall and clinical summary scores, and DASI scores at baseline and 6 months were calculated. Six-minute walk test (6MWT) distance at baseline were also available. Response to medical therapy was defined as having NT-proBNP at 12 months of less than 1,000 pg/mL. Median value of each measurement was used as a cutoff. Multivariate logistic regression analysis was used to determine independent associations between different QOL scores and NT-proBNP response after adjustment for age, comorbidities, baseline EF, NYHA functional class, and NT-proBNP. Results There were 193 (43%) responders. Compared with those who responded to the medical therapy, non-responders were older, and more likely to have comorbidities including coronary artery disease, stroke, PAD, AF, hypertension, COPD, DM, CKD, and dyslipidemia, as well as lower EF, NHYA functional class and higher baseline NT-proBNP. After adjustment for baseline characteristics, lower KCCQ (either overall or summary) scores at baseline and 6 months, and lower DASI scores at 6 months (but not baseline) were independently associated with lower likelihood of response to GDMT (Table). In contrast, baseline 6MWT distance did not predict non-response to GDMT after adjustments. Conclusions Only impaired baseline KCCQ scores were predictive of persistently elevated NT-proBNP, while lower KCCQ and DASI scores at 6 month were predictive of persistently elevated NT-proBNP. FUNDunding Acknowledgement Type of funding sources: None. Health Status Score below Median and ORs

Detection of Walk Tests in Free-Living Activities Using a Wrist-Worn Device

Exercise testing to assess the response to physical rehabilitation or lifestyle interventions is administered in clinics thus at best can be repeated only few times a year. This study explores a novel approach to collecting information on functional performance through walk tests, e.g., a 6-min walk test (6MWT), unintentionally performed in free-living activities. Walk tests are detected in step data provided by a wrist-worn device. Only those events of minute-to-minute variation in walking cadence, which is equal or lower than the empirically determined maximal SD (e.g., 5-steps), are considered as walk test candidates. Out of detected walk tests within the non-overlapping sliding time interval (e.g., 1-week), the one with the largest number of steps is chosen as the most representative. This approach is studied on a cohort of 99 subjects, assigned to the groups of patients with cardiovascular disease (CVD) and healthy subjects below and over 40-years-old, who were asked to wear the device while maintaining their usual physical activity regimen. The total wear time was 8,864 subject-days after excluding the intervals of occasionally discontinued monitoring. About 82% (23/28) of patients with CVD and 88% (21/24) of healthy subjects over 40-years-old had at least a single 6MWT over the 1st month of monitoring. About 52% of patients with CVD (12/23) and 91% (19/21) of healthy subjects over 40-years-old exceeded 500 m. Patients with CVD, on average, walked 46 m shorter 6MWT distance (p = 0.04) compared to healthy subjects. Unintentional walk testing is feasible and could be valuable for repeated assessment of functional performance outside the clinical setting.

Adaptive Capacities and Complexity of Heart Rate Variability in Patients With Chronic Obstructive Pulmonary Disease Throughout Pulmonary Rehabilitation

IntroductionThe complexity of bio-signals, like R-R intervals, is considered a reflection of the organism’s capacity to adapt. However, this association still remains to be consolidated. We investigated whether the complexity of R-R intervals at rest and during perturbation [6-minute walking test (6MWT)], yielded information regarding adaptive capacities in Chronic Obstructive Pulmonary Disease (COPD) patients during pulmonary rehabilitation (PR).MethodsIn total, 23 COPD patients (64 ± 8 years, with forced expiratory volume in 1 s of 55 ± 19% predicted) were tested three times at the start (T1), middle (T2), and end (T3) of 4 weeks PR. Each time, R-R intervals were measured at rest and during 6MWT. The complexity of R-R intervals was assessed by evenly spaced Detrended Fluctuations Analysis and evaluated by the fractal exponent α and deviation from maximal complexity |1-α|.ResultsThe 6MWT distance was significantly increased at T2 and T3 compared to T1. Neither α nor |1-α| at rest and during perturbation significantly changed throughout PR, nor were they consistently associated with 6MWT distances at each time. Throughout the PR program, complexity during the 6MWT was significantly lower compared to the rest. The level of α during 6MWT at T1 was positively correlated with the improvement of the 6MWT distance throughout the PR program.DiscussionReduced complexity in COPD patients during acute perturbation at the beginning of PR supports a decreased improvement of the 6MWT distance throughout PR. This result seems consistent with the notion that the complexity reflects the patients’ adaptive capacities and could therefore become a clinical indicator in an applied perspective.