Breast cancer and cardiovascular health.

Modern cancer therapies greatly improve clinical outcomes for both early and advanced breast cancer patients. However, these advances have raised concerns about potential short- and long-term toxicities, including cardiovascular toxicities. Therefore, understanding the common risk factors and underlying pathophysiological mechanisms contributing to cardiovascular toxicity is essential to ensure best breast cancer outcomes. While cardio-oncology has emerged as a sub-speciality to address these challenges, it is essential that all cardiologists recognize and understand the cardiovascular consequences of cancer therapy. This review aims to provide a comprehensive overview of the potential adverse cardiovascular effects associated with modern breast cancer therapies. A preventive, diagnostic, and therapeutic workflow to minimize the impact of cardiovascular toxicity on patient outcomes is presented. Key aspects of this workflow include regular monitoring of cardiovascular function, early detection and management of cancer therapy-related cardiovascular toxicities, and optimization of cardiovascular risk factor control. By highlighting the gaps in knowledge in some areas, this review aims to emphasize the critical role of cardio-oncology research in ensuring the holistic well-being of patients with breast cancer.

Effects of exercise therapy on chemotherapy delivery and response in primary breast cancer: A secondary analysis of a randomized trial.

BACKGROUND: Whether structured exercise therapy improves chemotherapy delivery, tolerability, and tumor response is unclear. METHODS: This was a secondary analysis of a phase 2 trial investigating exercise therapy (n = 72) versus usual care (n = 72) in patients with primary breast cancer. Exercise therapy comprised individualized treadmill walking three times weekly for 20-50 minutes per session at 55%-100% of pretreatment exercise capacity. Chemotherapy delivery was assessed according to the relative dose intensity (RDI), tolerability was assessed according to patient-reported outcomes and blood laboratory values, and response was assessed based on the pathologic complete response rate in patients who received neoadjuvant chemotherapy. RESULTS: In the exercise therapy group, 51 patients (71%) reached 100% RDI (median, 100%; interquartile range, 100%-100%) compared with 41 patients (57%) in the usual care group (median, 100%; interquartile range, 95%-100%; p = .08). Tolerability was similar in both groups; the rates of grade 3 or higher neutropenia and anemia were 22% versus 39% and 7% versus 10% in the exercise and usual care groups, respectively. In patients who received anthracyclines (n = 104), 41 (77%) had 100% chemotherapy RDI in the exercise therapy group versus 29 (57%) in the usual care group (p = .026). In the neoadjuvant chemotherapy subgroup (n = 51 tumors), the postneoadjuvant therapy (yp) pathologic complete response (ypT0ypN0) rate was 27% (95% confidence interval, 12%-50%) in the exercise therapy group compared with 28% (95% confidence interval, 13%-47%) in the usual care group (p > .9). CONCLUSIONS: In patients with primary breast cancer, exercise therapy was associated with improved delivery of anthracycline-based chemotherapy. Although exercise therapy was not significantly associated with tumor response, effects varied by tumor subtype (trial registration: Clinicaltrials.gov identifier NCT01943695).

Cancer Therapy and Exercise Intolerance: The Heart Is But a Part: JACC: CardioOncology State-of-the-Art Review.

The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond the heart. The authors provide a framework using the oxygen pathway to understand the impact of cancer treatment on peak oxygen uptake, a marker of integrative cardiopulmonary function and CVD risk. Peripheral toxicities and the impact on oxygen transport are discussed. Consideration for the broad effects of cancer therapies will improve the prediction and identification of cancer survivors at risk for CVD, functional disability, and premature mortality and those who would benefit from therapeutic intervention, ultimately improving patient outcomes.

Machine Learning-Driven Phenogrouping and Cardiorespiratory Fitness Response in Metastatic Breast Cancer.

PURPOSE: The magnitude of cardiorespiratory fitness (CRF) impairment during anticancer treatment and CRF response to aerobic exercise training (AT) are highly variable. The aim of this ancillary analysis was to leverage machine learning approaches to identify patients at high risk of impaired CRF and poor CRF response to AT. METHODS: We evaluated heterogeneity in CRF among 64 women with metastatic breast cancer randomly assigned to 12 weeks of highly structured AT (n = 33) or control (n = 31). Unsupervised hierarchical cluster analyses were used to identify representative variables from multidimensional prerandomization (baseline) data, and to categorize patients into mutually exclusive subgroups (ie, phenogroups). Logistic and linear regression evaluated the association between phenogroups and impaired CRF (ie, ≤16 mL O2·kg-1·min-1) and CRF response. RESULTS: Baseline CRF ranged from 10.2 to 38.8 mL O2·kg-1·min-1; CRF response ranged from -15.7 to 4.1 mL O2·kg-1·min-1. Of the n = 120 candidate baseline variables, n = 32 representative variables were identified. Patients were categorized into two phenogroups. Compared with phenogroup 1 (n = 27), phenogroup 2 (n = 37) contained a higher number of patients with none or >three lines of previous anticancer therapy for metastatic disease and had lower resting left ventricular systolic and diastolic function, cardiac output reserve, hematocrit, lymphocyte count, patient-reported outcomes, and CRF (P < .05) at baseline. Among patients allocated to AT (phenogroup 1, n = 12; 44%; phenogroup 2, n = 21; 57%), CRF response (-1.94 ± 3.80 mL O2·kg-1·min-1 v 0.70 ± 2.22 mL O2·kg-1·min-1) was blunted in phenogroup 2 compared with phenogroup 1. CONCLUSION: Phenotypic clustering identified two subgroups with unique baseline characteristics and CRF outcomes. The identification of CRF phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions among patients with cancer.

Exercise and nutrition to improve cancer Treatment-Related outcomes (ENICTO).

Chemotherapy treatment-related side-effects are common and increase the risk of suboptimal outcomes. Exercise interventions during cancer treatment improve self-reported physical functioning, fatigue, anxiety, and depression, but it is unclear whether these interventions improve important clinical outcomes, such as chemotherapy relative dose intensity (RDI). The National Cancer Institute funded the Exercise and Nutrition to Improve Cancer Treatment-Related Outcomes (ENICTO) Consortium, to address this knowledge gap. This paper describes the mechanisms hypothesized to underpin intervention effects on clinically-relevant treatment outcomes, briefly outlines each project's distinct research aims, summarizes the scope and organizational structure of ENICTO, and provides an overview of the integrated common data elements used to pursue research questions collectively. In addition, the paper includes a description of consortium-wide activities and broader research community opportunities for collaborative research. Findings from the ENICTO Consortium have the potential to accelerate a paradigm shift in oncology care such that cancer patients could receive exercise and nutrition programming as the standard of care in tandem with chemotherapy to improve RDI for a curative outcome.

Radiodensities of Skeletal Muscle and Visceral Adipose Tissues Are Prognostic Factors in Clear-Cell Renal Cell Carcinoma.

BACKGROUND: Body composition may be related to survival in patients with clear-cell renal cell carcinoma (ccRCC), but studies have not simultaneously considered adipose and muscle tissue quantity and radiodensity. METHODS: We analyzed data from 1,022 patients with ccRCC who underwent nephrectomy between 2000 and 2020 at Memorial Sloan Kettering Cancer Center. Skeletal muscle, visceral adipose tissue, and subcutaneous adipose tissue indexes (cm2/m2) and radiodensities [Hounsfield units (HU)] were assessed from noncontrast presurgical CT scans; clinical and demographic characteristics were available from the time of surgery. HRs and confidence intervals were estimated for overall (OS) and disease-free survival (DFS) through March 2023 in multivariable models that simultaneously accounted for all body composition measures. RESULTS: The median age of the patients was 58 years, 69% were male, and 90% were White. There were 169 OS events over 8,392 person-years and 253 DFS events over 7,753 person-years of follow-up. In adjusted analyses, poor OS was associated with lower skeletal muscle radiodensity [-10 HU, HR (95% confidence interval), 1.37 (1.05-1.77)] and greater visceral adipose tissue radiodensity [+10 HU, 1.66 (1.06-2.59)], with similar findings for DFS. Poor survival was also associated with greater visceral adipose tissue index [+40 cm2/m2, OS: 1.32 (0.97, 1.79); DFS: 1.33 (1.04, 1.71)]. Associations with skeletal muscle radiodensity were limited to patients with stage 1/2 disease. CONCLUSIONS: Radiodensities of skeletal muscle and visceral adipose tissues may be novel presurgical prognostic factors for patients with ccRCC. IMPACT: The findings underscore the importance of evaluating the full range of body composition features simultaneously in multivariable models.

Exercise Training Attenuates the Muscle Mitochondria Genomic Response to Bed Rest.

PURPOSE: Exercise training during the National Aeronautics and Space Administration 70-d bed rest study effectively counteracted the decline in aerobic capacity, muscle mass, strength, and endurance. We aimed to characterize the genomic response of the participants' vastus lateralis on day 64 of bed rest with and without exercise countermeasures. METHODS: Twenty-two healthy young males were randomized into three groups: 1) bed rest only ( n = 7), 2) bed rest + aerobic (6 d·wk -1 ) and resistance training (3 d·wk -1 ) on standard equipment ( n = 7), and 3) bed rest + aerobic and resistance training using a flywheel device ( n = 8). The vastus lateralis gene and microRNA microarrays were analyzed using GeneSpring GX 14.9.1 (Agilent Technologies, Palo Alto, CA). RESULTS: Bed rest significantly altered the expression of 2113 annotated genes in at least one out of the three study groups (fold change (FC) > 1.2; P < 0.05). Interaction analysis revealed that exercise attenuated the bed rest effect of 511 annotated genes (FC = 1.2, P < 0.05). In the bed rest only group, a predominant downregulation of genes was observed, whereas in the two exercise groups, there was a notable attenuation or reversal of this effect, with no significant differences between the two exercise modalities. Enrichment analysis identified functional categories and gene pathways, many of them related to the mitochondria. In addition, bed rest significantly altered the expression of 35 microRNAs (FC > 1.2, P < 0.05) with no difference between the three groups. Twelve are known to regulate some of the mitochondrial-related genes that were altered following bed rest. CONCLUSIONS: Mitochondrial gene expression was a significant component of the molecular response to long-term bed rest. Although exercise attenuated the FC in the downregulation of many genes, it did not completely counteract all the molecular consequences.

Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

PURPOSE: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. METHODS: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. RESULTS: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. CONCLUSIONS: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

Incorporating Exercise Training into Cardio-Oncology Care: Current Evidence and Opportunities: JACC: CardioOncology State-of-the-Art Review.

Cancer treatment-induced cardiotoxicities are an ongoing concern throughout the cancer care continuum from treatment initiation to survivorship. Several "standard-of-care" primary, secondary, and tertiary prevention strategies are available to prevent the development or further progression of cancer treatment-induced cardiotoxicities and their risk factors. Despite exercise's established benefits on the cardiovascular system, it has not been widely adopted as a nonpharmacologic cardioprotective strategy within cardio-oncology care. In this state-of-the-art review, the authors discuss cancer treatment-induced cardiotoxicities, review the existing evidence supporting the role of exercise in preventing and managing these sequelae in at-risk and affected individuals living after cancer diagnoses, and propose considerations for implementing exercise-based services in cardio-oncology practice.

Effects of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity.

OBJECTIVE: Animal data suggest that exercise during chemotherapy is cardioprotective, but clinical evidence to support this is limited. This study evaluated the effect of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity. METHODS: This is a follow-up study of two previously performed randomised trials in patients with breast cancer allocated to exercise during chemotherapy or non-exercise controls. Cardiac imaging parameters, including T1 mapping (native T1, extracellular volume fraction (ECV)), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), cardiorespiratory fitness, and physical activity levels, were acquired 8.5 years post-treatment. RESULTS: In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years), of whom 99% and 18% were treated with anthracyclines and trastuzumab, respectively. ECV and Native T1 were 25.3%±2.5% and 1026±51 ms in the control group, and 24.6%±2.8% and 1007±44 ms in the exercise group, respectively. LVEF was borderline normal in both groups, with an LVEF<50% prevalence of 22.5% (n=40/178) in all participants. Compared with control, native T1 was statistically significantly lower in the exercise group (ß=-20.16, 95% CI -35.35 to -4.97). We found no effect of exercise on ECV (ß=-0.69, 95% CI -1.62 to 0.25), LVEF (ß=-1.36, 95% CI -3.45 to 0.73) or GLS (ß=0.31, 95% CI -0.76 to 1.37). Higher self-reported physical activity levels during chemotherapy were significantly associated with better native T1 and ECV. CONCLUSIONS: In long-term breast cancer survivors, exercise and being more physically active during chemotherapy were associated with better structural but not functional cardiac parameters. The high prevalence of cardiac dysfunction calls for additional research on cardioprotective measures, including alternative exercise regimens. TRIAL REGISTRATION NUMBER: NTR7247.

Pan-Cancer Analysis of Postdiagnosis Exercise and Mortality.

PURPOSE: The impact of postdiagnosis exercise on cause-specific mortality in cancer survivors and whether this differs on the basis of cancer site is unclear. METHODS: We performed an analysis of 11,480 patients with cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. Patients with a confirmed diagnosis of cancer completing a standardized survey quantifying exercise after diagnosis were included. The primary outcome was all-cause mortality (ACM); secondary end points were cancer mortality and mortality from other causes. Cox models were used to estimate the cause-specific hazard ratios (HRs) for ACM, cancer, and noncancer mortality as a function of meeting exercise guidelines versus not meeting guidelines with adjustment for important clinical covariates. RESULTS: After a median follow-up of 16 years from diagnosis, 4,665 deaths were documented (1,940 due to cancer and 2,725 due to other causes). In multivariable analyses, exercise consistent with guidelines was associated with a 25% reduced risk of ACM compared with nonexercise (HR, 0.75; 95% CI, 0.70 to 0.80). Compared with nonexercise, exercise consistent with guidelines was associated with a significant reduction in cancer mortality (HR, 0.79; 95% CI, 0.72 to 0.88) and mortality from other causes (HR, 0.72; 95% CI, 0.66 to 0.78). The inverse relationship between exercise and cause-specific mortality varied by exercise dose. Exercise consistent with guidelines was associated with a reduced hazard of ACM for multiple cancer sites. Reduction in cancer mortality for exercisers was only observed in head and neck and renal cancer. CONCLUSION: In this pan-cancer sample of long-term cancer survivors, exercise consistent with guidelines was associated with substantial ACM benefit driven by both reductions in cancer and noncancer mortality. The cause-specific impact of exercise differed as a function of cancer site.

Effects of exercise countermeasures on multisystem function in long duration spaceflight astronauts.

Exercise training is a key countermeasure used to offset spaceflight-induced multisystem deconditioning. Here, we evaluated the effects of exercise countermeasures on multisystem function in a large cohort (N = 46) of astronauts on long-duration spaceflight missions. We found that during 178 ± 48 d of spaceflight, ~600 min/wk of aerobic and resistance exercise did not fully protect against multisystem deconditioning. However, substantial inter-individual heterogeneity in multisystem response was apparent with changes from pre to postflight ranging from -30% to +5%. We estimated that up to 17% of astronauts would experience performance-limiting deconditioning if current exercise countermeasures were used on future spaceflight missions. These findings support the need for refinement of current countermeasures, adjunct interventions, or enhanced requirements for preflight physiologic and functional capacity for the protection of astronaut health and performance during exploration missions to the moon and beyond.

Timing of exercise therapy when initiating adjuvant chemotherapy for breast cancer: a randomized trial.

AIMS: The most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer. METHODS AND RESULTS: Using a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens-concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20-50 min at 55%-100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, -0.88 mL O2·kg-1·min-1; 95% confidence interval (CI): -3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg-1·min-1, P < 0.001). CONCLUSION: There was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

Exercise Associated with Cognitive Function in Older Men with Prostate Cancer Undergoing Androgen Deprivation Therapy.

BACKGROUND: To examine associations between exercise and cognitive function in older men undergoing hormone therapy for prostate cancer. METHOD: Men ≥ 65 years old with prostate cancer, currently undergoing androgen deprivation therapy for ≥ 6 months (n = 50), completed the Godin-Shephard Leisure-Time Physical Activity Questionnaire, and standard neuropsychological tests. Pearson's correlations and linear regressions were used to examine associations between exercise and cognitive performance. RESULTS: Exercise was significantly positively correlated with performance on tests of memory, attention, and executive function. Linear regressions showed that when controlling for age and education, exercise remained a significant predictor of attention and executive function performance (p < 0.05), and showed moderate, but statistically non-significant effects on memory performance (p < 0.10). CONCLUSION: Greater exercise is associated with better functioning in multiple cognitive domains in men with prostate cancer undergoing hormone therapy, providing proof-of-concept evidence that exercise may be a feasible intervention to limit cognitive dysfunction in prostate cancer patients.

Validity of Estimated Cardiorespiratory Fitness in Patients With Primary Breast Cancer.

Background: Estimated peak oxygen consumption (Vo2peak) is widely used in oncology; however, estimated Vo2peak equations were developed in noncancer settings. Objectives: The aim of this study was to evaluate the validity of estimated Vo2peak in women with primary breast cancer and to develop oncology-specific estimated Vo2peak equations. Methods: Vo2peak was directly measured (TrueOne 2400, Parvo Medics) during 380 cardiopulmonary exercise tests in women previously treated for breast cancer (mean age: 59 ± 10 years; 3.1 ± 1.2 years post-therapy). The American College of Sports Medicine (ACSM), the Fitness Registry and the Importance of Exercise National Database (FRIEND), and heart failure (HF)-FRIEND equations were used to estimate Vo2peak. New equations were developed using patient and peak (Oncpeak) or submaximal (Oncsub) exercise test characteristics. Results: The median differences between measured and estimated Vo2peak were 7.0 mL O2·kg-1·min-1, 3.9 mL O2·kg-1·min-1, and -0.2 mL O2·kg-1·min-1 for ACSM, FRIEND, and HF-FRIEND, respectively. The number of estimated Vo2peak values within ±3.5 mL O2·kg-1·min-1 of the measured values was 70 (18%), 164 (43%), and 306 (81%) for ACSM, FRIEND, and HF-FRIEND, respectively. The Oncpeak and OncSub models included body mass index, age, a history of chemotherapy or radiation, the peak measured heart rate, and the treadmill grade and/or speed. The median differences between measured and estimated Vo2peak were 0.02 mL O2·kg-1·min-1 (Oncpeak) and -0.2 mL O2·kg-1·min-1 (Oncsub). Eighty-six percent (n = 325) and 76% (n = 283) estimated Vo2peak values were within ±3.5 mL O2·kg-1·min-1 of the measured Vo2peak values for Oncpeak and Oncsub, respectively. Conclusions: HF-FRIEND or oncology-specific equations could be applied to estimate Vo2peak in patients previously treated for breast cancer in settings where cardiopulmonary exercise tests are not available. (Trial Comparing the Effects of Linear Versus Nonlinear Aerobic Training in Women With Operable Breast Cancer [EXCITE]; NCT01186367.

Impact of Exercise on Susceptibility and Severity of COVID-19 in Patients with Cancer: A Retrospective Study.

BACKGROUND: Modifiable lifestyle-related factors heighten the risk and severity of coronavirus disease 2019 (COVID-19) in patients with cancer. Whether exercise lowers susceptibility or severity is not known. METHODS: We identified 944 cancer patients from Memorial Sloan Kettering Cancer Center (mean age: 64; 85% female; 78% White) completing an exercise survey before receiving a confirmed positive or negative SARS-CoV-2 test. Exercise was defined as reporting moderate-intensity ≥5 days per week, ≥30 minutes/session or strenuous-intensity ≥3 days per week, ≥20 minutes/session. Multivariable logistic regression was used to determine the relationship between exercise and COVID-19 susceptibility and severity (i.e., composite of hospital admission or death events) with adjustment for clinical-epidemiologic covariates. RESULTS: Twenty-four percent (230/944) of the overall cohort were diagnosed with COVID-19 and 35% (333/944) were exercisers. During a median follow-up of 10 months, 26% (156/611) of nonexercising patients were diagnosed with COVID-19 compared with 22% (74/333) of exercising patients. The adjusted OR for risk of COVID-19 was 0.65 [95% confidence interval (CI), 0.44-0.96, P = 0.03] for exercisers compared with nonexercisers. A total of 20% (47/230) of COVID-19 positive patients were hospitalized or died. No difference in the risk of severe COVID-19 as a function of exercise status was observed (P > 0.9). CONCLUSIONS: Exercise may reduce the risk of COVID-19 infection in patients with a history of cancer, but not its severity. IMPACT: This study provides the first data showing that exercise might lower the risk of COVID-19 in cancer patients, but further research is required.

Leveraging Spaceflight to Advance Cardiovascular Research on Earth.

The direct (eg, radiation, microgravity) and indirect (eg, lifestyle perturbations) effects of spaceflight extend across multiple systems resulting in whole-organism cardiovascular deconditioning. For over 50 years, National Aeronautics and Space Administration has continually enhanced a countermeasures program designed to characterize and offset the adverse cardiovascular consequences of spaceflight. In this review, we provide a historical overview of research evaluating the effects of spaceflight on cardiovascular health in astronauts and outline mechanisms underpinning spaceflight-related cardiovascular alterations. We also discuss how spaceflight could be leveraged for aging, industry, and model systems such as human induced pluripotent stem cell-derived cardiomyocytes, organoid, and organ-on-a-chip technologies. Finally, we outline the increasing opportunities for scientists and clinicians to engage in cardiovascular research in space and on Earth.

Effects and tolerability of exercise therapy modality on cardiorespiratory fitness in lung cancer: a randomized controlled trial.

BACKGROUND: Poor cardiorespiratory fitness (CRF) is a cardinal feature of post-treatment primary lung cancer. The most effective exercise therapy regimen to improve CRF has not been determined. METHODS: In this parallel-group factorial randomized controlled trial, lung cancer survivors with poor CRF (below age-sex sedentary values) were randomly allocated to receive 48 consecutive supervised sessions thrice weekly of (i) aerobic training (AT)-cycle ergometry at 55% to >95% of peak oxygen consumption (VO2 peak); (ii) resistance training (RT)-lower and upper extremity exercises at 50-85% of maximal strength; (iii) combination training (CT)-AT plus RT; or (iv) stretching attention control (AC) for 16 weeks. The primary endpoint was change in CRF (VO2 peak, mL O2 ·kg-1 ·min-1 ). Secondary endpoints were body composition, muscle strength, patient-reported outcomes, tolerability (relative dose intensity of exercise), and safety. Analysis of covariance determined change in primary and secondary endpoints from baseline to post-intervention (Week 17) with adjustment for baseline values of the endpoint and other relevant clinical covariates. RESULTS: Ninety patients (65 ± 9 years; 66% female) were randomized (AT, n = 24; RT, n = 23; CT, n = 20; and AC, n = 23) of the planned n = 160. No serious adverse events were observed. For the overall cohort, the lost-to-follow-up rate was 10%. Mean attendance was ≥75% in all groups. In intention-to-treat analysis, VO2 peak increased 1.1 mL O2 ·kg-1 ·min-1 [95% confidence interval (CI): 0.0, 2.2, P = 0.04] and 1.4 mL O2 ·kg-1 ·min-1 (95% CI: 0.2, 2.5, P = 0.02) in AT and CT, respectively, compared with AC. There was no difference in VO2 peak change between RT and AC (-0.1 mL O2 ·kg-1 ·min-1 , 95% CI: -1.2, 1.0, P = 0.88). Favourable improvements in maximal strength and body composition were observed in RT and CT groups compared with AT and AC groups (Ps < 0.05). No between-group changes were observed for any patient-reported outcomes. Relative dose intensity of exercise was lower in RT and CT compared with AT (Ps < 0.05). CONCLUSIONS: In the context of a smaller than planned sample size, AT and CT significantly improved VO2 peak in lung cancer survivors; however, the tolerability-to-benefit ratio was superior for AT and hence may be the preferred modality to target impaired CRF in post-treatment lung cancer survivors.

Comparing the reporting and conduct quality of exercise and pharmacological randomised controlled trials: a systematic review.

OBJECTIVE: Evaluate the quality of exercise randomised controlled trial (RCT) reporting and conduct in clinical populations (ie, adults with or at risk of chronic conditions) and compare with matched pharmacological RCTs. DESIGN: Systematic review. DATA SOURCES: Embase (Elsevier), PubMed (NLM) and CINAHL (EBSCO). STUDY SELECTION: RCTs of exercise in clinical populations with matching pharmacological RCTs published in leading clinical, medical and specialist journals with impact factors ≥15. REVIEW METHODS: Overall RCT quality was evaluated by two independent reviewers using three research reporting guidelines (ie, Consolidated Standards of Reporting Trials (CONSORT; pharmacological RCTs)/CONSORT for non-pharmacological treatments; exercise RCTs), CONSORT-Harms, Template for Intervention Description and Replication) and two risk of bias assessment (research conduct) tools (ie, Cochrane Risk of Bias, Jadad Scale). We compared research reporting and conduct quality within exercise RCTs with matched pharmacological RCTs, and examined factors associated with quality in exercise and pharmacological RCTs, separately. FINDINGS: Forty-eight exercise RCTs (11 658 patients; median sample n=138) and 48 matched pharmacological RCTs were evaluated (18 501 patients; median sample n=160). RCTs were conducted primarily in cardiovascular medicine (43%) or oncology (31%). Overall quality score (composite of all research reporting and conduct quality scores; primary endpoint) for exercise RCTs was 58% (median score 46 of 80; IQR: 39-51) compared with 77% (53 of 68; IQR: 47-58) in the matched pharmacological RCTs (p≤0.001). Individual quality scores for trial reporting and conduct were lower in exercise RCTs compared with matched pharmacological RCTs (p≤0.03). Factors associated with higher overall quality scores for exercise RCTs were journal impact factor (≥25), sample size (≥152) and publication year (≥2013). CONCLUSIONS AND RELEVANCE: Research reporting and conduct quality within exercise RCTs is inferior to matched pharmacological RCTs. Suboptimal RCT reporting and conduct impact the fidelity, interpretation, and reproducibility of exercise trials and, ultimately, implementation of exercise in clinical populations. PROSPERO REGISTRATION NUMBER: CRD42018095033.

Teleguided self-ultrasound scanning for longitudinal monitoring of muscle mass during spaceflight.

Loss of muscle mass is a major concern for long duration spaceflight. However, due to the need for specialized equipment, muscle size has only been assessed before and after spaceflight where ~20% loss is observed. Here, we demonstrate the utility of teleguided self-ultrasound scanning (Tele-SUS) to accurately monitor leg muscle size in astronauts during spaceflight. Over an average of 168 ± 57 days of spaceflight, 74 Tele-SUS sessions were performed. There were no significant differences between panoramic ultrasound images obtained by astronauts seven days prior to landing and expert sonographer after flight or between change in muscle size assessed by ultrasound and magnetic resonance imaging. These findings extend the current capabilities of ultrasound imaging to allow self-monitoring of muscle size with remote guidance.