Good-quality evidence has shown that early glycaemic, blood pressure and LDL-cholesterol control in people with type 2 diabetes (T2D) leads to better outcomes. In spite of that, diseases control have been inadequate globally, and therapeutic inertia could be one of the main cause. Evidence on therapeutic inertia has been lacking at primary care setting. This retrospective cohort study aimed to determine the proportions of therapeutic inertia when treatment targets of HbA1c, blood pressure and LDL-cholesterol were not achieved in adults with T2D at three public health clinics in Malaysia.The index prescriptions were those that when the annual blood tests were reviewed. Prescriptions of medication were verified, compared to the preceding prescriptions and classified as 1) no change, 2) stepping up and 3) stepping down. The treatment targets were HbA1c < 7.0% (53 mmol/mol), blood pressure (BP) < 140/90 mmHg and LDL-cholesterol < 2.6 mmol/L. Therapeutic inertia was defined as no change in the medication use in the present of not reaching the treatment targets. Descriptive, univariable, multivariable logistic regression and sensitive analyses were conducted.A total of 552 cohorts were available for the assessment of therapeutic inertia (78.9% completion rate). The mean (SD) age and diabetes duration were 60.0 (9.9) years and 5.0 (6.0) years, respectively. High therapeutic inertia were observed in oral anti-diabetic (61–72%), anti-hypertensive (34–65%) and lipid-lowering therapies (56–77%), and lesser in insulin (34–52%). Insulin therapeutic inertia was more likely among those with shorter diabetes duration . Those who did not achieve treatment targets were less likely to experience therapeutic inertia: HbA1c ≥ 7.0%: adjusted OR 0.10 ; BP ≥ 140/90 mmHg: 0.28 ; LDL-cholesterol ≥ 2.6 mmol/L: 0.37 .Although therapeutic intensifications were more likely in the presence of non-achieved treatment targets but the proportions of therapeutic inertia were high. Possible causes of therapeutic inertia were less of the physician behaviours but might be more of patient-related non-adherence or non-availability of the oral medications. These observations require urgent identification and rectification to improve disease control, avoiding detrimental health implications and costly consequences.NCT02730754, April 6, 2016.Number The online version contains supplementary material available at 10.1186/s12875-021-01472-2. Managing and achieving optimal control in glycaemia HbA1c), blood pressure and low-density lipoprotein cholesterol for people with type 2 diabetes (T2D) has been very difficult c, blood –6, and iClinical inertia is defined as a failure to initiate or intensify necessary treatments at a timely manner when faced with objective evidence of uncontrolled diseases in the present of clear clinical practice guidelines –19. TherThe problems of therapeutic inertia in diabetes care or a delayed response to poor glycaemic control were about 30–40% or six months to 2 years, respectively . In a reThe evidence on therapeutic inertia has been lacking at primary care setting, especially in low- and middle-income countries and in Asia . AccordiThis was a retrospective cohort study that included baseline data from a previous study in 2013 , togetheAt baseline, participants were sampled consecutively as they came to the clinics over a period of six months. Inclusion criteria at baseline: age 30 years or older, a diagnosis of T2D more than one year ago, and with at least three clinic visits in the previous year. The baseline exclusion criteria were pregnancy or lactating, psychiatric/ psychological disorders that could impair judgment and memory, and participants who could not read or understand English, Malay or Mandarin . The parBaseline demographic data included age, gender, ethnicity, religion, educational level, employment status, monthly income and life event within the past six months . StructuData analyses were carried out using SPSS software version 25.0 . Comparisons of mean levels were performed using the Student’s t-test or Mann-Whitney U test according to the data distribution, and the Chi-square test was used for proportionate samples between groups. Characteristics of the patients who have and did not have the required data for this study are presented as mean (SD) or median (IQR) for continuous variables, and counts and percentages for nominal variables using descriptive statistics according to the three health clinics.Assessment of therapeutic inertia was done for year 2015 because the required medication use data were captured from year 2014, and not possible for year 2016 as the study ended in the third quarter. Index of ADA, insulin and LLA medications prescription and use of the year were compared to the previous year index prescription. Changes of medication use were classified as 1) no change, 2) stepping up: dose increment or/and replacement with a stronger medication, and 3) stepping down: dose reduction or/and replacement with a weaker medication. All the classification was verified by the author himself and the resident family physicians in SK and SL health clinics. Therapeutic inertia is defined as no change in the medication use in the present of not reaching the recommended treatment targets. Therapeutic inertia was assessed for HbA1c (no change in ADA and insulin uses separately) and LDL-cholesterol (no change in LLA use) by looking at the treatment target in the same year because medication use and change was captured after the tests were reviewed. For those who did not have results for HbA1c and LDL-cholesterol in the same year, the results in the previous year were used. This reflects the actual clinical practice at these health clinics. The therapeutic inertia assessment for blood pressure (no change in AHA use) was assessed by looking for occurrence of persistent SBP/DBP above treatment targets over two occasions with no change of AHA use in the same year. Sensitive analysis was conducted to examine the states of therapeutic inertia for AHA use in the first half and the second half of the year when at least four SBP/DBP measurements were available, and at least two consecutive SBP/DBP measurements that were above the recommended treatment targets in the respective 6-month periods. The results were essentially similar.P value < 0.20 from the univariable analyses were included in the final multivariable analyses. Category ‘no change’ represents therapeutic inertia and category ‘stepping up and stepping down’ was used as the reference group. The final models were re-run with ‘stepping up’ as the reference group and the results did not change the interpretations. We reported the results with the treatment targets entered as one of the covariate, with the reference category ‘stepping up and stepping down’ because this could account for all possible reasons of therapeutic changes and render the modelling clinically more meaningful [P < 0.05.Possible clinic and patient’s factors on the therapeutic inertia were further evaluated using the multivariable logistic regression analysis. Besides the clinic, covariates with a aningful . StatistIn total, 552 participants have the required follow-up data for the assessment of therapeutic inertia, representing 78.9% of the baseline sample (n=700). There were no differences in the prescribed medications between the non-participants and participants except LLA use was more among the participants (72% vs. 83%) Table . CompareExcept for ADA and LLA, there were significant differences in insulin and AHA therapeutic patterns when treatment targets were not achieved at the three health clinics Fig. . DK was P = 0.454). Insulin therapeutic inertia was more likely among those with shorter diabetes duration    Table .Table 2FAHA inertia was observed in about half (51%) of the participants with BP > 140/90 mmHg, and only 34% had their AHA therapy stepped up. This inertia happened more among the younger age group, Indians, in active employment, shorter hypertension duration and not diagnosed of hypertension , hypertension (51%) and high LDL-cholesterol (61%). These proportions were still considered high after considering the possible true contraindications and intolerance to medications of about 15 to 20% based on the authors’ experience and early studies –35.High prevalent of therapeutic inertia in ADA in all three clinics might indicate limitation in the dosing of the oral medications when maximum doses have been prescribed and with the restricted choices of ADA . The comAHA therapeutic patterns noted a wide variation across the three clinics, and different clinic was one of the significant factors that showed an independent effect on AHA inertia in the multivariable model. DK was most likely to have AHA inertia compared to the other clinics. These could be due to the differences in healthcare system-related factors such as having a dedicated team and consultation room at SK . This miMultivariable analysis did not reveal any significant contributing factor towards LLA inertia except that of achieving the LDL-cholesterol target. This was an assuring finding observed in this study and elsewhere  but the Good sample size, representative samples of the participants  and reasAlthough therapeutic intensifications were more likely in the presence of non-achieved glycaemic, blood pressure and LDL-cholesterol treatment targets but the proportions of adults with T2D who faced therapeutic inertia were high at primary diabetes care in Malaysia. Possible causes of therapeutic inertia might be due to restricted choices of oral medications and patient-related factors besides physicians’ behaviours. Therapeutic inertia usually present with complex barriers that require multisectorial efforts to overcome. This will include multidisciplinary diabetes care team, people with diabetes, advocacy, policymakers, the industries and research institutes to effect change at all levels of the care ecosystem. These require urgent identification and rectification to improve disease control –45. The Additional file 1: Table S1. Characteristics of patients and uncontrolled HbA1c according to the anti-diabetics therapeutic changes in 2015, n (row %) unless stated otherwise. Table S2. Characteristics of patients and at least two consecutive blood pressure not at targets according to the anti-hypertensive therapeutic changes in 2015, n (row %) unless stated otherwise. Table S3. Characteristics of patients and uncontrolled low density lipoprotein-cholesterol according to the lipid lowering therapeutic changes in 2015, n (row %) unless stated otherwise.


CVD remains the major cause of mortality with graft functioning in Kidney transplant recipients (KTRs), with an estimated risk of CV events about 50-fold higher than in the general population. Many strategies have been considered to reduce the CV risk such as the use of mTOR inhibitors. We evaluate whether chronic mTOR inhibition might influence CV aging in KTRs studying the molecular mechanisms involved in this effect. We retrospectively analyzed 210 KTRs with stable graft function on therapy with CNI and mycophenolic acid , or with CNI and mTORi . The presence of mTOR inhibitor in immunosuppressive therapy was associated to increase serum levels of Klotho with concomitant reduction in FGF-23, with a significant decrease in left ventricular mass. In addition, KTRs with mTORi improved mitochondrial function/biogenesis in PBMC with more efficient oxidative phosphorylation, antioxidant capacity and glutathione peroxidase activity. Finally, group B KTRs presented reduced levels of inflammaging markers such as reduced serum pentraxin-3 and p21ink expression in PBMC. In conclusion, we demonstrated that mTOR inhibition in immunosuppressive protocols prevents the occurrence and signs of CV aging in KTRs. Patients with chronic kidney disease (CKD) face a dramatically increased risk of mortality from cardiovascular disease (CVD) , 2. StruMitochondria may represent a further link in this contest, since mitochondrial dysfunction has been reported in different models of CKD . These sMammalian target of rapamycin (mTOR) is a key cellular kinase, whose inhibition has been associated with an increased lifespan in worms, flies and mice , 14. In Specifically, in the setting of kidney transplant recipients (KTRs), CVD remains the major cause of mortality with functioning graft , with anIn this study we investigated whether chronic mTOR inhibition might influence CV aging in KTRs; moreover, we evaluated the molecular mechanisms involved in this effect, focusing on the role of klotho/FGF23 axis and mitochondrial function/biogenesis.We conducted a multicenter, observational, case–control study enrolling KTRs in Transplantation centers of Foggia and Bari . The study protocol was approved by the Ethical Committee of the coordinating center  according to the Declaration of Helsinki. Once written informed consent was collected, we included in the study 210 renal transplant recipients with stable graft function and affected by CKD stage 3–5, on therapy with CNI and mycophenolic acid , or with CNI and mTORi (Everolimus)  from at least one year. The patients were recruited after qualifying to the following criteria: inclusion criteria: age>18 years; recipient of a primary renal allograft from a cadaveric donor, stable graft function, calcineurin-inhibitors-based therapy; estimated GFR<60 ml/min, time from transplantation >12 and <60 months; leukocytes>4x109/L, platelets>100x109/L, fasting triglycerides<350mg/dL, fasting cholesterol<300mg/dL. Exclusion criteria: panel reactive antibodies >50%; an acute rejection episode in the previous 12 months; active systemic infection ; presencNo changes in immunosuppressive therapy were done from at least one-year former enrollment for all patients recruited. The enrollment period was 12 months and follow-up time was two years monitoring the principal CV events. The immunosuppressive efficacy was monitored through the measurement of the drugs trough level (T.L.). The two groups were matched for the main demographic features, graft function and transplantation vintage.All patients were evaluated by conventional 2D and TDI echocardiography under resting conditions as previously described .Transthoracic echocardiography was performed with the use of iE33  as previously described , 31.TDI was performed using apical views for the long-axis motion of the ventricles. Two-dimension echocardiography with TDI-color imaging was performed using aS5-1 Sector Array Transducer with Pure Wave Crystal Technology (5 to 1 MHz). Two-dimensional echocardiography with TDI color imaging views were optimized for pulse repetition frequency, color saturation, sector size, and depth and were allowed the highest possible frame rate. At least 3 consecutive beats were stored, and the images were analyzed offline with the aid of a customized software package .Twenty milliliters of whole blood were collected from patients (8 CNI-MPA and 10 CNI-EVE) at the time of enrollment (T0). For 5 out of 8 CNI-MPA patients, whole blood was harvested at T0 and after 6 (T1) and 12 months (T2) from conversion to Everolimus treatment. PBMCs were isolated by density separation over a Ficoll–Hypaque gradient . Total RNA was extracted by the RNeasy mini kit .Ct method (ΔΔCt) was used to quantify gene expression and the relative quantification (RQ) was calculated as 2−ΔΔCt.Reverse transcription of total RNA (500 ng) was performed as previously described . qPCR waCirculating Klotho/FGF23 and PTX3 were measured by ELISA, according to the manufacturer's instructions .Blood samples were obtained and treated as previously described .Serum fluorescent adducts formed between peroxidation-derived aldehydes (HNE and MDA) and proteins were measured by spectrofluorimetry as previously reported . The ant6cells/500 μl in 10 mM KH2PO4, 27 mM KCl, 1 mM MgCl2, 40 mM HEPES, 0.5 mM EGTA (pH 7.1) and evaluated O2 consumption by high resolution respirometry  at 37° C under continuous stirring. Next, we added oligomycin (8 μg/ml), followed by 5 min by the addition of valinomycin (2 μg/ml). Oxygen consumption rate (OCR) was corrected for 3 mM KCN-insensitive respiration and normalized to the cell number. finally, we calculated respiratory control ratio (RCR) by dividing the rates of oxygen consumption obtained before and after the addition of oligomycin.We resuspended freshly isolated PBMCs at 1 × 10We investigated mitochondrial injury and alteration in membrane potential (Δψ) by staining with 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetrathylbenzimidazolyl carbocyanine iodide ,.We detected reactive species by using 2′,7′-dichlorofluorescein diacetate . We washed the cells with PBS and incubated with 10 μM DCFH-DA for 30 min at 37° C. Analysis was carried out by a Flow Sight Imaging flow cytometer .Data were expressed as mean ± standard deviation of the mean (SDM). Gaussian distribution of the samples was evaluated by Kolmogorov–Smirnov test. The significance of differences between the two groups was assessed by the student’s t-test for unpaired samples .We expressed continuous variables as mean ± standard deviation, and categorical variables as percentages. We compared mean values with Student's t-test for variables with normal distribution or with the Mann–Whitney non-parametric U test for variables with a non-normal distribution. Percentages were compared with χ2 test. A p<0.05 was considered statistically significant.We did not observe statistical differences between the two groups of patients at the end of follow-up regarding age, transplant age, graft function, acute rejection episodes, appearance of de Novo Donor Specific antibodies, blood levels of immunosuppressive drugs, as well as for leukocytes, platelets, triglycerides, cholesterol, parathormone (PTH) and 1,25 dihydroxycholecalciferol .Interestingly, we observed a significant statistical difference between the two groups of patients for the values of FGF-23, Klotho, phosphate urine excretion  , Flow Mediated Dilation (FMD), ejection fraction (EF), LV-filling velocity and E-deceleration time (EDT), the ratio of trans-mitral early to late (E/A ratio), peak velocities of trans-mitral early (E) and late diastolic (A) LV filling. Moreover, none of patients had experiences of serious CV events before and during the follow-up period.In contrast, we observed a significant statistical difference between the two groups of patients in left ventricular mass (LVM)  . The carOF1-ATP synthase inhibitor oligomycin (OL) led to a significant OCR depression in both groups, suggesting that a significant part of mitochondrial respiration was coupled to ATP synthesis  restored the OCR to the levels of resting respiration in both groups  in resting conditions (RR) in the CNI+mTORi group compared with CNI-MPA . The addynthesis . The colh groups . We founThe difference between the RR and after OL addition represents the ATP-related oxygen consumption. As shown in The cytofluorimetric analysis of mitochondrial membrane potential highlighted significant differences between the PBMC groups, reflecting a significant higher mitochondrial polarization in CNI+mTORi treated patients than CNI-MPA . To deteTo verify whether the increased production of reactive species in PBMCs from patients treated with CNI+mTORi was related to circulating oxidative stress, the level of protein oxidation was measured in terms of serum HNE- and MDA-protein adducts . We did Thus, the systemic antioxidant defense in terms of blood trolox equivalent antioxidant capacity (TEAC) and glutathione peroxidase (GPx) activity in PBMC were studied. Interestingly, both TEAC and GPx activity were increased in the CNI+mTORi group with respect to CNI , 6B.ink. Interestingly, we observed a statistically significant difference between the values of these markers in the two groups of patients   .In this study, we demonstrated that mTOR inhibition prevents the occurrence and signs of CV aging in kidney transplant recipients. Our results acquired a particular significance because they have been obtained in a high-risk patient population, such as kidney transplant patients affected by chronic graft dysfunction, a population similar to CKD patients.2) with CV adverse events [Several lines of evidence demonstrated that impaired renal function led to increased CV risk in KTRs –41. A poe events ; in a poe events . These fe events . In thise events , 46. Alte events , howevere events . These fAnother important issue of our results is the effect of mTORi on Klotho/FGF23 axis. Klotho is probably the main ‘aging suppressor’ gene; its defect leads to multiple aging-like phenotypes with premature death around 2 months of age , 49. KloSeveral evidences suggest a direct and significant correlation between CVD and Klotho expression. Klotho can inhibit local phosphate uptake into VSMCs, counteract matrix mineralization and suppress osteoblast-like differentiation of VSMCs; moreover, Klotho can effici4ntly preserve endothelial function , 12, 49.α level:; this will lead to upregulation in Nox complex expression and activity, generating a vicious cycle [ink is known as a cyclin-dependent kinase inhibitor with a pivotal role in renal aging at the level of tubular epithelial and leucocytes; our data demonstrated that mTORi could reduce the activity of this kinase with positive effects on cellular homeostasis and vitality.The most relevant issue of our work was the results obtained from the study of mitochondrial function/biogenesis. We showed a significantly increased oxygen consumption rate in patients treated with mTORi, as well as the respiratory control ratio (RCR), indicating a more efficient oxidative phosphorylation in this group. Moreover, the increase in intracellular production of reactive species, observed in the mTORi treated group, was not correlated with circulating oxidative damage. Interestingly, the systemic antioxidant defense was increased in the mTORi group. Finally, our findings reflected a significantly higher mitochondrial polarization that is an important sign of cellular efficiency. This is an important viewpoint since cardiomyocytes must rely on a constant supply of high-energy phosphates from mitochondria to maintain physiological contractile function of the heart; as consequence, the dysregulation of their homeostasis may play a pivotal role in the onset and development of aging-related cardiovascular disorders . Mitochous cycle . Interesus cycle . In thisus cycle  in two gus cycle . PTX3 asus cycle . PTX3 caus cycle  thereforus cycle . Finallyus cycle . In addiPotential study limitations include its retrospective nature and the relatively small number of patients, other than the fact that no major CV events occurred during the two years of follow-up that prevent us doing a direct conclusion. Conversely, kidney graft recipients with CKD constituted our pts’ population. These subjects share the same or even a greater, CV risk and that the use of steroids and CNI had influenced our observation; since we do not plan to withdraw these drugs, the effects observed were uniquely due to mTOR inhibition and this represent a key strength of our study. Moreover, the main problem with the use of mTORi is the high drop-out rate due to side effects. However, with dose-proposed, none patients were drop-out.In summary, our findings represent, the first attempt, to our knowledge, to investigate the ability of chronic pharmacological mTOR inhibition to delay vascular changes in a human model of accelerated vascular aging like KTRs. In addition, our results may shed light on the mechanisms involved in the pathogenesis of CKD-induced CVD and clarify, in a clinical setting, the links between mTOR activation and other relevant regulatory systems in aging biology as klotho/FGF23 axis and mitochondrial function/biogenesis.


Both VRL and VRM protocols induced statistically significant improvements  in the senior fitness test , as compared to the GW. In addition, the VRM showed greater improvement for the 2 min step test when comparing with the VRL. Therefore, including VR in a warm-up protocol can result in superior SFT performance enhancement than the GW does in healthy older women.Vibration foam rolling (VR) can improve flexibility and sports performance. However, blood pressure (BP), heart rate (HR) and senior fitness test (SFT) responses induced by an acute VR session in older women are currently unknown. Fifteen healthy women (72.90 ± 4.32 years) completed three separated randomly sequenced experimental visits. During each visit, they started with a warm-up protocol : walking + static stretching (SS), SS + VR with light pressure (VRL), or SS + VR with moderate pressure (VRM)), and completed BP, HR, SFT measurements. The systolic BP increased significantly after all three warm up protocols ( Foam rollers (FR) are a common type of warm-up and relaxation tool. Users can press their limbs against the surface of a roller, apply weight, and roll back and forth to apply pressure to the target muscles. FRs are believed to provide the following benefits: increased joint range of motion (ROM), reduced pain at the trigger point, and alleviation of delayed-onset muscle soreness ,2. ThereThe benefits of FRs in terms of physiological mechanisms include the adaptation of soft tissues after compression, the decrease in tissue viscoelasticity and lactic acid accumulation after an increase in local blood circulation, and the decrease in local and systemic muscle tension caused by the regulation of reflex arcs and sympathetic nerves to inhibit muscle tissue after pressure sensation input .RegardinVibration rolling (VR) has a built-in vibrating motor that generates vibration, which can stimulate proprioceptors such as the muscle spindles and Golgi tendon organs ,8. HowevStudies have mostly focused on the benefits of warm-up exercises ,13,14,15Numerous studies have indicated that higher stretching intensity (stretching more than 50% of the point of discomfort (POD)) significantly reduces muscle strength or exercise performance ,20,21. FTherefore, the main purpose of the study was to examine the acute effects of VR with different pressure intensities on systolic blood pressure, diastolic blood pressure, heart rate, and senior fitness test results in older female adults. We hypothesize that adding the higher-pressure intensity VR may improve the older women’s functional test performance without affecting the blood pressure responses.2) were recruited to participate in this study. The inclusion criteria included the age range of 60–80 years of age. The exclusion criteria included the presence of any musculoskeletal injury or metabolic disease. Before any experimental testing, each participant signed an approved informed consent document. On all experimental visit days, participants were instructed not to consume any alcohol or caffeine. All the experimental procedures in this investigation were in accordance with the Declaration of Helsinki and approved by the China Medical University and Hospital Research Ethics Committee .Fifteen women , vibration foam rolling with light (VRL), and with moderate pressure (VRM) intensities on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and the senior fitness test (SFT). One week before the first experimental testing visit, all participants were familiarized with all the procedures. Next, participants completed three testing sessions on three separate days, each at least 7 days apart. Considering the majority of the tests conducted in the current study were low intensity exercises, a 7-day rest period would be enough for the recovery. In addition, extra effort was taken to ensure the tests were conducted at around the same time of day for each participant. Participants were refrained from vigorous physical activities 24 h before each test session. At the beginning of each session, participants performed 5 min walking . Baseline testing (pre-test), which consisted of systolic and diastolic blood pressure, heart rate, back scratch, chair sit and reach, 30 s arm curl, 30 s chair stand, 2 min step, and 8 foot up and go testing, was conducted after the 5 min of walking. After completing the pretest measurements, participants performed one of the warm-up protocols  randomly selected for that session. Post-test measures were performed in the same order as the pre-test measures immediately after the intervention protocol. The flowchart of the study design is presented in Pre-test and post-test systolic blood pressure, diastolic blood pressure, and heart rate were measured using an automatic oscillometric device . In accordance with Rikli and Jones , the SFTThe GW consisted of a 16-min static stretching routine. Specifically, the self-administered static stretching involved the participants holding still at the end of the range of motion for 30 s for each body part . The parThe VRL consisted of one set of self-administered static stretching exercises as mentioned above (8 min), followed by the passive vibration rolling (16 min). This study employed a commercial vibration foam roller  with the vibration frequency set at 48 Hz. The VR was administered passively by a research staff to roll the roller back and forth on the participants’ triceps brachii, biceps brachii, rotator cuff, latissimus dorsi, calf, quadriceps, gluteal, hamstrings muscles at both sides. The pressure pain intensity was instructed to maintain at 2–3 on a 10 mm visual analogue scale (VAS), based on each participant’s verbal feedback. Each set of rolling was performed for 60 s at a rate of 30 rolls per minute , using a metronome .For the VRM, the procedures were the same as the VRL, except the passive pressure pain intensity was maintained at 4–5 on a 10 mm VAS.t-tests. Cohen’s d values were reported to present the magnitude of the effect [p < 0.05.All data analyses were performed using SPSS version 19  software. All results are reported as mean ± SD. The normal distribution of the data was checked by the Shapiro–Wilk test. Separate 2-way (time: pre-test vs. post-test) × 3 (intervention: GW vs. VRL vs. VRM) repeated measures ANOVAs were used to analyze the data. When appropriate, follow-up tests included one-way repeated measures ANOVAs with Bonferroni-adjusted pairwise comparisons, as well as paired samples e effect . SignifiAt pre-test, there were no statistically significant differences among the three interventions for all dependent variables. p = 0.98) and no main effect of intervention (p = 0.69), but there was a significant main effect for time (p = 0.002). After clasping across time, systolic blood pressure significantly increased from pre-test to post-test. For both diastolic blood pressure and heart rate, no two-way interaction, main effects for both intervention and time were found. The results for systolic blood pressure, diastolic blood pressure, and heart rate are shown in The results for senior fitness test outcomes are shown in p < 0.001). Subsequently, the effects of three interventions were investigated separately. Compared with the pre-test, the participants showed significant improvements in BST after VRL (p < 0.001) and VRM (p < 0.001), but not after GW (p = 0.79). In addition, there was a significant main effect of intervention , indicating greater BST after the VRL (p = 0.04) and the VRM (p = 0.04) than that after the GW.A significant two-way interaction (time × intervention) was found for the BST  and main effect of intervention were not significant . However, the main effect of time was significant . With the time collapsed, the participants improved significantly in the CSRT after all three interventions (p < 0.001).For the CSRT, the time × intervention interaction . Compared to the pre-test, the participants showed significant improvements in 2MST after VRM (p < 0.001), but not after VRL (p = 0.95) and GW (p = 0.39). Additionally, participants showed significantly greater improvements after the VRM than those after the VRL (p = 0.03) and the GW (p = 0.02).There was a significant two-way interaction . The follow-up tests indicated that participants showed significantly greater improvements after the VRL (p = 0.004) and the VRM (p = 0.002) than that after the GW.For the 30SCST, a significant two-way interaction was found . The follow-up tests showed that the participants improved significantly in the 30SACT only after the VRM (p = 0.001). Additionally, participants showed significantly greater improvements after the VRL (p = 0.01) and the VRM (p = 0.003) than that after the GW.There was a significant two-way interaction . The follow-up tests showed that the participants improved significantly in the 8FUGT after the VRL (p = 0.001) and the VRM (p < 0.001), but not after the GW (p = 0.43). Additionally, participants showed significantly greater improvements after the VRL (p = 0.001) and the VRM (p = 0.03) than that after the GW.For the 8FUGT, a significant two-way interaction (time × intervention) was found  will be necessary for conducting future research. Second, we simultaneously examined the effectiveness of VR on cardiovascular parameters  and mobility functions . In this case, participants expected to undergo the movement tests, which could have affected their cardiovascular parameters. Third, because the participants of this study were older adults, who had difficulty operating the VR by themselves, the research staff had to implement the VR interventions. Thus, when comparing this study with other studies where self-administered rolling was performed, caution needs to be taken. Future study should explore the possible self-administered VR exercises that can be performed by older adults, and the potential benefits on activities of daily living. We conclude that vibration rolling is immediately effective on older women’s flexibility, muscle strength, cardiorespiratory endurance, and dynamic balance. The effectiveness of vibration rollers appears to be affected by the rolling pressure intensity. In practical situations, healthy older adults may adopt vibration rolling as a home exercise under proper supervision and guidance.Vibration rolling does not influence older women’s blood pressure parameters.Vibration rolling can improve acute flexibility, muscle strength, cardiorespiratory endurance, and dynamic balance.Under proper guidance, vibrating rolling can be used at home for older adults.


Obstructive sleep apnea (OSA) is a complex disorder characterized by collapse ofthe upper airway during sleep. Downstream effects involve the cardiovascular,pulmonary, and neurocognitive systems. OSA is more prevalent in men than women.Clinical symptoms suggest the diagnosis of OSA but none is pathognomonic of thecondition. With rising awareness of OSA and the increasing prevalence ofobesity, OSA is increasingly recognized as a major contributor to cardiovascularmorbidity including systemic and pulmonary arterial hypertension, heart failure,acute coronary syndromes, atrial fibrillation, and other arrhythmias. Pulmonarymanifestations include the development of chronic thromboembolic disease, whichcan then lead to chronic thromboembolic pulmonary hypertension (CTEPH).Neurocognitive morbidities include stroke and neurobehavioral disorders.Screening for OSA includes the use of symptom questionnaires and the diagnosisis confirmed by polysomnography. Management primarily includes the use ofcontinuous positive airway pressure (CPAP) or bi-level positive airway pressure(BiPAP) devices during sleep. Alternate options such as mandibular devices andsurgical procedures are considered for certain patient populations. The change in airway muscle tone during sleep leads to collapseof the upper airways (predominantly during the inspiratory phase of breathing),which leads to intermittent episodes of hypopnea and/or apnea2,3. During these episodes the arterialoxygen saturation falls, which can lead to autonomic dysregulation3. These acute changes result overtime in chronic conditions that affect the cardiovascular, pulmonary, andneurocognitive systems2,3. In 1956, Bickelmann et al.4 described obesity hypoventilation syndrome (OHS) in a reportregarding an obese business executive who presented to the hospital complaining ofexcessive daytime sleepiness. These investigators attributed the name “Pickwickiansyndrome” to the condition based on the description of a similar fictional characterin Charles Dickens’ first novel (1836-37) “The posthumous papers of the PickwickClub”4. Following that,numerous descriptions of the obesity hypoventilation syndrome, central sleep apneaand obstructive sleep apnea were published under the rubric of sleep- disorderedbreathing (SDB).Obstructive sleep apnea (OSA) is a disorder caused by upper airway obstruction  during sleep2,5,6.The goal of this article is to compile and therefore understand the impact OSA hason other organ systems.Currently, obstructive sleep apnea (OSA) is the most prevalent, clinicallysignificant SDB, and it is known to be associated with numerous diseases includinghypertension, atrial fibrillation, heart failure, cerebrovascular accidents,pulmonary hypertension and others1,2. Benjafield et al.7 performed an extensive review to gauge the worldwideprevalence of this disease, which consisted of reliable prevalence data from 16countries including Brazil, Germany, Spain, China, Switzerland, and USA. Theworldwide prevalence of OSA was extrapolated from this data and showed thatabout 1 billion people aged 30-65 years are affected by OSA, 425 million ofthose deemed to have moderate to severe OSA7. The prevalence of SDB among 30-49-year-old men in NorthAmerica is 10% compared to 3% among women in the same age bracket, and 17% among50-70-year-old men, compared to 9% among women in the same age bracket3.OSA is more prevalent in men than womenNumerous risk factors are associated with OSA that can be detected on physicalexamination.1,6;Obesity and high body mass index are the strongest risk factorspredisposing OSA. There is a linear correlation between OSA andobesity8;Neck circumference greater than 17 inches (43cm) in men and 15 inches(38cm) in women1;Male gender1,2;Age more than 50 years2,5,8.Other risk factors include menopause, neuropathy or myopathy that mayaffect the upper airway muscles (particularly the genioglossusmuscle), craniofacial anatomical structure (particularly in theAsian population), family history, smoking, and nasalcongestion9.Patients with acromegaly may have OSA due to macroglossia and theydevelop central sleep apnea due to altered respiratorycontrolClinical symptoms play a key role in identifying patients with OSA but none ispathognomonic of the disease.10. Patientswith OSA are more likely to be involved in motor vehicle collisions10.Patients usually complain of fatigue, excessive daytime sleepiness, snoring,drooling, nocturnal gasping or choking, headaches and/or falling asleep whiledrivingThe purpose of this article is to review the prevalence, risk factors, clinicalpresentation, effects of OSA on different organ systems, diagnostic criteria,and to discuss current approaches to the management of patients with OSA.OSA is well recognized as a major contributor of cardiovascular disease. Previousstudies have not definitively identified the direct link between OSA andcardiovascular disease, since patients with OSA often have other risk factorsfor cardiovascular disease such as hypertension (HTN), obesity, diabetes, andsmoking. Theoretical explanations of the association of OSA and cardiovasculardisease include the observations that OSA produces a chronic inflammatory state,which leads to increased atherosclerotic changes in the blood vessels of thepatient.11. OSA leads to sleep fragmentation, intermittenthypoxemia and in some instances, recurrent hypercapnia, which in turn, stimulateincreased sympathetic activity, increased systemic inflammation, and increasedoxidative stress. The end result of these changes is endothelial dysfunction andmetabolic dysfunction which accounts for the increase in cardiovascular disease.Among the aforementioned factors, intermittent hypoxemia has been shown to playa critical role by promoting increased production of inflammatory markers, asdepicted in 11-14.Similar to obesity, which is also considered a low-grade inflammatory state, OSAhas been shown to stimulate the white adipose tissue (WAT) leading to theproduction of inflammatory mediators15 associated systemichypertension with snoring in the general population. In 1985, Fletcher etal.16 evaluatedforty-six middle aged/older men with essential hypertension and thirty-fournormotensive, age and weight matched controls for undiagnosed sleep apnea.Thirteen in the study group and three in the control group were found to haveundiagnosed sleep apnea. Seven men with hypertension and sleep apnea weretreated with protriptyline and one underwent uvulopalatopharyngoplasty (UPPP). Areduction in mean blood pressure (BP) was observed (149/95mmHg to 139/90mmHg)accompanied by a significant decrease in the apnea-hypopnea index (AHI) by 77%.The investigators concluded that OSA could be either the cause or a contributorto systemic arterial hypertension16.Evidence has been growing steadily for systemic arterial hypertension (HTN) andOSA as cardiovascular disease risk factors. In 1980, Lugaresi et al.17,18. However, more recently association of nocturnal OSA anddaytime hypertension has been demonstrated, even after the adjustment for bodymass index19-21. A prospective longitudinal cohort study with 1889participants followed for 12.2 years (median) years identified an independentassociation of OSA and HTN from the confounders including age and obesity. Thestudy demonstrated an increased hazard ratio for incident HTN in patients withOSA compared to the control subjects. Further follow up revealed a dose-responserelationship between the severity of OSA and the cumulative incidence ofHTN22.Due to the prevalence of obesity as a confounding factor among studied patientpopulations, the confirmation of the association between OSA and HTN has beenchallengingThe pathophysiology of the association between OSA and HTN is multifactorial. Thepotential causative factors are summarized in 22. Adipose tissuedeposition in the oropharyngeal around the upper airway contributes toapnea.Obesity has been identified as an independent risk factor both for OSA andHTN23-26. The nocturnal dipping pattern of BP is anormal physiological phenomenon that is affected by OSA27. Intermittent hypoxia andhypercapnia cause autonomic derangements which lead to nighttime increases inBP, and increased catecholamine levels which persist during daytime, worseningHTN28. OSA is wellknown to cause sleep inefficiency, which in itself has been shown to becorrelated with several cardiovascular risk factors such as non-dipping ofnocturnal BP, endothelial dysfunction, arterial stiffness, and increasedsympathetic activity. The renin-angiotensin system (RAS) is known to beactivated by obesity and more recently, it is known to be activated by OSA. Thepresence of OSA has a cumulative effect on obesity-induced activation of RAS,thereby worsening HTN29.Downstream effects of OSA include physical inactivity, poor dietary habits,insulin resistance, hyperleptinemia, and systemic inflammation. The viciouscycle between obesity and apnea exacerbates HTN30. However, the meta-analysis by Montesi etal.31 demonstrated asignificant reduction in the systolic and diastolic blood pressure of patientswhen treated with CPAP for their OSA. Reduced nighttime BP and sympathetictraffic can be achieved with effective OSA treatment resulting in moresuccessful BP control31.Phillips et al performed a randomized controlled trial to compare the change incardiovascular and neurobehavioral outcomes among patients using CPAP andmandibular advancement devices (MAD). They found that although CPAP was moreeffective at reducing AHI, patient compliance was better with MADs. They alsofound that neither treatment improved blood pressure32. However, OSA often remains asan undiagnosed risk and contributing factor for heart failure. Paulino etal.33 demonstratedthat the prevalence of sleep breathing disorder was 81% (n=256) in 316 patients,30% of whom were classified as CSA and 70% as OSA. Among this cohort ofpatients, both CSA and OSA existed together due to certain pathophysiologicalchanges brought on by heart failure leading to SDB.Sleep-disordered breathing (SDB), , was foundto be more prevalent in patients with heart failure (HF)11. Inaddition, the high negative intrathoracic pressure exerted during inspirationthrough a narrowed or occluded upper airway may increase pulmonary capillaryfluid efflux contributing to interstitial edema.The interactions of the heart failure and OSA are illustrated in 34. Chronic untreated OSA can lead topersistently elevated BP with absent nighttime dipping of BP, contributing toleft ventricular systolic dysfunction35.Increased sympathetic activity leads to increased angiotensin II release which isa potent vasoconstrictor promoting aldosterone production via the adrenalcortex. Aldosterone increases water and salt reabsorption leading to increasedintravascular volume, worsening HTN and heart failure36. In systolic heart failurepatients, nighttime rostral fluid shift from the legs is a contributingpathophysiological mechanism causing worsening of OSA in HF37. Overnight rostral leg fluiddisplacement and an increase in neck circumference have been shown tosignificantly worsen OSA and CSA. There is a positive correlation with thevolume of lower extremity extravascular fluid volume37. The brain stem respiratory centers in themedulla and pons receive input from peripheral arteries and the respiratorysystem. The effectors for the ventilatory center are the respiratory muscles.Heart failure leads to hypoxemia and increased afferent activity from the juxtacapillary receptors (due to pulmonary capillary engorgement) which in turndrives the ventilatory center leading to hyperventilation38. Hyperventilation leads todecreased PaCO2 levels, resulting in hypopnea and/or apnea.There are varied mechanisms by which heart failure may worsen OSA and induceapnea. Fluid overload leading to upper airway (UA) narrowing and upper airwayedema are important mechanisms leading to worsening OSA39.Also, increased circulation time leads to slower feedback from the chemoreceptorsin the peripheral arteries. Pulmonary vascular congestion and edema lead tolower alveolar PAO2 and PACO2 reserve adds to ventilatory instability11.OSA is prevalent in patients with preexisting cardiovascular diseases. Theplausible factors contributing to the development and maintenance ofcardiovascular impairment in patients with OSA include intermittent hypoxemia,development of acidosis, increase in blood pressure and sympatheticvasoconstriction40 was done to establish the association betweenOSA and incident coronary artery disease and heart failure. For the purposes ofdata collection and analysis regarding incident coronary disease, the firstoccurrence of myocardial infarction, coronary heart disease (CHD), death, orcoronary revascularization procedures were included. The rate of incident CHDwas 20.1 events per 1000 person-years of follow-up in men and 8.7 events per1,000 person-years in women. Event rates increased with severity of OSA in men.When these models were adjusted for age, race, BMI, and smoking status, therewas a significant association of apnea/hypopnea index (AHI) with incident CHD inmen but not in women. However, this association was not statisticallysignificant after accounting for diabetes mellitus and lipid measures,adjustment for systolic and diastolic blood pressure and anti-hypertensivemedication use also diminished the significance of the association.The prospective sleep heart health study (SHHS)41 assessedwhether OSA increased the risk of cardiovascular events. The outcomes studiedincluded MI, coronary artery revascularization procedures and death fromcardiovascular causes. These investigators found that patients with OSA had anincreased risk of these outcomes, despite controlling for other cardiovascularrisk factors including diabetes, hypertension, hyperlipidemia, tobacco, andalcohol use. A systematic review by Porto et al.42 supported an association between OSA and MI,which was greater in men.Other prospective studies have shown an increased association between OSA andCHD. Shah et al.43. Fatal myocardialinfarction (MI) and stroke, non-fatal MI, non-fatal stroke, coronary arterybypass surgery, and coronary angiography were the study parameters. Severe OSAsignificantly increased the risk of fatal and non-fatal cardiovascular outcomes.The study also demonstrated that CPAP treatment in patients with severe OSAreduced the aforementioned adverse outcomes and those patients with mild andmoderate OSA, did not exhibit increased risk of these outcomes. Buchner etal.44 reported thatOSA treatment with CPAP had a benefit for patients with all severities of OSAand resulted reduced adverse cardiovascular outcomes. Interestingly the SAVE(sleep apnea cardiovascular endpoints) study45, a randomized control trial conducted to assess theeffects of CPAP on major cardiovascular events, showed that CPAP use did notprevent cardiovascular events in patients with moderate to severe sleep apnea.It did reduce snoring and daytime sleepiness and improved health-related qualityof life and mood. Interestingly the observational study conducted by Anandam etal.46 showed thatCPAPs and MADs may have similar effectiveness in reducing cardiovascularmortality.Another observational study compared cardiovascular outcomes  in men with OSA who were being treated with CPAP versus untreated menwith OSA47. OSA may trigger the onset of and contributesto its persistence48. However,OSA is more common and less frequently detected in patients with AF47,49. The severity of OSAcorrelated with a higher incidence of AF and may also be a predictor of AFrecurrence after cardioversion and/or ablation procedures50,51. There is limited success ofantiarrhythmic therapy in patients with severe OSA52. Patients with OSA are more likely to developAF post coronary artery by-pass graft surgery (CABG)53. OSA is associated with an increased incidenceof AF in patients with heart failure54, coronary artery disease (CAD), and hypertrophiccardiomyopathy (HCM)55.Atrial fibrillation (AF) is the most common arrhythmia linked with OSA. Theprevalence of AF in patients with known OSA is 5%11,47. Episodes of hypopnea/apnea and post apneicreoxygenation also lead to oxidative stress, which contributes to the remodelingof the myocardium47. OSA isassociated with higher levels of CRP and IL-656, however the use of CPAP therapy has beenshown to decrease these inflammatory markers in patients with OSA56.Mechanisms linked to the development of AF in patients with OSA include thehemodynamic changes occurring during the apneic episodes. Hypoxemia andhypercapnia during episodes of hypopnea/apnea leads to tachycardia andhypertension. These changes are accompanied by increased myocardial oxygendemand, despite the restricted supply of oxygen during these episodes. Thisleads to myocardial injury and fibrosis, which promote the development ofAF57. This structural and electrical remodeling contributes tothe development of AF.OSA is also associated with atrial enlargement, conduction abnormalities, andprolonged sinus node recovery time58 and found that the negativeintrathoracic pressure led to a decrease in the left atrial volume, increase inleft ventricular systolic function and an increase in the ventricular afterload.These dynamic changes can be implicated in the development of AF. Repetitivecycles of negative intrathoracic pressure also lead to atrial stretch, whichcontributes to the enlargement of the chambers and development of AF48. Negative intratrachealpressure causes shortening of the atrial effective refractory period throughvagal stimulation, which also predisposes to the development of AF59.Negative intrathoracic pressure during apneic episodes may be associated with thedevelopment of AF. The Mueller maneuver was performed on healthy adults tosimulate the changes in the upper airway, which occur during OSA47. Current evidence suggests that continuouspositive airway pressure is the standard treatment for OSA. Shah etal.60 showed that CPAPhad a beneficial effect on left ventricular remodeling. Use of CPAP isassociated with effective lowering of blood pressure, decreased atrial size andventricular mass, and a lower risk for AF recurrence after ablation61. Recurrence of AF aftercardioversion is also less frequent in patients being treated with CPAP comparedto patients not being treated with62. Bayir et al.63 showed that after 6 months of therapy with CPAP in patientswith OSA, there was an improvement in the interatrial, left intra-atrial andright intra-atrial electromechanical delays when compared to pretreatmentmeasurements and possibly a decreased risk for OSA related AF63. CPAP can also help reverseleft atrial volumetric abnormalities in as little as 12 weeks and improve leftatrial remodeling over a period of 24 weeks64. Furthermore, it reduces the risk of progression fromparoxysmal AF to persistent AF65. Drug refractory AF is often treated with catheter ablation(or a convergent procedure); however, screening patients with atrialfibrillation for OSA prior to catheter ablation may be beneficial, and couldpossibly obviate the need for the procedure66.OSA is considered a modifiable risk factor for AF66. Despite thefailure of RND in managing drug resistant hypertension, there are newexperimental studies suggesting that it may control arrhythmias caused byhyperactivity of the sympathetic nervous system67,68. Linz et al.68 studied the effects of RND on anesthetizedpigs and determined that RND reduced AF caused by negative intratrachealpressure and reduced shortening of the atrial effective refractory period, incontrast to administration of atenolol which did achieve the sameresults68. They alsoreported that RND prevented post apneic elevation in blood pressure, decreasedplasma renin activity and aldosterone levels68.Renal nerve denervation (RND) is an emerging modality that may be ofbenefit69,70.OSA is associated other arrhythmias including ventricular tachycardia, prematureventricular contractions, ventricular fibrillation, sinus bradycardia and sicksinus syndrome (SSS)71conducted a study on 23 patients with an established diagnosis of OSA toevaluate their arrhythmias and to determine the effect of CPAP therapy on thosearrhythmias. These investigators noted that these patients had multiple episodesof bradycardia and long pauses during sleep. Their study also showed thattreatment with CPAP reduced these episodes. In another report, the prevalence ofSSS was 31.6% in patients with OSA72.OSA is also associated with bradycardia, long pauses and sick sinus syndrome.Simantirakis et al.73 performed a studyon 1,394 Japanese patients and found that CPAP therapy substantially reduced theincidence of AF, PVCs, sinus bradycardia, and sinus pauses.Abe et al.74.The prevalence of PH in OSA ranges from 17 to 53%74. According the updated guidelines from 6thWorld Symposium on PH , PH is defined by a mean pulmonary arterypressure (mPAP) >20mmHg rather than >25mmHg, and a pulmonary vascularresistance (PVR) >3 wood units is included to distinguish those withpre-capillary PH75.Pulmonary hypertension (PH) is frequently associated with OSA, and often is adirect consequence of OSAAlveolar hypoxia, causing pulmonary vasoconstriction and endothelialremodeling;Mechanical related to increased inspiratory effort resulting in, morenegative intrathoracic pressure, variations in heart rate andcardiac output, increased left heart filling pressures;76.Reflex mechanisms directly influencing the vasculature76. However,the role of OSA as an independent risk factor for the development of daytime PHis not fully established. Severe OSA frequently causes daytime PH in the absenceof significant co-existing cardiopulmonary and vascular diseases, and CPAPtherapy significantly reduces the levels of daytime pulmonary arterypressure77.Acute pulmonary artery pressure changes during sleep have been reported withobstructive apneas78 leading to both pulmonary vasoconstriction and vascularendothelial remodeling, but there may also be a post capillary componentattributable to episodic or permanent elevations in LV fillingpressure79. Theapplication of nocturnal CPAP therapy can lead to the abolition of bothnocturnal hypoxemia and the accompanying sympathetic surges, resulting inimprovement in LV diastolic relaxation and decreased LV afterload. This maypromote the restoration of the balance among these endothelial vasoactivemediators. Long-term CPAP therapy may avoid irreversible structural pulmonaryvascular and right ventricle changes by reducing the pulmonary artery systolicpressure, possibly improving the prognosis77.Daytime PH may have a precapillary component related to repetitivehypoxia-reoxygenation56 and activates the coagulation cascade, whichincrease the risk of acute thromboembolic events, and also predisposes patientsto the development of Type 4 CTEPH (chronic thromboembolic pulmonaryhypertension)80.OSA promotes the release of inflammatory markers80,81.Evidence supports the pathophysiological association of sleep-disorderedbreathing as an independent risk factor for venous thromboembolism. There isincreased prevalence of sleep apnea in patients with acute pulmonary embolismand/or deep vein thrombosis82.Obstructive sleep apnea-related hemodynamic alterations may result in venousstasis, increased thrombogenicity (on a vascular and molecular level), increasedinflammatory insult and injury, thus fulfilling the criteria for thenomenclature of Virchow’s triad82,83. Chronic hypoxia and hypercapnia in OSA impair thrombusresolution due to inadequate fibrinolysis, persistent inflammation, vascularsmooth muscle activation, accelerated adhesion molecule expression and plateletactivation82-84.The development of CTEPH may be promoted by the persistence of thromboticmaterial in the circulation, stemming from inadequate/incomplete thrombusresolution85. EEGmicroarousals and awakenings frequently follow respiratory compromise. Repeatedoxyhemoglobin desaturation causes alterations in sympathetic nerve activity,oxidative stress, inflammatory markers and endothelial function, which areassociated with decreased vasoreactivity, increased arterial wall stiffness,increased platelet activation and vascular adhesion, resulting in increased riskfor cardiovascular and cerebrovascular insults.Obstructive sleep apnea has been associated with hypoxic-ischemic brain injury(HI-BI), the severity of which depends on the duration and intensity ofhypoxemia and ischemia86,87. A systematic review of 37studies with 3,242 patients showed a high prevalence of OSA in patients withcerebrovascular disease (61.9%)88. A meta-analysis of 16 cohort studies reporting data on24,308 patients demonstrated that moderate and severe OSA are associated with anincreased risk of vascular outcomes, including stroke11. Patients with OSA are more likely to have astroke or die than those without OSA87. There is an association between OSA and nocturnalcerebrovascular events89-91, and a dose-effect relationship has been described betweenthe adjusted risk and OSA severity, as measured by AHI and oxygen desaturationindex, viz., the mean number of desaturations of 4% or more per hour ofsleep86. OSAcontributes to ischemic stroke both as a predisposing risk factor and as atriggering factor; there is a statistically significant association betweenpreceding OSA symptoms and wake-up stroke (WUS)92. A higher percentage of cerebral white matterdisease, radiographic deep grey matter disease or macroangiopathic strokes isnoted in individuals with OSA89. A study of 61 patients with silent cerebral infarct and122 without silent lacunar cerebral infarct demonstrated that the presence ofsevere OSA syndrome was significantly higher in silent cerebral infarct incomparison to patients without lacunar infarcts 93. Fluctuations in cerebral blood flow velocity (CBFV) havebeen documented in OSA, with CBFV increasing along with arterial pressuresduring OSA episodes. Both CBFV and systemic arterial pressures decrease upontermination of the apneic episode, at the lowest level of oxyhemoglobindesaturation94.Numerous studies have shown the association between OSA and stroke95. An impairment in cerebralautoregulation by means of measurement of the recovery of CBFV andcerebrovascular conductance  has been observedafter orthostatic challenges, with slower recovery noted in patients with OSAcompared to control subjects96. A dose-relationship between severity of sleep respiratorydisturbance (as measured by AHI) and impaired cerebral autoregulation has alsobeen noted97. An impairment incerebrovascular CO2 reactivity, measured by the CBF with increasingAHI was demonstrated in one case control study98. Global cerebral blood flow increases duringepisodes of hypoxemia. A study comparing the increase in CBF in patients withOSA compared to that in healthy subjects demonstrated less increase CBF in OSApatients compared to the control subjects, and this difference was notdemonstrable after 3 months of treatment with CPAP99. Data from other studies suggest that it ispossible to normalize cerebral vasoreactivity and cerebral blood flow with CPAPtreatment100,101.Transcranial Doppler imaging has shown decreased cerebrovascular reactivity andincreased arterial stiffness, particularly during OSA episodes102. Increasedmortality 60 months after stroke was observed in those with higher AHI89. The nocturnal nadir ofoxyhemoglobin saturation is an independent predictor of poor functionaloutcomes103. Onestudy demonstrated that higher severity of SDB correlated with a poorerfunctional outcome based on the modified Rankin scale score104.Functional outcomes and long-term mortality of stroke patients with OSA are poorcompared to those without OSA. Patients with a higher AHI required longerinpatient rehabilitation and had lower Functional Independence Measure (FIM)scores89,105.There have been concerns about the safety CPAP treatment in patients of acutestroke occurring in the setting of OSA. It is thought that CPAP treatment mayreduce cerebral perfusion by altering blood oxygen and carbon dioxide balance.Despite these concerns, current data obtained from prospective and cohortstudies suggest no adverse effect of CPAP treatment in patients with OSA duringacute stroke35. A meta-analysis of seven randomized controlled trialswhich included 4,268 patients showed a significant reduction in relative risk ormajor adverse cardiovascular events and stroke, which correlated with increasedCPAP usage time (adherence time >4 hours)106. Another systematic review and meta-analysisof 4 randomized clinical trials and 1 prospectively matched observationalcohort,  showed a mean decrease in National Institutes ofHealth Stroke Scale scores during the first (≤30) days of acute ischemicstroke in patients treated with non-invasive ventilation (NIV) compared tocontrol subjects 107.The effect of continuous positive airway pressure (CPAP) treatment was evaluatedas a primary outcome measure for prevention of new vascular events among OSApatients with stroke. Concurrently, secondary outcome measures were designed toassess post stroke clinical outcomes utilizing the Barthel index and themodified Rankin scale. Measurement of neuropsychological parameters suggestedbetter stroke outcomes and there was a trend toward favorable outcomes vis-a-visreduced recurrence of vascular eventsAlthough several studies have demonstrated the beneficial effect of CPAP onrecovery outcomes in stroke patients, including more rapid functional recovery,reduced hospitalization time, and decreased frequency of re-hospitalization,significant challenges remain due to post stroke disability which may lead tolimited CPAP adherence in the hospital environment.108.Consequently, there has been increased interest in alternate options to treat SDBsuch as mandibular advancement surgery and supine avoidance. Additional studiesare needed to evaluate their efficacy in post-stroke rehabilitationoutcomes109.OSA increased the risk of developing optic neuropathy after controlling forcomorbidities as demonstrated in a Taiwanese population-based cohort study;however, treatment with CPAP did not reduce the risk of opticneuropathy110 highlights OSA as a risk factor for developingglaucoma. Another important point to note is that CPAP therapy can triggerglaucoma damage by raising the intraocular pressure (IOP), which would warrantglaucoma screening in patients on CPAP.Review performed by Chaitanya et al.111.A study to investigate the association between obstructive sleep apnea (OSA) andmiddle ear acoustic transference/cochlear function demonstrated that severe OSAis associated with cochlear function impairment in patients. Patients withsevere OSA presented with significantly lower distortion product otoacousticemissions (DPOAE) amplitudes when compared to the control, mild, and moderateOSA groups112 in a patient with obstructive sleep apneahypopnea syndrome (OSAHS). Five adults OSA patients who presented with enuresis,enuresis resolved after treatment with continuous positive airway pressure(CPAP)113, andsimilar improvement was noted in another case report114.Fecal and urinary incontinence has been reported to resolve after treatment withpositive airway pressure non-invasive ventilation85. Excessivedaytime sleepiness, as measured by the subjective Epworth sleepiness scale (ESS)and the objective multiple sleep latency test (MSLT) and the maintenance ofwakefulness test (MWT) is the most common neurobehavioral consequence of OSA.Other behavioral problems occurring in this patient population includedisinhibition, distractibility, and irritability115,116. Physical skills and cognitive abilities,including selective attention, vigilance, short-term and working memory, andexecutive and motor functioning are adversely affected by OSA115-121. Most neurobehavioraldeficits, except executive dysfunction, have been found to be reversible withCPAP treatment of OSA118,122-124. CPAP treatment for as little as 2 weeks has beenshown to improve daytime sleepiness, including reduction in subjectivesleepiness as measured by the ESS, but no significant changes were observed inobjective sleepiness measured by MSLT or MWT125-127. Several key neurobehavioral indices failed tonormalize despite 3 months of CPAP treatment, even in those who were maximallycompliant with treatment. Forty percent of patients in this trial had anabnormal Epworth sleepiness scale score at the conclusion of the trial128. Despite this, CPAPtreatments have been shown to result in significant improvement in attention,alertness, speed of visual motion perception, vigilance, speed of informationprocessing immediate visual memory, working memory and cognition122,126,129. A prospective 12-monthobservational study of CPAP treatment of OSA assessed its effects on non-motorsymptoms in 67 patients with Parkinson’s disease. Overall improvement innon-motor symptoms, sleep quality, anxiety, and global cognitive function wereobserved130.Patients with OSA demonstrate impairments in behavior, cognition, and physicalskills2.Clinical symptoms play a key role in the diagnosis of OSA, although no sign orsymptom is specific for the diagnosis of OSA. Once there is a high suspicionquestionnaires and symptom- scoring scales can be used to increase the accuracyof diagnosis. Screening questionnaires are used in the outpatient setting, forsymptomatic patients, to determine whether a patient should undergopolysomnography. Polysomnography is the standard for diagnostic confirmation,however it is expensive and not always available8.The Mallampati classification  is used toevaluate if tonsillar, uvular, and tongue enlargement are affecting the airwayvolume131-133.Activation of the pro-inflammatory transcription factor nuclear kappa factor B(NF-kB) by apnea-induced hypoxia is an important pathway linking obstructivesleep apnea with systemic inflammation. It can also stimulate the downstreaminflammatory markers resulting in end- organ cardiovascular disease. NF-kBactivity is elevated in circulating neutrophils and monocytes in patients withobstructive sleep apnea and studies have revealed decreased activity withcontinuous positive airway pressure therapy in adults134,135.Questionnaires are sensitive however not very specific, therefore when a patienthas low scores, it is helpful to attempt to reduce the diagnostic likelihood ofOSA, in some instances avoiding the need to proceed withpolysomnography135.Every parameter is scored one point; and a score of >3 indicates a highrisk of OSA.The STOP-bang questionnaire includes questions on snoring, tiredness,observed apneas, blood pressure, BMI, age, neck circumference, and gender.It is one of the most sensitive questionnaires available for use in theclinical settingSleep apnea clinical score (SACS)It includes data on the neck circumference, hypertension, habitual snoring,and nocturnal gasping or choking. The score ranges from zero to 100 and ascore greater than 15 increases the likelihood of being positive forOSA.135.The questionnaire has ten sections distributed in three categories, whichinclude data on snoring, non-restorative sleep, sleepiness while driving,apneas during sleep, hypertension, and BMI. Points are assigned for eachcategory and the patient is identified as high risk or low risk based on thepoints136.The system assesses five components including neck circumference, BMI, snoring,age, and sex. A cut-off of eight points is used to identify patients withsleep-disordered breathing2. The preferred approach is to perform overnightPSG in the sleep laboratory; however, it is costly and may not be available (norapproved by third party insurers) at all times. Therefore, home sleep apneatesting (HSAT) can be used for certain patient populations137. HSAT can be performed forpatients who have a high pre-test probability of OSA and do not have othercomorbidities137.However, if a HSAT is inconclusive, inadequate or negative, PSG should beperformed137.Patients with comorbidities such as cardiovascular disease, respiratory muscleweakness secondary to neuromuscular disorders, history of strokes or otherischemic disease, and chronic opioid use should undergo PSG rather thanHSAT137.PSG is the standard procedure for the diagnosis of OSA2. Respiratory airflow recommended: simultaneousmonitoring of two physical variables: air temperature  andair pressure , respiratory effort, oxyhemoglobin saturation,and ECG are monitored21. Todiagnose OSA, apnea-hypopnea index (AHI) is measured, i.e., the number of apneicand hypopneic episodes per hour of sleep are tabulated21. Apnea is an episode of stoppage ofrespiratory airflow for a minimum of 10 seconds. Hypopnea is the decrease inairflow, associated with either a drop-in oxyhemoglobin saturation or an episodeof arousal21. AHI of greaterthan five is diagnostic of OSA. AHI greater than or equal to five but less thanfifteen is classified as mild, greater than or equal to fifteen but less thanthirty is classified as moderate, and greater than or equal to thirty isclassified as severe OSA22.Several parameters are monitored during PSG. Electroencephalography (EEG), chinelectromyography (EMG) and electrooculography (EOG) are done to identifyepisodes of arousal and to determine sleep stage2,138. CPAP treatment prevents (or ameliorates) collapse ofthe upper airways137. Changein dietary habits, regular exercise, and weight loss can also contribute to themanagement of OSA139.Bariatric surgery is an option in extreme cases, and may be associated withsignificant improvement; however, it has not been shown to totally reverse OSAand does not replace the use of CPAP as the primary treatment140. However, after surgery andsignificant weight loss polysomnography should be repeated and CPAP titrationshould be performed141. Othersurgical options include tonsillectomy, uvulopalatopharyngoplasty, tonguesurgery (to reduce the size) and maxillomandibular advancement surgery142. Another alternative is theuse of mandibular advancement devices (MAD). The purpose of the device is toexpand and stabilize the airway and to lessen the collapse. Although these arenot as effective as CPAP in reducing AHI142,143 they can be used in certain circumstances when thereis insufficient compliance with CPAP use.CPAP is the primary management strategy for OSA as it decreases symptoms ofsleepiness and improves quality of life in patients with moderate and severedisease144 performed aclinical study with 8 patients, comparing the use of CPAP and MAD and found thatthe symptoms improved to greater extent with CPAP. In cases where adherence toCPAP is low, these alternative options can be considered. However, CPAP istreatment of choice and has shown the best outcomes, including reduction inall-cause mortality2,138,145. Yearly follow up should be performed after CPAP isinitially set up146. Oralappliances can be used for patients mild to moderate OSA under certainconditions146. Ramaret al.147 publishedrecommendations based on an extensive review that endorsed the use of oralappliances for patients with snoring (without OSA) and for patients with OSAthat are intolerant of CPAP or prefer an alternate treatment. Their guidelinesalso included the use of custom oral devices for patients with oversight byqualified dentists to monitor for dental side effects, and follow up testing bysleep physicians to check for treatment effectiveness.Wojda et al.OSA affects multiple organ systems. OSA may first present with cardiovascular orneurological morbidity, rather than respiratory symptomatology. It is important touse clinical judgement and to keep a low threshold for diagnosis when patientspresent with these varied signs and symptoms in order to make a timely diagnosis andto intervene to prevent morbidity and mortality.


The current guidelines for managing hypertension recommend strict blood pressure (BP) control to prevent bleeding complications in patients with hypertension on antithrombotic therapy. However, the target BP value of <130/80 mmHg is achieved in a small proportion of these patients. This study aimed to examine the factors associated with nonachievement of target BP value (≥130/80 mmHg) in patients on antithrombotic therapy. This retrospective study was conducted at an outpatient clinic in 2018. Clinical parameters were obtained from the center’s electronic medical database. Office BP was measured once in the sitting position. A target BP value of <130/80 mmHg was defined according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2019. Of the 26,803 outpatients who had scheduled visits during this time, 2,427 received antithrombotic therapy. Patients with chronic kidney disease stage 5 or on hemodialysis and those with missing data on body mass index were excluded from the study; eventually, 2,201 outpatients met the inclusion criteria. BP values of <140/90 mmHg were observed in 59.2% of these outpatients; however, only 30.6% displayed the target BP value of <130/80 mmHg. Univariate and multivariate logistic regression analyses indicated that male gender and obesity significantly correlated with nonachievement of the target BP (≥130/80 mmHg). However, heart failure and ischemic heart disease were negatively but significantly related to nonachievement of the target BP. The target BP value was achieved in only a small proportion of the patients treated with antithrombotic drugs. In patients on antithrombotic therapy, obesity appeared to be a modifiable risk factor, whereas cardiovascular comorbidities, such as heart failure, were negative factors contributing to nonachievement of the target BP.  Observational studies (7), post hoc analyses of randomized clinical trials (RCTs) (10), and phase III clinical trials of non-vitamin K antagonist oral anticoagulants (12) have demonstrated a strong association between blood pressure (BP) levels and the hemorrhagic complications of antithrombotic therapy. However, the target BP value to prevent the hemorrhagic complications of antithrombotic therapy remains to be determined.Although antithrombotic therapy is widely prescribed for the secondary prevention of ischemic stroke, ischemic heart disease, and other cardiovascular diseases, it has been associated with a modest increase in hemorrhagic complications (15), the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2019 (JSH 2019) recommend that BP should be carefully controlled in patients with hypertension on antithrombotic therapy, with a target BP value of <130/80 mmHg, despite the insufficient evidence for target BP values that prevent bleeding complications during antithrombotic therapy (15). We recently demonstrated that most patients with hypertension on antithrombotic therapy in real-world practice exhibit a BP value of <140/90 mmHg, while the target BP value of <130/80 mmHg is achieved only in a small proportion of these patients (16). However, other previous studies on the association between BP and the hemorrhagic complications of antithrombotic therapy have included not only patients with hypertension but also those without (18). Accordingly, this study aimed to investigate the attainment status of target BP (130/80 mmHg) and the factors associated with nonachievement of target BP in patients receiving antithrombotic therapy in real-world practice.Among the recently updated major hypertension guidelines This study was designed in accordance with the principles of the Declaration of Helsinki and was approved by the human research ethics committee of Keiaikai . Because this was a retrospective study, written informed consent could not be obtained from each patient. However, according to the Ethical Guidelines for Clinical Research issued by The Japanese Ministry of Health, Labour and Welfare, all relevant details regarding the objectives and procedure of this study were published on the official homepage of the authors’ hospital to allow patients to refuse participation in the study if they so wished.Clinical data from outpatients attending the Keiaikai Chibana Clinic between January 1, 2018 and December 31, 2018 were obtained from the center’s electronic medical database. Patients who met the following criteria were recruited: (1) age of ≥20 years, (2) at least one regular scheduled visit to the clinic, (3) at least 1 month of regular follow-up, and (4) an office BP measurement. Those with chronic kidney disease (CKD) stage 5, on hemodialysis, and with missing data on the body mass index (BMI) were excluded from the study.(15). Obesity was defined as BMI of ≥25 kg/m2; diabetes mellitus as fasting blood glucose (BG) of ≥126 mg/dL, casual BG of ≥200 mg/dL, hemoglobin A1c of ≥6.5%, or using antidiabetic drugs; dyslipidemia as low-density lipoprotein cholesterol of ≥140 mg/dL, triglycerides of ≥150 mg/dL, high-density lipoprotein cholesterol of <40 mg/dL, or using antilipidemic drugs; and CKD as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 or proteinuria by urine dipstick test (≥1+). Atrial fibrillation (AF) was recorded if documented any time on 12-lead electrocardiograms or Holter monitors. The definitions were taken from the International Statistical Classification of Diseases and Related Health Problems 10th revision (ICD-10) codes as follows: hypertension (I10-I15), diabetes mellitus (E10-E14), dyslipidemia (E78), cerebrovascular disease (I60-I69), ischemic heart disease (I20-I25), heart failure (I50), CKD (N18), and AF (I48).The extracted data included age, gender, office BP, height, body weight, BMI, cardiovascular risk factors, past history of cardiovascular disease, comorbidities, prescriptions, and routine laboratory tests. Office BP was measured once in the sitting position using an aneroid or electric automatic sphygmomanometer at the first scheduled visit. Hypertension was defined as systolic BP (SBP) of ≥140 mmHg, diastolic BP (DBP) of ≥90 mmHg, or ongoing treatment with antihypertensive drugs. The office BP value was classified according to the JSH 2019 guidelines as follows: normal BP, SBP of <120 mmHg and DBP of <80 mmHg; high-normal BP, SBP of 120-129 mmHg and DBP of <80 mmHg; elevated BP, SBP of 130-139 mmHg and/or DBP of 80-89 mmHg; grade I hypertension, SBP of 140-159 mmHg and/or DBP of 90-99 mmHg; grade II hypertension, SBP of 160-179 mmHg and/or DBP of 100-109 mmHg; and grade III hypertension, SBP of ≥180 mmHg and/or DBP of ≥110 mmHg (15).Diagnoses of cerebrovascular disease, ischemic heart disease, and heart failure were also extracted from the database. Cardiovascular risk was then categorized according to the JSH 2019 guidelines as follows: category I, patients without any factors affecting the prognosis other than BP; category II, having at least one factor except age of ≥65 years, male gender, dyslipidemia, and current smoking; category III, having at least one factor other than a history of cardiovascular diseases, nonvalvular AF, diabetes mellitus, and proteinuria positive CKD, or ≥3 of the category II risk factors The primary outcomes of interest were the rate of attainment of the target BP value of <130/80 mmHg and factors associated with nonachievement of target BP in patients on antithrombotic therapy. The secondary outcomes were the status of BP distribution and cardiovascular risk categorization in this population.Continuous variables are expressed as mean ± standard deviation. Categorical variables are presented as frequencies and percentages. Categorical variables were analyzed using Chi-square test. The odds ratios (ORs) for nonachievement of target BP were calculated using univariate and multivariate logistic regression analyses. The explanatory variables for the multivariate analysis were also adopted from well-known cardiovascular risk factors and comorbidities, such as cerebrovascular disease, ischemic heart disease, heart failure, CKD, and AF. Additionally, the ORs for nonachievement of target BP were also calculated in patients with or without AF. Antihypertensive drug use was not included as an explanatory variable in the multivariate analysis to avoid multicollinearity. We used JMP version 13.0.0  for statistical analysis. Two-sided p-values of <0.05 were considered statistically significant.Of the 26,803 screened subjects, 2,427 received antithrombotic therapy. Following the exclusion of outpatients with CKD stage 5 (n = 17), patients on hemodialysis (n = 12), and patients with missing data on BMI (n = 197), the remaining 2,201 patients met the inclusion criteria. (15) revealed that 0.2%, 5.2%, and 94.6% of the patients on antithrombotic therapy were in risk categories 1, 2, and 3, respectively.(15). Therefore, we conducted a subgroup analysis of the status of BP control in 381 patients with AF as a complication. A mean SBP of 131.0 ± 18.5 mmHg and a mean DBP of 76.0 ± 14.0 mmHg were observed in patients with AF on antithrombotic therapy, of whom 42.8% achieved a target SBP value of <130 mmHg.The JSH 2019 proposes that BP control with a target SBP of <130 mmHg should be performed in patients with AF Univariate logistic regression models indicated that male gender , obesity , and dyslipidemia  were positively associated with nonachievement of the target BP (≥130/80 mmHg) in patients on antithrombotic therapy. Heart failure , ischemic heart disease , and age of ≥75 years  were negatively associated with nonachievement of the target BP . MultivaIn this study, most patients on antithrombotic therapy achieved a BP value of <140/90 mmHg, while only approximately 30% of them attained the target BP value of <130/80 mmHg. Univariate and multivariate logistic regression modeling suggested that in patients on antithrombotic therapy, obesity is a modifiable risk factor, whereas comorbidities with cardiovascular diseases, such as heart failure, are negative factors contributing to nonachievement of the target BP.(3), antithrombotic therapy is associated with a modest increase in hemorrhagic complications, especially intracranial hemorrhage (3). The Perindopril Protection Against Recurrent Stroke Study involving patients on antithrombotic therapy demonstrated that antihypertensive drug treatment decreased the mean BP and that the antihypertensive drug group had a 46% lower incidence of intracranial hemorrhage than the placebo group (8). The Bleeding with Antithrombotic Therapy study found a significant positive correlation between on-treatment BP and the incidence of intracranial hemorrhage, with a cutoff BP value of 130/81 mmHg predicting the onset of intracranial hemorrhage (4). In the Secondary Prevention of Small Subcortical Strokes trial, which compared patients with lacunar infarction who received aspirin alone with those on dual antiplatelet therapy, the rate of intracerebral hemorrhage in patients with a target SBP value of <130 mmHg was significantly reduced by 67% compared with that in patients with a target SBP value of 130-149 mmHg (9). The JSH 2019 guidelines state that BP control should be more carefully evaluated in patients with hypertension on antithrombotic therapy with a target BP value of <130/80 mmHg, despite the insufficient evidence for target BP values that prevent bleeding complications during antithrombotic therapy (15). We recently demonstrated a target BP value of <130/80 mmHg in 31.1% of patients with hypertension on antithrombotic therapy (16), a low rate of achieving the target BP. Other previous investigations on the association between BP and the hemorrhagic complications of antithrombotic therapy involved not only patients with hypertension but also those without (18). In this present study, we extended the inclusion criteria of our previous study and investigated the status of BP control and its correlates in patients on antithrombotic therapy. We confirmed that the rate of BP < 130/80 mmHg has remained low and found that more than 90% of the patients were in cardiovascular risk category 3 of JSH 2019. Thus, this population requires stricter BP control. Furthermore, comorbidity with obesity is a modifiable factor associated with nonachievement of target BP. Regarding the BP-lowering effects of weight reduction, it has been estimated that a weight loss of 1.0 kg lowers both SBP and DBP by approximately 1.0 mmHg (19), and a meta-analysis reported a significant reduction in BP following a weight loss of 4 kg (20).Although antithrombotic therapy is widely used for the secondary prevention of ischemic stroke, ischemic heart disease, and other cardiovascular diseases and oral anticoagulants have been prescribed to prevent cardiogenic embolism and deep venous thrombosis (22). RCTs have demonstrated that the management of hypertension reduces the risk of heart failure by ~50% (24). However, not only higher BP but also lower BP were associated with higher mortality in patients with heart failure (26). Thus, the effect of optimal BP levels on the prognosis of patients with heart failure remains unclear. No target BP levels have yet been recommended to adjust the dose of the neurohormonal blockade, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and/or mineralocorticoid receptor blockers (28). In RCTs, the use of the maximal tolerable dose is recommended irrespective of BP values. Additionally, lower SBP could be associated with a reduced stroke volume in patients with heart failure. In this study, univariate and multivariate logistic analyses indicated that heart failure was negatively but significantly associated with nonachievement of the target BP. The use of neurohormonal blockade of patients with heart failure was higher than that of patients without heart failure (data not shown). These may affect the association between the attainment of the target BP value of <130/80 mmHg and heart failure in this population.Hypertension is the most important modifiable risk factor for the development of cardiovascular diseases such as heart failure (29). In a meta-analysis of patients with coronary artery disease, target SBP value of <130/80 mmHg was related to a 30% reduction in heart failure and a 20% reduction in stroke, without increasing all-cause mortality or cardiovascular mortality, compared with target SBP value of 136-140 mmHg (30). Additionally, in a meta-analysis of patients with coronary artery disease without complications of hypertension, antihypertensive treatment reduced incidence of stroke by 23%, myocardial infarction by 20%, heart failure by 29%, cardiovascular death by 17%, and all-cause mortality by 13% (31). JSH 2019 recommends an antihypertensive target of <130/80 mmHg for patients with coronary artery disease (15). In this study, univariate and multivariate logistic analyses also indicated that ischemic heart disease was negatively associated with nonachievement of the target BP. Although the precise reason(s) for ischemic heart disease being a negative factor for attaining the target BP value of <130/80 mmHg remain unclear, the number of antihypertensive medications of patients with ischemic heart disease was higher than that of patients without ischemic heart disease (data not shown).A meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration has shown that antihypertensive treatment reduces coronary artery disease in patients with hypertension, regardless of the type of antihypertensive medications (15). The Japanese Rhythm Management Trial for AF demonstrated that the highest quartile of on-treatment SBP (≥136 mmHg) and SBP at the end of the follow-up period were reported to be significantly associated with the incidence of major hemorrhage and thromboembolism (6). A recent meta-analysis regarding the BP thresholds for patients with AF on direct oral anticoagulant therapy demonstrated that the nadir SBP for cardiovascular mortality was 130 mmHg (32). Additionally, worse BP control during follow-up appeared to be a predictor of higher risk of stroke and systemic embolism in patients with AF on antithrombotic therapy (33). In this study, we also demonstrated that in patients with AF on antithrombotic therapy, obesity was a positive correlate, whereas heart failure was a negative correlate of nonachievement of the target BP. Barrios et al. investigated the BP control rates of anticoagulated patients with hypertension and AF (34). The target BP values were defined according to the 2013 European Society of Hypertension/European Society of Cardiology guidelines (35). The authors reported that more than 75% of patients with hypertension with AF attained target BP values (34). However, the target BP values of the 2013 European guidelines (35) were different from those of current guidelines (15). The JSH 2019 proposes that, in addition to adequate antithrombotic therapy and heart rate control, BP control with a target SBP of <130 mmHg should be performed in patients with AF (15). We conducted a subgroup analysis of the status of BP control in 381 patients with AF as a complication. Only approximately 40% of them attained the target SBP value of <130 mmHg.In patients with AF on antithrombotic therapy, insufficient BP control is known to be a major risk factor for hemorrhagic complications The current study has several limitations. First, this is a single-center study, which hinders the generalizability of our findings to the entire population of people on antithrombotic therapy. Second, this was a retrospective study; therefore, the results do not prove a causal relationship between BP and the correlative factors. Third, office BP was measured once for each patient, and the times and methods of measurement were not uniform for all patients. Fourth, the choice of the treatment method was left to the discretion of the attending physician. Finally, the adherence of patients to medication and the effects of lifestyle modifications or nonpharmacological therapy on BP were not considered. Since these limitations may affect the status of BP control and its correlates, careful consideration is needed when comparing the present results to those of other studies.In patients on antithrombotic therapy in real-world practice, only ~30% achieved the target BP value of <130/80 mmHg. This study also pointed out that in patients on antithrombotic therapy, obesity was a modifiable factor but cardiovascular comorbidities were negative factors associated with nonachievement of the target BP.Nonewww.enago.com) for the English language review.The authors would like to thank Enago


Background and Objectives: Renal artery denervation (RDN) procedure is a broadly discussed method in the treatment of resistant hypertension. Many studies report short-term (3–12 months) results for blood pressure and arterial stiffness. The primary endpoints were changes in 24 h mean systolic blood pressure (BP) and office systolic BP 48 months after RDN. The secondary endpoints were changes in aortic pulse wave velocity and impact of polypharmacy on these variables. Materials and Methods: Renal artery denervation was performed in 73 patients treated for resistant hypertension; 49 patients remained in final analysis. Patient examination was carried out before the procedure, and subsequently at 3, 6, 12, 24, and 48 months later. Patients’ antihypertensive and overall medication regimens were carefully analysed. Results: Mean 24 h arterial blood pressure lowered and was sustained at lower levels for up to 48 months; median (interequartile range—IQR) from 158(23.5)/100(14.2) to 140(26.5)/86(16.2) mmHg. Mean reduction in 24 h ambulatory systolic BP was −11 ± 25 mmHg , while office systolic BP reduced by −7 ± 23 mmHg . A significant reduction in median aortic pulse wave velocity 12 months after the procedure (drop from baseline 11.2 [3.15] m/s (95%CI 6.1 to 16.2) to 9.8 [2.1] m/s ). After 48 months, there was no worsening compared to the baseline level of 10.3 [4.0] m/s (95% CI 6.9 to 17.8) (p > 0.05). The total mean number of antihypertensive drugs remained unchanged: 5.97(±1.1) vs. 5.24 (±1.45). A higher number of pills after 48 months was associated with higher aortic pulse wave velocity  (p = 0.003). Conclusions: Antihypertensive effect after renal denervation lasts up to 48 months with no worsening of arterial stiffness compared to baseline. In our study, polypharmacy was associated with increased arterial stiffness 48 months after the procedure. Arterial hypertension (HTN) remains the main risk factor for death and disability in the world . ApproxiOver the past few years, there have been some studies with opposing conclusions on the effectiveness of renal artery denervation (RDN). SYMPLICITY HTN-1 and HTN-2 Trials presented a significant antihypertensive effect. Unfortunately, SYMPLICITY HTN-3 failed to prove a significant reduction in peripheral BP six months after RDN procedure in comparison to a placebo . In 2017Aortic pulse wave velocity (AoPWV) is supposed to be the “gold standard” for estimating aortic stiffness as an independent variable for foreseeing adverse cardiovascular events due to its responsibility for the majority of pathophysiological pathways that results in causing cardiovascular outcomes ,10. BranIn our previous study, we also observed a significant reduction in blood pressure and AoPWV that was sustained for up to 12 months after the RDN procedure  years. Pre-intervention median (IQR) office blood pressure was 180(40)/110(15) mmHg in the study group of patients treated with an average of 6.25 [5.8–6.9] antihypertensive drugs at maximum or maximum tolerated doses. Baseline characteristics of the patients before the procedure are presented in When analysing our follow-up data, we observed a significant decrease in the median office BP from baseline at month 3, i.e., from 180/110 to 162.5/94.5 mm Hg, which was sustained at months 6, 12, 24 and 48 . Immediap < 0.001), while office systolic BP reduced by −7 ± 23 mm Hg; .A significant decrease in the median 24 h ambulatory BP from baseline was measured at month 6, i.e., from 158/100 to 146/89 mmHg, and persisted at months 12, 24 and 48. Office and 24 h ambulatory BP values with regard to other timeframes are presented in p = 0.002), mean reduction −1.4 ± 0.98 m/s (95% CI −3.1 to −0.3). cfPWV remained unchanged at 6 and 24 months and was 10.3 [4.0] m/s (95% CI 6.9 to 17.8) at the 48-month follow-up. (We observed a significant decrease in median [IQR] cfPWV 12 months after the procedure (drop from baseline 11.2 [3.15] m/s (95% CI 6.1 to 16.2) to 9.8 [2.1] m/s   and compared them in time with blood pressure and cfPWV. There were no significant differences found between pill groups in 24 h BP monitoring a. Howeve= 0.003) b.n = 7.33 (±2.44) prescribed for treating arterial hypertension and concomitant pathologies. For instance, some of our patients were taking as many as 14 pills per day. As presented in To our knowledge, our study has shown, for the first time, that the antihypertensive effect lasts up to 48 months after RDN, and our data expand beyond the previously reported 36-month RDN sustainability period . Since tArterial wall stiffness is recognized as an important independent risk factor for cardiovascular outcomes causing increased systolic BP and increased pulse pressure in the microcirculation of target organs resulting in their damage. Such conditions as ageing, hypertension, diabetes mellitus and CKD increase arterial wall stiffness. This process is decided by common molecular and cellular pathophysiological pathways, resulting in endothelial dysfunction ,20. DespAccording to a study by Diaz et al. , a mean From the perspective of personalised HTN treatment strategy, despite a number of trials and meta-analyses, there still are many unknown facts related to the RDN procedure. Several studies report that younger patients suffering from abdominal obesity, combined systolic–diastolic hypertension after exclusion of secondary causes and high baseline heart rate would benefit most from the RDN procedure . In our Trials by our colleagues analysed above and our data suggest that renal denervation could be an effective adjuvant procedure to optimised medication regimens in treating resistant or refractory hypertension.The blood pressure lowering effect lasts up to 48 months after RDN, with no worsening of arterial stiffness compared to baseline. In our study, polypharmacy was associated with increased CfPWV at 48 months after RDN.The major limitation of the present research is the size of our study group and our lack of a control group. Therefore, the study is not a comparative study, but rather an interventional study that represents a trend of blood pressure and arterial wall stiffness after RDN. Another drawback is the deficiency of direct data measuring sympathetic nervous activity. The third limitation is the lack of patients’ plasma or urine drug concentration analysis, given that drug non-adherence has been a hot topic in the past decade. Finally, we lost some follow-up data due to the outbreak of the COVID-19 pandemic.