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INTRODUCTION | death, glucose tolerance, cancer, diabetes mellitus, biochemically-relapsed, non-cutaneous malignancy, metabolic syndrome, type II diabetes | CANCER, DIABETES MELLITUS, SECONDARY, INSULIN RESISTANCE, PROSTATE CANCER, METABOLIC SYNDROME, INCREASED INSULIN, TYPE II DIABETES | Background: Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation.Materials and Methods: To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT. Fasting serum glucose, insulin, PSA, metformin, weight and waist circumference (WC) were measured at baseline, week 12 and 28. The primary endpoint was a group of MS metrics. Secondary endpoints include PSA response, safety, serum metformin concentrations and analysis of downstream an mTOR target, phospho-S6-kinase.Results: 36 men were randomized to either metformin or placebo. Mean age was 68.4. Mean weight, WC and insulin levels increased in both arms. At week 12 and 28, no statistical differences in weight, WC or insulin were observed in either arm. No significant difference in percentage of patients with PSA <0.2 at week 28 between metformin (45.5%) vs. placebo (46.7%). Analysis in the metformin-arm showed variable down-regulation of phospho-S6 kinase.Conclusions: In our small study, metformin added to ADT did not show a reduced risk of ADT-related MS or differences in PSA response.Prostate cancer (PC) is the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer related death in U.S. men [ADT has been shown to be associated with increased fasting glucose levels, elevated serum insulin and insulin resistance, including the diagnosis of diabetes mellitus [Metformin is an oral anti-hyperglycemic drug used in the management of type II diabetes that improves overall glucose tolerance [AMPK is involved in energy homeostasis at both the cellular and macroscopic level. Metformin activates AMPK leading to inhibition of the mTOR pathway by phosphorylating TSC2 and Raptor. Phosphorylation of TSC2 and Raptor subsequently decreases phosphorylation of S6 Kinase 1 (S6K1) resulting in decreased protein and lipid synthesis [We hypothesized that control of increased insulin uptake by overcoming resistance may lead to improved control of metabolic syndrome in PC patients through metrics such as weight, waist circumference and serum insulin levels. We also hypothesized that metformin may enhance ADT’s anti-tumor effects either directly or indirectly through improved control of metabolic syndrome. To test these hypotheses, we conducted a phase II randomized, placebo-controlled, prospective study of metformin vs. placebo in patients with advanced, castrate sensitive PC treated with ADT (NCT:01620593). | PMC10278660 |
RESULTS | PMC10278660 | |||
Patients and treatments | Prostate Cancer | EXTENSIVE DISEASE, PROSTATE CANCER | Eligible patients who provided written informed consent were recruited at one center, University of Texas Health Science Center, San Antonio, United States between July of 2011 through July of 2015.During this period, three randomized phase III trials reported the clinical benefit of adding docetaxel to ADT: Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED); [Forty-one patients signed consent; five patients failed screening. Two of the patients who failed screening were lost to follow up, two patients did not meet inclusion criteria and one patient moved out of the region. Thirty-six patients were randomized from which 19 were allocated to empiric treatment with metformin, the remaining 17 patients were allocated to placebo. All 19 patients in the metformin arm and 17 patients in the placebo arms were included in analysis ( | PMC10278660 |
CONSORT diagram: identification, enrollment and randomization of patients. | DISEASE CHARACTERISTIC | The baseline demographic and disease characteristics, including mean BMI, were well balanced between the two groups ( | PMC10278660 | |
Metabolic syndrome | metabolic syndrome | METABOLIC SYNDROME | At baseline, markers of metabolic syndrome including mean weight, WC, serum Insulin concentration in the metformin cohort were 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in the placebo cohort. An increase in mean weight and serum insulin concentrations were seen across both cohorts ( | PMC10278660 |
Adverse events and serious adverse events | PMC10278660 | |||
HOMA-IR | INSULIN RESISTANCE | Homeostatic model assessment is a method for assessing beta-cell function and insulin resistance from basal (fasting) glucose and insulin concentrations [ | PMC10278660 | |
Mean HOMO-ir levels for metformin and placebo cohorts over time. | PMC10278660 | |||
PSA efficacy and pharmacodynamic analysis | The median baseline PSA for the placebo and metformin cohort was 31.95 (5.7–77.15) and 25 (6.2–58.7) respectively (Phospho-S6-kinase levels were analyzed from patient derived blood samples and although there were some downregulation in patients 7, 25, 34 and 37 who received metformin, overall variable regulation of protein levels on western blot in both metformin and placebo cohorts at all time points measured ( | PMC10278660 | ||
Variable changes in phosphorylation of S6 kinase 1 was observed in both cohorts. | ( | PMC10278660 | ||
DISCUSSION | metabolic syndrome, diabetes | NON-SMALL CELL LUNG CANCER, RECURRENCE, MULTIPLE CANCER, ADVERSE EVENT, INSULIN RESISTANCE, METABOLIC SYNDROME, DIABETES | The results presented are after empiric therapy with metformin compared to placebo to measure its effects on the development of metabolic syndrome in patients with PC on ADT. We caveat that all results in are study are underpowered due to changes in the standard of care as described in Results which limits the generalizability of any conclusions. However, although metformin reduces serum insulin and may have chemoprevention properties, in our small study we found no impact of the addition of metformin to ADT therapy on risk of metabolic syndrome associated with castration therapy and no additional anti-tumor effects.Multiple studies have demonstrated that markers of metabolic syndrome including weight, WC, BMI and fasting glucose increase shortly after receiving androgen deprivation therapy [We present a phase II prospective study which randomized patients receiving androgen deprivation therapy to receive metformin compared to placebo and the data (albeit limited by sample size due to explanation in Results) did not show a statistically significant difference in mean markers of metabolic syndrome. We noted a trend towards increase in all categories regardless of randomization to placebo or metformin groups. We expect that serum fasting insulin concentrations would rise in the setting of metabolic syndrome due to insulin resistance and therefore these insulin concentrations were monitored. There was an increase in serum insulin concentrations across both groups but without statistical significance. We investigated delta change in markers of metabolic syndrome and again did not demonstrate statistically significant difference.As was first described by Matthews et al., we investigated homeostatic modeling in our patient population to quantify insulin resistance and beta-cell function [Additionally, serum fasting insulin concentration means remained without significant change upon exclusion of patients with serum metformin concentration of 0. Metformin is excreted renally and does not undergo hepatic metabolism nor biliary excretion. Following oral administration, about 90% of metformin is excreted renally in 24 hours. Lack of proper absorption could lead to decreased concentration of metformin in the setting of reported compliance.The data in this analysis contrasts with previous studies. A randomized pilot study of ADT and metformin vs. ADT alone, 20 patients in each arm suggested significant improvements in abdominal girth, weight, body mass index and blood pressure was observed, although this study again did not detect changes in biomarkers of insulin resistance between cohorts [Larger studies have demonstrated the potential chemo-preventative effects of metformin on multiple cancers [Recent research has shown that metformin combined with chemotherapy drugs can significantly decrease local recurrence in patients with diabetes and non-small cell lung cancer [Despite evidence that metformin activates AMPK leading to inhibition of the mTOR pathway and decreases in phosphorylation of S6 Kinase 1 (pS6K1) [PSA was monitored at all intervals of patients in our study of both cohorts, metformin and placebo. Each patient received ADT and patients were started on metformin at the start of ADT. Approximately the same proportion of patients in both the metformin and placebo cohorts achieved PSA <0.02 by week 28. The difference between the two groups was marginal and statistically not significant (Adverse events overall were increased in the metformin cohort by comparison to placebo ( | PMC10278660 |
MATERIALS AND METHODS | PMC10278660 | |||
Trial Design and oversight | METASTATIC DISEASE | We present a randomized, prospective, double-blind, placebo-controlled phase II trial evaluating the efficacy of empiric glycemic control with metformin in castrated men with advanced PC (NCT:01620593). The trial was designed to enroll a total of 94 men with advanced metastatic PC and men with PC who were candidates for castration therapy despite no evidence of definite metastatic disease including patient with biochemical failure for up to a year. Patients were randomly assigned at a 1:1 ratio to receive either metformin (500 mg TID PO) or placebo.The randomization phase involved enrollment of patients who had undergone screening for eligibility criteria and had pathologically proven metastatic PC ( | PMC10278660 | |
Patients | Tumors, visceral disease, disability, diabetes | IMPAIRED GLUCOSE TOLERANCE, METASTATIC DISEASE, TUMORS, METASTATIC PROSTATE CANCER, DIABETES | Patients had histologically proven PC and an ECOG performance status of 0 to 2 (on a 5-point scale, with 0 indicating an absence of disability and higher numbers indicating greater disability). Patients required castration therapy with either an LHRH analogue (continuous) or surgical castration. Patient were permitted to use anti-androgen therapy prior to castration; with enrollment into study at the time of castration or within 30 days of castration. All patients were required to have baseline oral glucose tolerance test (OGTT) and patients with values of >200 mg/dL at 2 hours, suggesting a diagnosis of diabetes, were excluded from study and referred for treatment of diabetes. Patients with values between 140 mg/dL and 200 mg/dL indicating impaired glucose tolerance were permitted to enroll and advised dietary modification. Patients with normal values of less than 140 mg/dL were permitted to enroll.All patients with metastatic disease were documented through computed tomography (CT) or nuclear bone scan, according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Patients were excluded if they were being treated with any anti-hyperglycemic medications prior to study, had BUN, creatinine, bilirubin levels less than or equal to 1.3 times the upper limit of normal. Safety and dosing adherence were evaluated during each trial visit.Medical castration using gonadotropin-releasing hormone (GnRH) agonist for all subjects based on treating physician preference was done within 72 hours of an oral glucose tolerance test or baseline visit. Patients were randomly assigned in a 1:1 ratio to receive ADT with metformin (one 500 mg tablet TID) or color matched placebo (the placebo group). Patients were stratified according to the presence or absence of measurable visceral disease, PSA and ECOG performance status score (0 or 1 vs. 2). Metformin or placebo were allowed to be started within 72 hours of medical castration. Men who had previously started castration therapy for metastatic prostate cancer or biochemical flair were also permitted to enter study provided castration therapy was within 4–6 weeks of study entry.All patients who had not undergone surgical castration, received ongoing ADT to reach or maintain a serum testosterone level of less than 50 ng per deciliter (1.7 nmol per liter). | PMC10278660 |
Study end points | Cancer, hyperinsulinemia | CANCER, SECONDARY, INSULIN RESISTANCE, HYPERINSULINEMIA | The primary end point was a group of metrics that reflected the metabolic consequences of ADT including development of hyperinsulinemia and insulin resistance, comparing metformin to placebo in men receiving ADT. Subjects had normal oral glucose tolerance test at baseline. Measurements of metabolic consequences including weight, waist circumference, fasting serum glucose and fasting serum insulin levels were measured in intervals of 4 weeks, results presented at week 12 and week 28. In addition, serum metformin concentration and blood metformin concentration analysis for downstream mTOR protein target inhibition was assessed.Secondary endpoints included PSA response, defined as a PSA ≤4 ng/ml or PSA <0.02 value at 7 months. A rise of PSA over 25% and PSA ≥2 ng/ml above the nadir required the clinician to repeat PSA again in one month to confirm the further rise and possible treatment failure. Tolerability was followed as a secondary endpoint as is defined by the National Cancer Institute Common Terminology Criteria for AEs (Version 4.0), of metformin and ADT compared to ADT alone. | PMC10278660 |
Quantification of metformin levels | A liquid chromatography/tandem mass spectrometry (LC-MS-MS) method was implemented for the quantitation of metformin as previously described [ | PMC10278660 | ||
Pharmacodynamic analysis | Collection of peripheral blood mononuclear cells (PBMCs) were extracted from whole blood in a CPT Vacutainer as recommended by the manufacturer. Briefly, 8 ml of whole blood were collected from patients at baseline, week 12 and 28 and centrifuged at 1500 × g for 20 min at room temperature to isolate the PBMC fraction. The PBMC fraction was then transferred to a 15-ml conical tube, with phosphate buffered saline (PBS) and added PBS to fill the tube and were centrifuged at 600 × g for 10 min at room temperature. After PBS was aspirated, the PBMC pellet was snap frozen and stored at 80°C until use. For analysis, using western immunoblotting was used and probed with phospo-p70S6 kinase and GAPDH antibody (both purchased from Thermofisher). | PMC10278660 | ||
Statistical analysis | In a cross-sectional study of men with PC and who received androgen deprivation therapy, the mean fasting insulin was 45.0 mU/mL ± 7.25 mU/mL and a mean HOMAUnder these assumptions, the same sample size requirement is attained using HOMA | PMC10278660 | ||
Availability of data and material | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10278660 | ||
CONCLUSIONS | metabolic syndrome, cardiovascular death | METABOLIC SYNDROME, DISEASE | The present study has numerous strengths including the longitudinal, prospective and placebo-controlled design. The main limitation in assessing the effect of empiric metformin in this study is the limited sample size and variance in criteria to determine metabolic syndrome. Outside of our study, there is evidence to suggest that ADT increases the risk of metabolic syndrome that led to cardiovascular death with prolonged use. For men with PC requiring ADT, many of whom required lifelong ADT, efforts to reduce metabolic syndrome through lifestyle modification including diet and exercise may mitigate some of the risks of ADT. Numerous studies of metformin have been completed in a variety of disease states and settings and future metanalyses may help determine metformin’s true benefit in PC. We anticipate that future larger interventional studies assessing both therapeutic modulation and lifestyle changes will determine whether survival of men with PC requiring ADT can ultimately be improved by this approach. | PMC10278660 |
SUPPLEMENTARY MATERIALS | PMC10278660 | |||
ACKNOWLEDGMENTS AND FUNDING | ICH, Cancer | CANCER | Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio; San Antonio, TX. Cancer Center Support Grant P30CA054174. Bill and Ella Owens foundation grant. Christos Fountzilas was a recipient of a Cancer Research Training Award (RP 140105) funded by the Cancer Prevention and Research Institute of Texas. Metformin and matched color placebo for this study was provided by Pharmascience, Inc., Canada.
Conceptualization and design: Mahalingam, Thompson. Study Selection and Data Acquisition: Mahalingam, Hanni, Fountzilas, Michalek, Hernandez, Sarantopoulous, Datta, Romero, Pillair, Kun, Pollak, Thompson. Data analysis/Statistical Analysis: Mahalingam, Hanni, Fountzilas, Michalek, Hernandez, Sarantopoulous, Datta, Romero, Pillair, Kun, Pollak, Thompson, Serritella. Manuscript writing and revision: Mahalingam, Hanni, Fountzilas, Michalek, Hernandez, Sarantopoulous, Datta, Romero, Pillair, Kun, Pollak, Thompson, Serritella. Supervision: Mahalingam, Thompson.
Mahalingam- research funding from Merck, Oncolytics and Amgen. Scientific Advisory board- Qurient, OncoOne. Advisory/speaker bureau for Amgen, BMS, Eisai and Exelixis.
This study was conducted upon approval of the Institutional Review Board (IRB) at the University of Texas (IRB Number: HSC20110273) and in accordance with current U.S. Food and Drug Administration (FDA) regulations, the International Conference on Harmonization (ICH), Good Clinical Practices (GCPs), the Declaration of Helsinki, and local ethical and legal requirements. Eligible patients who provided written informed consent were recruited at one center in the United States between July of 2011 through July of 2015. The review boards of all participating institutions approved the study. All patients signed a written informed consent before the conduct of any study procedures and after a full explanation of the study to the patient by the study investigator. | PMC10278660 |
REFERENCES | PMC10278660 | |||
Subject terms | Whereas cardiopulmonary responses are well understood in endurance training, they are rarely described in strength training. This cross-over study examined acute cardiopulmonary responses in strength training. Fourteen healthy male strength training-experienced participants (age 24.5 ± 2.9 years; BMI 24.1 ± 2.0 kg/mOpen Access funding enabled and organized by Projekt DEAL. | PMC10126007 | ||
Introduction | stroke | HYPERTROPHIC, STROKE | The preventive and rehabilitative effects of physical exercise have generally been well-studiedThe cellular response to ST is widely acknowledged, as are the associated hypertrophic effects of skeletal muscleNot conclusively clarified and unlike endurance training, the acute hemodynamic adaptations (stroke volume and cardiac output) of strength exercises have rarely been describedHowever, strength training protocols differ with respect to working-muscle groups, modality (dynamic vs. isometric, body weight vs. device-supported), duration, and intensity. Whereby, the intensity and cumulative volume of strength training protocols exert a decisive influence on muscular adaptationsAlthough strength training has grown increasingly popular in recent decades and regular strength training’s long-term effects have been widely documentedThe aim of this randomized crossover study was, therefore, to investigate hemodynamic cardiopulmonary responses (stroke volume, cardiac output, cardiac work, end-expiratory gas concentrations) during and after strength training with different intensities (50%, 62.5%, and 75% of the 3-Repetition Maximum; 3-RM). Based on the known long-term effects of exercise training, we expect the strongest cardiopulmonary and vascular peripheral responses at 75% of the maximum load. | PMC10126007 |
Materials and methods | PMC10126007 | |||
Participants | Our study was conducted in accordance with the latest version of the Declaration of Helsinki and approved by the Ethics Committee of the Medical Faculty of the University of Leipzig (272/21-ek). Written informed consent was obtained from all participants. The study group consisted of 14 healthy and strength training experienced men (Table Baseline characteristics of the study participants (n = 14).Values are presented as the means and standard deviation; | PMC10126007 | ||
Study design | cardiac and pulmonary maximum | After the initial pre-examination, all participants completed three experimental sessions involving standardized squats on a smith machine (Technogym Germany GmbH, Germany) over a three-week period. To standardize the training sessions, the individual three-repetition-maximum at 50%, 62.5% and 75% were used. The pre-examination included medical history, lifestyle questionnaire (physical activity, smoking, and alcohol consumption), incremental exercise test (IET), and bioelectrical impedance analysis (Bioimpedance Analyzer BIACORPUS RX 4004 M, MEDI CAL HealthCare GmbH, Germany). The participants performed an incremental exercise test (IET) to exhaustion to determine maximum power output (Pmax), cardiac and pulmonary maximum values.All participants performed three load conditions on separate days at the same time with a break lasting at least 5 days to ensure adequate recovery. On the first strength training session, the individual 3-repetition maximum (3-RM) after a warm-up period was determined via the approximation method, which corresponds to the maximum amount of weight lifted in clean execution for three repetitions in the smith machine. The 3-RM tests followed the ACSM guidelines for 1-RM tests | PMC10126007 | |
Strength training: squats in a smith machine with 50% 3-RM, 62.5% 3-RM, and 75% 3-RM | All participants took part in a warm up-period lasting 5 min on a bicycle ergometer (100 W; 75 rpm) at each training session, followed by one set of 10 repetitions without external load, five repetitions with 50% of the subsequent testing load and 3 repetitions with 75% of the subsequent load. For each training session three sets of 10 repetitions were completed for each load with a 4-min rest period between each setshows the timeline of measurements ( | PMC10126007 | ||
Incremental exertion test (IET) | RPE | The IET was performed on a semi-recumbent ergometer (ergometrics 900, ergoline GmbH, Bitz, Germany) at a constant speed of 60–70 rpm. The test started with a 50 W load, which was increased by 15 W every minute until exhaustion occurred. The criteria for exhaustion were a cycling cadence below 60 revolutions per minute, a respiratory quotient above 1.1 and/or reaching the limit of perceived exertion. Each subject continued the test for an additional 5-min recovery period at a 25% load of Pmax. Spirometry (K4b, Cosmed, Italy), thoracic impedance (PhysioFlow, Manatec Biomedical, France), and an electrocardiogram (custo, BT300 custo GmbH, Germany) were synchronized and ran simultaneously during the entire time. Impedance cardiography employs disposable sensors on the neck and chest to measure electrical and impedance changes in the thorax. The change in impedance signal and its timing due to blood flow in the aorta are used to calculate hemodynamic parameters. Furthermore, blood pressure (BP) and rating of perceived exertion (RPE) were recorded every 3 min during the IET. The maximal load and cardiopulmonary parameters (IET 100%) at this level represent the reference for the maximum dynamic workload (Tables Mean values during exercise period (n = 14; three sets of 10 repetitions, excluding warm-up and recovery phases).Significant values are in bold.Values are presented as the means and standard deviation; Mean values during the post-exercise period (n = 14; mean at one minute after exercise periods).Significant values are in bold.Values are presented as the means and standard deviation; | PMC10126007 | |
Measurements during strength training | stroke | STROKE | The three strength training sessions in this study focused on mean exercise (three sets lasting 1 min), mean immediate post-exercise (1 min after three sets), and cumulated values (three sets with complete post-exercise period). Peak exercise and mean post-exercise values (4 min after three sets) are shown in the supplementary material.Cardiac output (CO), stroke volume (SV), end-diastolic volume (EDV), ejections fraction (EF), and heart rate (HR) measured by impedance cardiography (sampling interval 10 s), maximum oxygen consumption (VOFor editing purposes, the values were averaged at 10-s intervals. We calculated mean and peak values during the sets (60 s. excluding warm-up, rest and cool down), as well as mean and peak values during the resting phase (240 s.). For the comparison of the acute post-exercise period (Table The arteriovenous oxygen difference (avDO | PMC10126007 |
Blood pressure assessement during strength training | RPE | BLOOD | Blood pressure (BP) and rating of perceived exertion (RPE; from 1 to 10, if 10 was total exhaustion) were observed at rest, immediately after each set, and after 1.30 and 2.30 min of recovery. On a separate day, participants had to perform the squats in a single-arm position in an additional examination to enable blood pressure to be measured while exercising at 62.5% of the 3-RM. An experienced investigator took the blood pressure measurements with an upper arm cuff and a stethoscope. The subject did only one set of 10 repetitions with a slower repetition frequency, and blood pressure was measured indirectly during the eccentric movement between the seventh and tenth repetitions according to the method of Riva-Rocci. We took these measurements in 12 participants of the described study group. Decelerated repetitions of the squats allowed the investigator to move along with them and take the measurements with no interference. | PMC10126007 |
Statistical analysis | All values are expressed as the means and standard deviation unless otherwise stated, and the significance level was defined as p < 0.05. Data were analyzed using Microsoft Office Excel | PMC10126007 | ||
Compliance with ethical standards | All procedures described in this study will be performed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the principles of the Declaration of Helsinki of 1964 and its latest version. Written informed consent or its equivalent will be obtained from all patients. The protocol has been approved by the Ethics Committee of the Medical Faculty of the University of Leipzig (272/21-ek). | PMC10126007 | ||
Results | PMC10126007 | |||
Incremental exertion test | Maximum IET values are shown in Table | PMC10126007 | ||
Cardiopulmonary response during strength training sessions | Baseline values were measured prior to each session (values not shown), and we observed no significant hemodynamic differences. Figures Graphs show the mean cardiac response (n = 14) during strength training sessions with (Graphs show the mean pulmonary response (n = 14) during strength training sessions: (Graphs show the mean periphery and end-tidal course during strength training sessions with (Table The mean values of the three intensities revealed large differences in the cardiopulmonary response (Table V | PMC10126007 | ||
Cardiopulmonary response immediately after training sessions | Table | PMC10126007 | ||
Discussion | The main finding of this randomized cross-over study was the specific post-exercise responses of cardiopulmonary parameters (SV, V | PMC10126007 | ||
Pulmonary response | COIn | During the exercise period, only VDuring the post-exercise period, all pulmonary parameters exhibited significant intensity-dependent differences. Breathing regulation after the exercise period seems to be affected by the exercise-related breathing pattern. Therefore, the training-induced oxygen deficit and COIn summary, an intermittent Valsalva maneuver during exercise has been observed at all three intensities | PMC10126007 | |
Cardiovascular response | intensity-related increase | During the exercise period a significant intensity-related increase in HR and CO was evident (Tables The present results show that the HR and CO during exercise and during cumulative exercise and resting times was significantly higher at 75% intensity than at the two lower intensities (Table We recorded the blood pressure during exercise at 62.5% RM in follow-up examinations. The squats were done with one arm at a slowed repetition frequency. As doing the squats while measuring blood pressure was equivalent to the training sessions except for the lower speed, one can assume the assessed blood pressure values to be representative, with a tendency to higher valuesIn the post-exercise period SBP and DBP did not differ between intensities. This might relate to decreased vascular resistance (TPR) after strength exercise with higher intensity because of either higher flow-mediated and/or metabolic vasodilationStrength training does not seem to stimulate oxygen uptake substantially more than endurance trainingTo summarize: the cardiac parameters (unlike the pulmonary parameters due to pressurized breathing), reveal a more distinct intensity-dependent response during exercise. Significant increases in CO are evident during the post-exercise period, which is attributable to the lower blood pressure without load. | PMC10126007 | |
Study limitations | The sample size is small, and we selected only male and recreationally-active participants for this study to prevent compromising interference from possible gender differences in cardiopulmonary function, and muscle performance differences. Therefore, the interpretability and generalizability of the results is limited and only apply to a young male-only and healthy population. The main difficulty during our investigation was measuring blood pressure during strength exercises. For safety reasons (requiring a single-arm execution) and because of the repetition sequence’s influence, we were unable to take blood-pressure measurements during our participants’ strength sessions. We thus cannot quantify differences in blood pressure during exercise. Nevertheless, we did take single-arm blood pressure measurements (Riva-Rocci/Korotkoff) in 12 participants at an additional session during which the squats were performed at a slower repetition frequency (62.5% 3-RM). Cardiac parameters obtained via impedance cardiography may be overestimated using absolute values | PMC10126007 | ||
Conclusions | muscle mass, stroke | BLOOD, STROKE | With this randomized cross-over study, we examined the acute hemodynamic response to standardized strength training at different intensities but of the same duration and muscle mass and during exercise and post-exercise periods. The cumulative cardiopulmonary response of exercise and post-exercise periods corresponds to the intensity differences. However, during the exercise period, a repetition-dependent breathing pattern was observed. Equipment-supported high-intensity strength training resulted in repetition-adjusted ventilation with breath holding and a markedly increase in blood pressure during the exercise period. Blood pressure dropped immediately after exercise, followed by a substantial increase in stroke volume during the immediate post-exercise period. The training-induced oxygen deficit and CO | PMC10126007 |
Supplementary Information |
Supplementary Information. | PMC10126007 | ||
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-33873-x. | PMC10126007 | ||
Acknowledgements | We thank Carole Cürten for English editing. | PMC10126007 | ||
Author contributions | T.M., R.K. and J.L. | R.F., T.M., R.K. and J.L. conceived and designed this research. R.F., Z.U., T.M., R.K. and J.L. conducted experiments. R.F. and J.L. analyzed and interpreted the data. R.F. and J.L. drafted and revised the manuscript. All authors have read and approved the final version of this manuscript. | PMC10126007 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. No funds, grants, or other support was received. | PMC10126007 | ||
Data availability | The original contributions presented in the study are included in the article’s supplementary material; further inquiries can be directed to the corresponding author/s. | PMC10126007 | ||
Competing interests | The authors declare no competing interests. | PMC10126007 | ||
References | PMC10126007 | |||
Background | stroke, ’ disease | REGRESSION, STROKE | There are few reported studies on stigma in young and middle-aged stroke patients during the rehabilitation period, however, the rehabilitation period plays a key role in the patients’ disease regression. Exploring the level of stigma and the influencing factors in young and middle-aged stroke patients during the rehabilitation period is crucial for determining how to reduce the level of stigma and improve the patients’ motivation for rehabilitation treatment. Therefore, this study investigated the level of stigma in young and middle-aged stroke patients and analyzed the factors influencing stigma in order to provide a reference or basis for healthcare professionals to develop effective and targeted stigma intervention programs. | PMC10067210 |
Methods | stroke, Stroke | REGRESSION, STROKE, POSITIVE, STROKE | Using a convenience sampling method, 285 young and middle-aged stroke patients admitted to the rehabilitation medicine department of a tertiary care hospital in Shenzhen, China, from November 2021 to September 2022 were selected and surveyed using a general information questionnaire, the Stroke Stigma Scale(SSS), the Barthel Index(BI), and the Positive and Negative Emotions Scale(PANAS), and multiple linear regression and smoothed curve fitting were used to analyze the factors influencing the stigma of young and middle-aged stroke patients during the rehabilitation period. | PMC10067210 |
Results | SSS score of 45.08 | PMC10067210 | ||
Conclusion | stroke | STROKE | Young and middle-aged stroke patients have a moderate level of stigma. Medical staff should focus on young patients aged 18–44 years, those with high monthly income before the stroke, those with poor self-care ability, and those with low positive and high negative emotion scores, and conduct early assessments and adopt targeted intervention programs according to the influencing factors to reduce the stigma of young and middle-aged stroke patients, improve their motivation for rehabilitation, and help them return to their families and society as soon as possible. | PMC10067210 |
Trial Registration | Registration number of China Clinical Trials Registration Center: 20,220,328,004-FS01. | PMC10067210 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12883-023-03189-4. | PMC10067210 | ||
Keywords | PMC10067210 | |||
Introduction | death, Stroke, stroke, neurological deficits, disability | CIRCULATION DISORDERS, STROKE, STROKE, DISEASE, CEREBROVASCULAR ACCIDENT | Stroke is a group of acute episodes of neurological deficits caused by multiple causes of local cerebral blood circulation disorders, also known as stroke or cerebrovascular accident [It is the second-leading cause of death and disability worldwide [Stigma, originally from the Greek word meaning “brand,“ was first introduced by the American sociologist Goffman in 1963 and refers to an internal experience of shame caused by discrimination and isolation from others because of a disease [Stigma is commonly present in stroke patients, but at inconsistent levels [ | PMC10067210 |
Methods | PMC10067210 | |||
Research subjects | stroke | STROKE | Young and middle-aged stroke patients hospitalized in the rehabilitation medicine department of a tertiary care hospital in Shenzhen, China, were selected as the study population using a convenience sampling method. Inclusion criteria: (1) meeting stroke diagnostic criteria [ | PMC10067210 |
Research tools | PMC10067210 | |||
General information questionnaire | comorbid chronic diseases, strokes | STROKES | It was designed by the investigators themselves and included two sections with demographic and sociological information (gender, age, marital status, occupation, education, pre-stroke monthly income, insurance type, smoking, drinking, primary caregiver) and disease-related information (comorbid chronic diseases, number of strokes, genetic history). | PMC10067210 |
Stroke stigma scale (SSS) | The SSS, constructed by Zhu Minfang et al. [ | PMC10067210 | ||
Positive and negative affect scale (PANAS) | The scale was developed by Watson et al. [ | PMC10067210 | ||
Barthel index (BI) | It is an international rehabilitation medicine method for assessing patients’ ability to perform activities of daily living [ | PMC10067210 | ||
Information collection | The researcher was mainly responsible for the receipt and distribution of questionnaires, and another graduate student assisted. Prior to the survey, the unified instructional language was used to explain the purpose of the survey and the method of filling out the questionnaire to the respondents, etc. All questionnaires were anonymous and collected on the spot after completion, and any omissions were made up in time. | PMC10067210 | ||
Results | PMC10067210 | |||
Description of the patient screening process | In this study, 300 patients were initially included, and 15 cases with missing basic information were excluded, leaving 285 cases for the final data analysis, as detailed in the flow chart (Fig.
Description of the participant screening process | PMC10067210 | ||
General data description of young and middle-aged stroke patients | stroke | STROKE | The results showed statistically significant differences (
Description of general data of young and middle-aged stroke patients (N = 285)MaritalStatusMonthlyIncome(¥)Note: a represents | PMC10067210 |
SSS, PANAS and BI scores of young and middle-aged stroke patients | The results of the study showed that the SSS score for young and middle-aged people are 45.08
Scores on each scale (N = 285) | PMC10067210 | ||
Description of the linear relationship of factors influencing disease stigma in young and middle-aged stroke patients | PMC10067210 | |||
Multiple linear regression analysis of the factors influencing stigma | stroke, chronic disease status, primary caregiver | REGRESSION, STROKE | The SSS for young and middle-aged stroke patients was used as the dependent variable, and statistically significant data (age, occupation, education, monthly income, type of health insurance, chronic disease status, primary caregiver), the Barthel Index, positive emotions, and negative emotions were used as independent variables in a multiple linear regression analysis. The independent variables were assigned as shown in Table
Assignment of independent variablesMonthly income(<1000 = 1, 1000–2999 = 2, 3000–4999 = 3, 5000–10,000 = 4,>10,000 = 5Urban Insurance = 1, Resident Insurance = 2,Rural Insurance = 3, Self-funded = 4
Multiple linear regression analysis of factors influencing stigma (N = 285) | PMC10067210 |
Description of the non-linear relationship of factors influencing stigma in young and middle-aged stroke patients | PMC10067210 | |||
Relationship between general information and stigma | REGRESSION | The general information (age and monthly income) that was significant in the multiple linear regression analysis was described by smoothing curve fitting, where the red solid line indicates the smoothed curve fitting between the variables and the blue dashed line indicates the 95% confidence interval of the fitting. A non-linear relationship was observed between age and stigma, with different trends in stigma levels among patients of different ages but a general trend of decreasing stigma levels with increasing age (Fig.
The relationship between age and stigma
The relationship between income and stigma | PMC10067210 | |
The relationship between BI and stigma | The non-linear relationship between BI and stigma was observed by smoothed curve fitting, where the red solid line indicates the smoothed curve fitting between the variables and the blue dashed line indicates the 95% confidence interval of the fitting, where it can be observed that there are different decreasing trends of the stigma curve for patients with different independent levels of daily living self-care (Fig.
The relationship between BI and stigma | PMC10067210 | ||
Relationship between PANAS and stigma | The relationship between positive and negative emotions and stigma was observed through a smoothed curve fit, where the red solid line indicates the smoothed curve fit between the variables and the blue dashed line indicates the 95% confidence interval of the fit. We observed that when positive emotions were scored at 30, the total score of stigma would not decrease (Fig.
The relationship between positive emotion and stigma
The relationship between negative emotion and stigma | PMC10067210 | ||
Discussion | PMC10067210 | |||
Current status of stigma in young and middle-aged patients recovering from stroke | The results of this study showed that the total stigma score of 45.08 | PMC10067210 | ||
Factors influencing stigma in young and middle-aged patients recovering from stroke | PMC10067210 | |||
Age was negatively correlated with the level of stigma | According to the criteria for delineating the age of Chinese residents and the age cut-off for Chinese residents in previous studies in the cardiovascular literature, middle-aged and young adults are defined as 18–64 years old, 18–44 years old as young adults, and 45–64 years old as middle-aged [ | PMC10067210 | ||
Monthly income was positively correlated with the level of stigma | In 2021, the average annual salary of urban non-private sector employees in 31 provinces in China was ¥106,837 [ | PMC10067210 | ||
BI was negatively correlated with the level of stigma | stroke | STROKE | This study found that the poorer the ability to perform daily living, the higher the stigma score, which is consistent with a cross-sectional survey of 72 stroke patients by Tong Qi [ | PMC10067210 |
Emotional state correlates with disease stigma | stroke, vessel disease | STROKE | The present study showed that positive emotions were negatively correlated with stigma and negative emotions were positively correlated with stigma in young and middle-aged patients recovering from stroke, which is In line with Wang Xiao [However, there are some limitations to our study. On one side, it was a cross-sectional survey and did not follow up on the patients’ sense of stigma. On the other hand, because small vessel disease of the brain is a heterogeneous series of pathophysiological processes [ | PMC10067210 |
Conclusion | stroke, ’ | STROKE | The research results show that the sense of stigma among middle-aged and young stroke patients is at a moderate or higher level. Currently, solutions for stroke patients’ feelings of stigma have yielded positive results [In conclusion, this study not only lays the foundation for future interventional studies on stigma in young and middle-aged stroke patients but also provides a reference for tertiary prevention of stroke patients to facilitate their early return to their families and society and to reduce the economic burden on families and society. | PMC10067210 |
Acknowledgements | The authors would like to thank Miss. Xinlin Chen and Mr. Chi Chen of the Empower.Institute for their help. | PMC10067210 | ||
Author Contribution | RS, HL | ZZ contributed to the drafting of the manuscript; ZZ, YZ, HL contributed to the data collection; ZZ, RS, YW contributed to Analysis and interpretation of data; CY contributed to the conception and critical revision of the manuscript; and approved the final version of the submitted manuscript. | PMC10067210 | |
Funding | stroke | STROKE | This work was supported by ID (LHGJ20220676). A study of the impact of a PERMA model-based intervention program on stigma in young and middle-aged stroke patients. | PMC10067210 |
Data Availability | All data generated or analyzed during this study are included in this published article [and its supplementary information files: Additional File 1]. | PMC10067210 | ||
Declarations | PMC10067210 | |||
Conflicts of interest | The authors declare that they have no conflicts of interest. | PMC10067210 | ||
Ethics approval and consent to participate | Firstly, in this study, all methods used by the researcher throughout the questionnaire survey of the study participants were carried out in accordance with the relevant guidelines and regulations.Secondly, this study was approved by the Clinical Research Ethics Committee of the Shenzhen Second People’s Hospital (approval number: 2022038004-FS01) and all experimental protocols were approved by the Clinical Research Ethics Committee of the Shenzhen Second People’s Hospital. The clinical trial was registered with the Chinese Clinical Trials Registry (ChiCTR2200060103) and certified that the study was conducted in accordance with the ethical standards set out in the 1964 Declaration of Helsinki.Finally, all participants in this study were young and middle-aged and had normal consciousness and cognitive ability, and all subjects gave their informed consent and signed a written informed consent form. | PMC10067210 | ||
Consent for publication | Not applicable. | PMC10067210 | ||
Abbreviations | Stroke | STROKE | Stroke Stigma ScalePositive and Negative Affect ScaleBarthel Index | PMC10067210 |
References | PMC10067210 | |||
Condensed Abstract | obesity, coronary artery disease, nonvalvular atrial fibrillation | OBESITY, CORONARY ARTERY DISEASE | We hypothesize that a novel tailor-made cardiac rehabilitation (CR) program for obesity patients (OPTICARE XL) has better outcomes as compared to usual CR regarding parameters of cardiac function as measured by conventional and advanced transthoracic echocardiography. This is an open-label, randomized controlled trial. Inclusion criteria were: patients referred to CR with a body mass index (BMI) ≥30 kg/m2, and age ≥18 years with either coronary artery disease or nonvalvular atrial fibrillation. The experimental group participated in OPTICARE XL and the controls received the usual CR. Subjects randomized to OPTICARE XL received on top of usual CR behavioural therapy for a healthy diet and an active lifestyle for the first 12 weeks. Also, the exercise program was more tailored. Furthermore, a behavioural after-care program was organized with 6 meetings between weeks 13-52. Transthoracic (speckle tracking) echocardiography was performed at baseline and one-year follow-up. A total of 42 patients completed the follow-up, 21 in both groups. There was a mild but statistically significant reduction in weight over time, however, this was comparable between groups. There was no improvement observed in any of the echocardiographic parameters. In conclusion, cardiac function in obesity patients was not improved one-year after a novel tailor-made CR program (OPTICARE XL) as compared to usual CR.We hypothesized that a novel state of the art cardiac rehabilitation program designed for patients with obesity has better outcomes as compared to standard CR regarding parameters of cardiac function as measured by transthoracic echocardiography. However, cardiac function in patients with obesity did not improve as compared to standard CR. | PMC10160212 |
Keywords | PMC10160212 | |||
Introduction | overweight, weight loss | CARDIAC DISEASE | Cardiac rehabilitation (CR) is a valuable treatment for patients with a broad spectrum of cardiac disease. Currently, CR has a class 1 recommendation (evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective) in several European society of cardiology (ESC) and American college of cardiology (ACC) guidelines [Currently, at entry into CR over 80% of the patients are overweight (body mass index (BMI) ≥ 25 kg/mRecently, we have shown that weight loss achieved by bariatric surgery improves many echocardiographic parameters of cardiac function and dimension at one-year follow-up [ | PMC10160212 |
Methods | PMC10160212 | |||
Study population and design | obesity, Weight loss, weight loss | OBESITY | The OPTICARE XL CR (OPTImal CArdiac REhabilitation XL CR) study is an open-label, randomized controlled trial [The experimental group participated in OPTICARE XL CR, and the controls received standard CR as recommended by the guidelines [In order to enter cardiac rehabilitation, patients are exposed to a symptom-limited exercise test (on a bike in a controlled setting, with a safety protocol). Based on the achievements on this exercise test, patients started standard cardiac rehabilitation on a certain intensity level (low, moderate, or high intensity), or when randomized to OPTICARE XL CR started OPTICARE XL CR. The cycle ergometer, the rowing ergometer and fitness equipment were used for strength training. The training modalities for patients in the standard CR group consisted mainly of activities such as walking, jogging and group sports. During cardiac rehabilitation the patient is monitored every week and the training schedule is revised upon consultation with the multidisciplinary treatment team. Standard CR programs terminate once the patients’ physical and psychosocial recovery is sufficient. In most cases this goal is reached between 6 and 12 weeks, whereas the performance of the patient is evaluated in consultation with the multidisciplinary team. The OPTICARE XL CR program lasted for 12 weeks, since it was assumed that patients with obesity need at least 12 weeks of care in order to facilitate in behavioral changes. Furthermore, a behavioural after-care program was organized with 6 meetings (one hour each) between weeks 13–52 for the OPTICARE XL CR patients. This was done in small groups with a maximum of 8 participants instead of the standard CR groups with a maximum of 25 participants.Weight loss was defined as any decrease in weight and measured with a calibrated weight scale. Clinically significant weight loss was defined as a loss of 5% of body weight at baseline [ | PMC10160212 |
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