There was also a 0.62% increase in muscle mass in the AG vs. the NAG (p < 0.05), while the body fat decreased by 1% (p < 0.05 in AG vs. NAG). Overall, the AG gained twice the amount of muscle mass and lost twice as much body fat as the NAG. No effects on the mean weighted average heart rate were recorded in the subjects. The results suggest that oral supplementation with arginine can improve blood pressure and body composition, potentially counteracting the stress induced by resistance exercise training. Supplementation with arginine can be a suitable adjuvant for these health benefits in individuals undertaking regular resistance training.Resistance exercise training is well documented as having cardiovascular benefits, but paradoxically, it seems to increase arterial stiffness, favoring the development of high blood pressure. The present study investigates the potential effects of oral supplementation with arginine in healthy individuals performing exercise resistance training. We studied 70 non-smoking male subjects between the ages of 30 and 45 with normal or mildly increased blood pressure on ambulatory monitoring (for 24 h) and normal blood samples and echocardiography, who performed regular resistance exercise training for at least five years with a minimum of three workouts per week. They were divided into two groups in a random manner: 35 males were placed in the arginine group (AG) that followed a 6-month supplementation of their regular diets with 5 g of oral arginine powder taken before their exercise workout, and the control (non-arginine) group (NAG) consisted of 35 males. All subjects underwent body composition analysis, 24 h blood pressure monitoring and pulse wave analysis at enrollment and at six months. After six months of supplementation, blood pressure values did not change in the NAG, while in the AG, we found a decrease of 5.6 mmHg ( Arginine is classified as a semi-essential or essential conditioned amino acid and plays a central role in the optimal development and maintenance of an individual’s health. However, there are certain situations in which the internal synthesis of arginine cannot be achieved, and its external supplementation is necessary ,2,3.The first stage in the arginine synthesis process is citrulline production, from glutamine and glutamate, in the intestinal epithelial cells . SubsequThe intestinal–renal axis is the primary mechanism of internal arginine synthesis, but smaller amounts are also produced in many other cells at a lower level. Arginine production ability increases under circumstances that induce the activity of inducible nitric oxide synthase (iNOS) . CitrullA phenomenon that is still yet to be explained is the L-arginine paradox, which means that, despite the fact that nitric oxide synthases are saturated with exogenous L-arginine, the amino acid creates no mediated biological effects through the activation of guanylyl cyclase. Among the hypotheses for this phenomenon, we have the vasodilatory role of insulin, the secretion of which is induced by L-arginine, or the fact that NOS activity is determined by neither the extracellular nor intracellular concentration, but rather by the amount of amino acids carried across the plasma membrane. Nakaki T. and Hishikawa K. consider, in their study, that NOS endogenous inhibitors may play a role in the reduced enzyme sensitivity to L-arginine, or that L-citrulline could be an important NOS inhibitor, which consequently leads to L-arginine–L-citrulline competition ,13.Oral arginine supplementation in patients with mild arterial hypertension leads to increased citrulline plasma levels and total antioxidant status ,15. ElevA study that included hypertensive patients treated with oral arginine supplementation (6 g per day in three doses for four weeks) showed a marked improvement in angina pectoris class (graded according to the Canadian Cardiovascular Society), mean blood pressure values and quality of life. Improved values were also recorded in maximal forearm blood flow (FBF), plasma l-arginine levels and cyclic guanosine monophosphate (cGMP) . The benThe endothelial lining of the penis’ corpus cavernosum is significantly vulnerable to free radical action and atherosclerotic plaque formation. As is well-established, this area is more sensitive to these hazards than any other in the body . A poor Paradoxically, strength training seems to increase arterial stiffness, a predictor for developing arterial hypertension and an independent risk parameter for cardiovascular morbi-mortality ,29. CurrConsidering the hypothesis that resistance exercise leads to arterial stiffness to be true, we evaluated the impact of arginine supplementation on vascular elasticity in healthy individuals who practice regular resistance exercise training.Seventy-four non-smoking males between 30 and 45 years old, who had been performing regular resistance exercise training at least three times a week for more than five years, were enrolled in several fitness facilities in Bucharest for a period of two years (1 June 2020–1 June 2022). The initial goal was to create mixed study groups regarding gender, but a lack of effective enrollment of female participants led to our inability to form a representative group. Thus, only male patients were evaluated. The inclusion criteria were: age (between 30 and 45 years old), no personal or familial history of arterial hypertension, type 2 diabetes mellitus, cardiovascular or renal disease and the ability to fully understand the informed consent. Subjects under 18, those without the ability to understand informed consent and subjects diagnosed with cardiovascular disease during initial assessments were excluded. Four of the enrolled participants were excluded from the study after the initial medical assessments, so the final number of participants was 70. There were no dropouts during the study. In our opinion, this was due to certain inclusion criteria , the pre-enrolment counseling sessions (describing the study in detail and the importance of continuous participation) and last but not least, the minimal impact the study had on the participants’ daily schedule.After receiving all the appropriate information and training, the subject’s participation in the study was voluntary. Patient data protection was ensured through pseudo-anonymization. Each participant was assigned an identifier, which had the role of separating personal information from the study’s data collection. No patients were at risk of physical, social, psychological or legal harm during the study. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Carol Davila University of Medicine and Pharmacy, Bucharest, Romania for studies involving humans.A clinical evaluation was performed at baseline consisting of blood samples , 24 h blood pressure monitoring, electrocardiogram recording and transthoracic echocardiography.Body composition was assessed using a 4-electrode  weight scale with bioelectrical impedance analysis. In addition, pulse wave analysis was completed using a device based on the oscillometric principle.After the baseline evaluation, patients were randomly split into two groups: one group consisted of 35 males selected to take an oral supplement of 5 g of arginine powder before each resistance training session for six months . The other group of 35 subjects was a control group that was assigned to take 5 g of placebo powder . They were not allowed to consume any other oral or injectable performance-enhancement supplements during this period. The dose of arginine administered to the study’s participants was decided considering the fact that pre-workout arginine supplements have a standard measure of 5 g and that current studies demonstrate benefits in cardiovascular disease patients at doses between 6 and 30 g ,32.After six months, a clinical and paraclinical assessment consisted of clinical evaluation, blood samples, resting ECG, 24 h blood pressure monitoring, body composition assessment and pulse wave analysis.t-test and chi-squared. Evaluation of the correlations of the variables was performed by scatter graphs. Results with p < 0.05 were considered statistically significant. All statistical analysis was performed using the SPSS program and Microsoft Excel.Statistical analysis was performed via the F-test, At baseline , the meap < 0.001)  .p < 0.001) improvements in muscle mass, total fat, systolic and diastolic blood pressure, heart rate and pulse wave velocity. Consequently, after taking a dose of 5 g arginine, the participants had an increase in muscle mass and a decrease in total body fat, systolic and diastolic blood pressure, heart rate and pulse wave velocity  with increases in muscle mass and a decrease in fat percentage in both groups .t-test (p > 0.05). In the NAG, there was a 0.5% reduction in the total fat (p < 0.05) compared to the AG, which had a 1% reduction in the total body fat (p < 0.05). In addition, in the NAG, there was a 0.3% increase in the total muscle mass (p < 0.05) compared to the 0.62% increase in the AG (p < 0.05).Using a paired sample t-test , a compap = 0.694), diastolic average blood pressure decreased by 0.05 mmHg (p = 0.896) and there was a mean pulse average reduction of 1.5 beats per minute (p < 0.05). Meanwhile, in the AG, the 24 h blood pressure monitoring systolic average blood pressure values decreased with a mean of 5.6 mmHg (p < 0.05), diastolic average blood pressure decreased by 4.5 mmHg (p < 0.05) and there was a mean pulse weighted average reduction of 1.5 beats per minute (p < 0.05). In addition, in the NAG, pulse wave velocities decreased by 0.03 m/s compared to the AG, where the reduction was 0.15 m/s (p < 0.05).In the NAG, following the 24 h blood pressure monitoring, systolic average blood pressure values decreased with a mean of 0.22 mmHg  of the brachial artery before and after administering l-arginine. The results were then compared to a placebo group. Although no change was observed in either group in heart rate, blood pressure or baseline diameter, the l-arginine administration improved FMD. Thus, it was concluded that l-arginine supplementation improves forearm blood flow in hypertensive patients .Another study evaluated the role of arginine supplementation on arterial resistance, inflammatory processes and metabolic parameters in patients with multiple cardiovascular risk factors. Patients were assessed for lipid and glycemic profiles, systemic inflammation and renin and aldosterone levels. Their arterial elasticity was evaluated through pulse wave contour analysis. At baseline, no differences were found between the groups on the large artery elasticity index (LAEI). However, the LAEI showed a significant improvement in patients treated with l-arginine supplements. At the six-month evaluation, systemic vascular resistance was lower in this group compared to the placebo one. Meanwhile, the small artery elasticity index (SAEI) did not change in value from baseline. Plasmatic aldosterone levels decreased significantly. This study demonstrated the benefits of arginine supplementation for large artery elasticity in patients with cardiovascular disease. Furthermore, improved arterial elasticity has been associated with lower blood pressure values, decreased vascular resistance and reduced aldosterone levels .Puga et al. evaluated the effects of arginine supplementation on postmenopausal women who perform aerobic exercise and found a significant decrease in diastolic blood pressure values, while no beneficial changes were noted in cardio-inflammatory markers . HoweverMorais et al. observed the effects of I-arginine on rats after a single session of resistance training. They found immunomodulatory effects of I-arginine in resolving the resistance to exercise-induced muscle inflammation by reducing the expression of atrogin-1 and MuRF-1 atrophic genes . A meta-Muscle hypertrophy and muscular strength are well-established benefits of habitual resistance exercise (RE) ,40,41,42Arginine might be used in the future as a possible adjuvant supplement in the primary prevention measures to reduce cardiovascular risk and early-stage hypertension in sedentary patients; however, it is advisable first to initiate lifestyle interventions.Our study suggests that oral arginine supplementation improves the body composition and arterial elasticity in healthy individuals performing resistance training exercises. Our results are mainly of interest to high-intensity resistance training athletes seeking to combat the effects of this type of exercise on blood pressure and vascular stiffness. Further studies are needed to evaluate the benefits of these supplements in patients with known arterial hypertension.Limitations of the study include how the groups’ workout programs could not be standardized and the groups were not mixed in terms of gender. All subjects performed regular resistance training exercises at different intensities and weight regimens. Subjects reported no other nutritional supplementation during the research, but their personal dietary intake could not be monitored.


The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines on hypertension management recommend new stage 1 hypertension thresholds (130-139/80-89 mmHg) for starting antihypertensive treatment. To analyze the impact of the 2017 ACC/AHA guidelines on patients’ diagnoses within daily practice, in comparison with management using the 2018 European hypertension guidelines, regarding the new thresholds. Cross-sectional study conducted in a hypertension outpatient clinic at a tertiary-level public hospital. The diagnosis of hypertension was defined separately using each guideline. The participants were patients who were attending the hypertension clinic, who were evaluated using the thresholds of two guidelines, based on cardiovascular risk factors, including age, gender, smoking status, diabetes mellitus, dyslipidemia, obesity, osteoporosis, chronic renal failure and family history of hypertension. After adapting the guidelines to the blood pressure values of our sample, 74.5% (n = 277) of the patients were diagnosed as hypertensive according to the blood pressure classification of the European Society of Cardiology (ESC) guidelines published in 2018, while 91.1% (n = 339) of the patients were hypertensive according to the new 2017 ACC/AHA guidelines. Multivariate regression analysis revealed that the significant demographic and cardiovascular risk factors associated with hypertension, based on the 2018 European Society of Hypertension (ESH)/ESC guidelines, were age , obesity  and family history of hypertension . The factors associated with the definition of hypertension may vary through changing the threshold values. Hypertension is one of the leading public health problems in both developed and developing countries. Studies have shown that cardiovascular morbidity and mortality are closely related to systolic and diastolic blood pressure. Up-to-date guidelines are needed in order to achieve the targets that have been accepted as international standards for diagnosing and treating hypertension. Although the guidelines are not decisive in themselves alone, they assist physicians in the approach that they take towards hypertension.In 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) released new guidelines for prevention, detection, evaluation and management of hypertension in adults. The new guidelines lower the threshold for the diagnosis of hypertension and target blood pressure levels of 130/80 mmHg in the general population. The new classification will add a large number of patients who will now be diagnosed as hypertensive, whose blood pressure was previously considered to be within the normal range.The 2017 ACC/AHA guidelines differ from the criteria of the Eighth Joint National Committee (JNC-8) report, which was published in 2014.Unlike the 2017 ACC/AHA guidelines, the 2013 guidelines of the European Society of Hypertension (ESH) and European Society of Cardiology (ESC) defined the threshold for stage 1 hypertension and for starting pharmacological treatment as 140-159 mmHg of systolic blood pressure (SBP) or 90-99 mmHg of diastolic blood pressure (DBP).Threshold values for identifying and classifying the diagnosis of hypertension, and for determining the time to start pharmacological treatment, the target values and the treatment strategies, are important for community health and for healthcare costs. In the present study, these two current guidelines, based on different threshold values for diagnosing hypertension and on different classification tables, were evaluated through our sample. In addition, the association between demographic and cardiovascular risk factors and hypertension was examined based on the diagnostic threshold values for hypertension that are accepted in each of the two guidelines.The objective of this study was to analyze the impact of each threshold, i.e. those accepted by 2017 ACC/AHA guidelines and the 2018 European hypertension guidelines, on patients’ diagnoses. In addition, we sought to ascertain the associations between the cardiovascular risk factors and each of the thresholds.This observational cross-sectional study was conducted at Gülhane Educational and Research Hospital, Ankara, Turkey.A total of 437 consecutive patients who had been admitted to the hypertension outpatient clinic with a diagnosis of hypertension at the baseline assessment were recruited for this study. The baseline SBP/DBP values of this sample, from among all the enrolled patients for whom blood pressures were evaluated between 1990 and 2010, were extracted from the patients’ medical files. Patients with mental disorders and malignancies, and those younger than 18 years, were excluded from the study. After the initial evaluation of inclusion criteria and after excluding patients with deficient laboratory results, a total of 372 participants (85.1%) remained enrolled in the study.2 versus BMI < 30 kg/m2), smoking status (current smoker versus others) and family history of hypertension (yes versus no). Presence of any of the following diseases was also assessed: coronary artery disease (CAD), both types of diabetes mellitus (DM), dyslipidemia and chronic kidney disease (CKD). Presence of comorbidities was ascertained according to self-reports from the study participants at the baseline evaluation. The patients’ laboratory values were obtained from the hospital’s electronic biochemistry data service and from the patients’ files.All the study variables including the blood pressure measurement were obtained at the baseline assessment on the patients. The personal characteristics surveyed included the patients’ age group (≤ 45 years versus 46-65 years versus > 60 years), sex, obesity . This study was conducted in accordance with the principles of the Declaration of Helsinki. The researchers also guaranteed that the participants’ identities and related health records would be kept confidential.The patient groups were categorized according to the thresholds for the diagnosis of hypertension indicated by the two sets of guidelines. The statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS) software .Descriptive statistics were presented as percentages for categorical variables and as the mean ± standard deviation (SD) for continuous variables. All the continuous variables, including age, growth factor receptor (GFR) level, total cholesterol level, BMI and blood pressure values, were analyzed for normal distribution using the Kolmogorov-Smirnov test and were found to be normally distributed. Comparison of categorical variables was performed using the chi-square test.Binary logistic regression modeling was used to examine the association between cardiovascular risk factors and the diagnosis of hypertension based on these two sets of guidelines, while controlling for and including all other variables.The results were presented as odds ratios (OR) and 95% confidence intervals (95% CI). The data were considered to be statistically significant at P-values < 0.05.A total of 372 patients with a mean age of 62.36 ± 11.45 years (range: 25-88) were enrolled in this study. Just over three-fourths  of the study participants were female. Among all the patients, 43.3% (n = 161) were in the age group > 65 years, while 48.7% (n = 181) were in the age group 46-65 years. Only a small proportion of the patients (14%) were smoking currently. Other cardiovascular risk factors and comorbid diseases are shown in In the whole study group, 74.5% (n = 277) of the patients were diagnosed as presenting hypertension according to the ESC guidelines for blood pressure classification (SBP/DBP > 140/90 mmHg), published in 2018. Conversely, 91.1% (n = 339) of the patient sample were hypertensive according to the 2017 ACC/AHA guidelines for blood pressure classification (SBP/DBP > 130/80 mmHg), published in 2017. Based on the 2018 ESH/ESC guidelines for blood pressure classification, 22.6% of the patients were in stage 1, 21.8% in stage 2 and 19.1% in stage 3 group. However, based on the 2017 ACC/AHA guidelines for blood pressure classification, 14.5% were in stage 1 and 76.6% were in stage 2 .Using the definition of the 2018 ESH/ESC guidelines, and comparing the patients with and without hypertension, we found that the patients in the hypertension group had more family history of hypertension . Among the patients with hypertension, 26.0% (n = 72) were obese, while this was observed in 10.5% (n = 10) of the patients without hypertension (P = 0.002). Regarding osteoporosis, the number of patients presenting this in the group with hypertension  was significantly lower than the number of patients with osteoporosis in the group without hypertension .In accordance with the definition of the 2018 ESH/ESC guidelines, comparing the patients who had hypertension with those who did not, although the patients in the hypertension group were older and more frequently presented obesity, no statistically significant difference was detected based on cardiovascular risk factors and comorbidities . AccordiThe results from the multivariate logistic regression analysis revealed that the significant demographic and cardiovascular risk factors associated with the diagnosis of hypertension according to the 2018 ESH/ESC guidelines were the following: age , obesity  and family history of hypertension . According to the regression analysis, no significant difference was detected in terms of the association between cardiovascular risk factors and the diagnosis of hypertension according to the 2017 ACC/AHA guidelines .It has been predicted that, through lowering the threshold for making the diagnosis of hypertension to 130/80 mmHg, the 2017 ACC/AHA guidelines will increase the number of patients who will be diagnosed with hypertension and need treatment. The proportion of our sample that was not hypertensive using the 2018 ESH/ESC guideline thresholds was approximately three times higher (25.5% versus 8.9%) than it was using the 2017 ACC/AHA guideline thresholds. Compared with the 2018 ESH/ESC guidelines, the number of hypertensive patients according to the 2017 ACC/AHA guidelines was 16.6% higher in our study sample. Age, obesity and family history of hypertension were significant variables according to the 2018 ESH/ESC guidelines, but use of the 2017 ACC/AHA guidelines did not give rise to any significant change among the factors associated with the diagnosis of hypertension, defined through these two different sets of guidelines.,The evidence supporting the lowering of the hypertension thresholds came from a meta-analysis on randomized controlled trial (RCTs) published in The Lancet in 2016, particularly from the data of the Systolic Blood Pressure Intervention Trial (SPRINT), in relation to antihypertensive drug treatment.The difference between the 2017 ACC/AHA guidelines and the previous guidelines means that the number of hypertensive patients in the United States is expected to increase from 32% to 46%, simply through changing the definition of hypertension. Moreover, the target blood pressure has decreased along with the lowering of the diagnostic threshold. According to the authors of the 2017 ACC/AHA guidelines, the prevalence of hypertension was expected to increase significantly through these guidelines. However, they claimed that early diagnosing of cardiovascular events may become possible and awareness of hypertension among patients at risk will increase over the course of these individuals’ future lives.In addition to hypertension, conditions of accompanying cardiovascular disease or diabetes, or 10-year risk of developing cardiovascular disease greater than 10%, should be taken into consideration in the management of antihypertensive treatment. The latest (2017) ACC/AHA guidelines have emphasized the importance of home blood pressure monitoring and teamwork in the management of disease.The new blood pressure classification proposed in the 2017 ACC/AHA guidelines has been adapted to hypertension studies in different countries. Application of the threshold value of 130/80 mmHg to the latest national Chinese research data showed that the hypertension rate rose from 25% to 50%. The proportion of patients requiring medication in the Chinese population was 2.0% in the general population and 5.5% in the geriatric patient population according to the 2017 ACC/AHA guidelines.,Based on the threshold of ≥ 140/90 mmHg, the current prevalence of hypertension in India is approximately 28.9% in both men and women. In the Indian population, in which there are interactions with various social, cultural and economic factors, hypertension management has become quite difficult with the lower blood pressure values that have redefined hypertension in the new 2017 ACC/AHA guidelines.Another factor affecting the international generalizability of the new guidelines, which basically arose from the SPRINT study data, is blood pressure differences based on ethnicity disparities between countries. Since the proportion of East Asian ethnicity in the SPRINT trial was very low (< 2%), it is doubtful whether the results can be generalized to countries like Taiwan.In our study, the patients who enrolled at the hypertension outpatient clinic were evaluated regarding blood pressure thresholds, using both guidelines separately. From this perspective, the proportion of hypertensive patients increased from 74.5% (2018 ESH/ESC guidelines) to 91.1% (2017 ACC/AHA guidelines) in our patient sample. This increase in the proportion of hypertension diagnoses, of 16.6 percentage points, which was caused by lowering the threshold value to 130/80 mmHg, is quite spectacular. Projection of the new guidelines into various different communities has led to predictions that increases in the numbers of hypertensive patients of 14% in the United States,Another noteworthy point in the present study was that significant associations were detected between the presence of hypertension and the variables of family history of hypertension, obesity and age, according to the 2018 ESH/ESC guidelines. However, no significant relationship between the presence of hypertension and these variables was observed regarding the 2017 ACC/AHA guidelines, although age and family history of hypertension were close to being significant. The results from this analysis indicate that the demographic and cardiovascular factors that are effective for making the diagnosis of hypertension might vary with the change in hypertension threshold values.Our study conducted in Turkey can be considered to be a pilot reflecting the thresholds of the new 2017 ACC/AHA guidelines in our society. However, these increased rates of hypertension cannot be generalized to the entire Turkish population because our study had some limitations, including its small sample size and the structure of the outpatient clinic studied, which only serves hypertensive patients. Furthermore, the number of female patients evaluated was higher than the number of male patients.The decreases in hypertension threshold values proposed through the 2017 ACC/AHA guidelines have increased the number of patients diagnosed with hypertension worldwide, including in Turkey. This increase was by 16.6 percentage points in our sample.We consider that updates to the relationship between cardiovascular risk factors and the diagnosis of hypertension through the change in threshold values may come to be presented in the near future, consequent to ongoing studies in various countries worldwide. In the current study, age, obesity and family history of hypertension were significantly associated with the diagnosis of hypertension according to the 2018 ESC guidelines, while no relationship was detected between cardiovascular risk factors and the diagnosis of hypertension using the 2017 ACC guidelines. Studies involving higher numbers of patient samples will be effective in explaining the relationship between these risk factors and the diagnosis of hypertension.


Patients were evaluated and randomized into two groups . Patients were included only if they met the global criteria for asthma. The experimental intervention period lasted 10 weeks with 3 weekly training sessions lasting 30-40 min. The maximal inspiratory pressure , pulmonary function test, baseline dyspnoea index (BDI), oxygen saturation, and 6 min walking test (6MWT) performance were all measured at baseline and postintervention. Also, an assessment of the 1 min repeated exercise performance (leg extension and leg press) was performed. Moreover, St. George Respiratory Questionnaire was used to quantify the quality of life (SGRQ). Statistical analysis displayed significant favourable effects on 6MWT, leg press, and FRV1, for patients using both devices  with lower torso athletic training. The other variables, weight SPO2 and SGRO, also showed no significant change in neither EXP-1 nor EXP-2. Thus, the new respiratory training device (EXP-2) appeared to be as effective as the conventional threshold loading device (EXP-1). In conclusion, our findings demonstrated beneficial effects of combining respiratory training with athletic training in asthma patients. Additionally, the validity of a unique respiratory training device for asthma patients was confirmed.This study investigated the influence of two different devices with lower torso sports training in patients with asthma. Patients with asthma ( Asthma is one of the most prevalent chronic respiratory disorders and is estimated to affect 262 million people globally, resulting in 461,000 fatalities . Due to Breathing exercises (BE) performed with the aid of equipment such as threshold loading training (TLT) and innovative respiratory training (IRT) and lower torso sports training (LTST) are nonpharmacological interventions that have been shown to improve asthma conditions . Sport eThreshold loading training (TLT) and novel methods of respiratory training (IRT) are quantitative techniques used to improve the strength of the inspiratory muscles during inspiration. Exercise with respiratory devices produces an effect by adjusting the inspiratory muscles to overcome resistance. Training using a threshold loading device is likely to decrease exertional dyspnoea, increase diaphragm function and structure, and decrease the oxygen cost of breathing in asthma patients . In addiLTST is also a critical training routine for individuals with asthma since it improves physical capacity and health-related quality of life. The guideline from the British thoracic society for the physiotherapy management of asthma patients recommends athletic training to improve cardiorespiratory endurance and fitness and overall health-related quality of life . Asthma Some asthma patients may show less tolerance to lower torso exercise because of worsening asthma symptoms. This may prevent them from attempting to keep fit. Upper or lower torso training programs for asthma patients have been designed to improve muscle function, muscle coordination, physical fitness, and confidence and reduce symptoms of dyspnea . Lower tStudies on pulmonary disease patients have demonstrated that lower limb muscles were more affected than upper limb muscles. Thus, the average quadriceps strength reduction was 30% compared to healthy individuals . EnduranCollectively, data on the effect of threshold loading with lower torso sport training on the test and pulmonary function tests are scarce and limited to those obtained from studies evaluating handgrip endurance and maximal inspiratory pressure (PI-max). Thus, it is interesting to investigate and compare two novel devices to ascertain their effect on both physical performance, pulmonary function ability, and quality of life. Therefore, this study applied a broad-spectrum test battery and is aimed at investigating the influence on both pulmonary function, physical ability, and quality of life of the LTST with IRT and LTST with TLT on patients with asthma and comparing TLT and IRT devices to test the validity of the innovative device. Thus, we are evaluating the effect of lower torso sports training combination with threshold loading device training on broad-scaled asthma symptoms. We hypothesize that TLT and LTST may affect physical ability, pulmonary function, and quality of life in asthma patients and that IRT with LTST may also impact these parameters.Medical professionals referred three hundred thoracic outpatients presenting a follow-up clinic at a regional medical centre in Al-Hillah City/Babylon government hospital and volunteered to participate in this study . They we∗Power 3 with a priori power analysis was performed, using a predefined power of 0.8, an effect size of 0.8, and an alpha level of 0.05 (GBD 2015). 300 participants were recruited and randomly divided into two intervention groups , who used TLT with LTST and experimental group 2 (EXP-2), who used IRT with LTST) with each group involving 150 asthma patients. After baseline screening and testing, all 300 eligible participants were assigned to the TLT with LTST or IRT with LTST group by a third person in a blinded manner randomly  using block randomization targeting group sizes of n = 150. Our study is the high sample size and high adherence to the training. Block randomization works by randomizing participants within blocks such that an equal number are assigned to each treatment.The study was a prospective randomized trial with two groups that compared the nonpharmacological interventions TLT and IRT with LTST. GPre- and postintervention assessments were all conducted by an expert with special respiratory training. During the 10-week program, the two groups participated in 30 to 40 min sessions three times in a week. The sessions emphasized breathing rhythm regulation, increasing LTST, increasing expiratory time, boosting diaphragmatic and nasal breathing, and slowing the respiratory flow. Each session was initiated with activities to warm up the lower torso and thoracic wall muscles. LTST was performed with TLT and IRT and with diaphragmatic and pursed-lip breathing. By utilizing the TLT , the patients were instructed to breathe through their mouths and clip their noses shut, and they were encouraged to exhale “the whole air content of their lungs.” Each breath was 40–60% of maximal inspiratory pressure (PImax), and LTST was 40%–60% of PImax. The patients were encouraged to maintain a modest breathing frequency to minimize hyperventilation and to gradually increase the resistive load until 40 breaths approximated the inspiratory muscle tolerance limit. To ensure that patients adhered to the training requirements of their training interventions, they were required to visit the laboratory monthly to complete their tests.There is a mask that covers both mouth and nose. Inhalation and exhalation are taken inside the mask without exposure to the air pollutants of the external environment. In contrast, threshold loading device is placed in the mouth onlyTwo side filters filter the air from dust and other pollutants entering the lungs. While threshold loading device does not have a filterThere is a pulley for timing the intensity from zero to 100%, which is suitable for all degrees of shortness of breath, while the intensity of the threshold loading device is 40% which is unsuitable for all degrees of dyspneaThe innovative device works with electricity or batteries, and this aids the patient in the process of inhaling air more efficiently. However, unfortunately, we do not find that in the threshold loading deviceThe innovative device can be carried back without affecting the patient's movement. However, simultaneously, the threshold loading device must be held by a hand, which may affect patient movementThe innovative device can be linked to a computer to read the percentage of inhaled oxygen and exhaled carbon dioxide. We do not find that in the threshold loading deviceThe differences between TLT and LTST machine are as follows:The innovative device has two gates, one for air entry and the other for air exit, while the threshold loading device has one gate.The 6 min walk test and the pulmonary function test are simple objectives for determining a patient's capacity to walk as far as feasible while breathing easily. They are also an inexpensive and reliable device for estimating functional activity and submaximal exercise proficiency . The 6 mThe used devices: FEV1 will be used to assess lung function. A spirometer  will beTest method: FEV1 was evaluated by allowing the patients to sit on a chair at the height of (40 cm), where the feet are touching the ground, and the back is straight and resting on the back of the chair. The researcher begins to teach the patient the technique of the test by taking a deep inhale and then forcefully and quickly expelling the air from the chest  until the lungs empty or until the device makes a sound, and the nose is closed with an airtight stopper to ensure that the inhalation is taken out from the mouth only. Scoring method: the patients must continue to completely expel the exhaled air until apnoea and the inability to continue, and it must be at least (6) seconds and may last up to 12 seconds or more, and the test was performed on three attempts for each patient with one-minute rest among tests recording the best performance, noting that the reading of the attempt appears directly on the device's screen, and then, it is printed to become a graph paper, and the unit of measurement is the percentage (%).Spirometer (German type) measurements were conducted under American Thoracic Society (ATS) guidelines  using prHeight and weight were determined and the body mass index (BMI) [weight/height squared]. Resistance was determined on the right side of the body in the flat posture using the . Kyle anA validated version of the St. George Respiratory Questionnaire (SGRQ) was used to assess patient quality of life (QoL)  In additThe maximum inspiratory pressure was determined as previously described . At the The following activities were performed: leg extension (quadriceps) and leg press . Before the test, 12 repetitions with a modest weight were performed to mitigate learning effects. All participants completed the 1 min time limit on two attempts. Between repetitions, 1–2 minutes of relaxation were allowed. The Valsalva manoeuvre was avoided, and the proper technique for doing each muscle group's workout was emphasized .According to American Thoracic Society guidelines , patientTo investigate intervention induced between and within-group changes, ANCOVA test from the SPSS software was used. BMI was chosen as body composition measures, whilst FEV1 and Spo2 were chosen as pulmonary function metrics. As a dependent variable, the 6MWT was defined. Data are except correlation coefficients presented as means ± SD.F value in case of body weight is 0.126 which is not significant at 0.05 level of significance (P = 0.722); hence, it does not show significant difference between the EXP-1 and EXP-2  and 71.48 kg (±1.06), respectively. In the postimplementation of experiments, the mean of EXP-1 and EXP-2 was 71.14 kg (±1.22) and 71.16 (±1.16), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of FEV1 is 3.892 which is significant at 0.05 level of significance (P = 0.049) it shows significance difference between the effect of EXP 1 and EXP2 on FEV1The mean of FEV1 before the implementation of experiments EXP-1 and EXP-2 was 66.37 (±1.12) and 66.36 (±1.11), respectively. In the postimplementation of experiments, the mean of exp1 and exp 2 was 76.27 (±1.09) and 76.01 (±1.19), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of SPO2 is 0.644 which is not significant at 0.05 level of significance (P = 0.423); hence, it does not show significant difference between the EXP-1 and EXP-2 Tables 2The mean of SPO2 before the EXP-1 and EXP-2 was 90.96 (±1.21) and 91.02 (±1.13), respectively. In the postimplementation of experiments, the mean of exp1 and exp 2 was 91.56 (±0.73) and 91.50 (±0.75), respectively. Further, the pos test scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of PImax is 3.551 which is significant at 0.05 level of significance (P = 0.06); it shows significant difference between the scores of EXP-1 and EXP-2 Tables 2The mean of PImax before the implementation of experiments EXP-1 and EXP-2 was 66.30 (±1.02) and 66.36 (±1.11), respectively. In the postimplementation of experiments, the mean of EXP1 and EXP 2 was 62.65 (±1.09) and 62.89 (±1.10), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of BDI is 6.694 which is significant at 0.05 level of significance (P < 0.01) it shows significant difference between the scores of EXP-1 and EXP-2 (Tables 2The mean of BDI before the implementation of EXP-1 and EXP-2 was 21.84 (±1.31) and 21.85 (±1.18), respectively. In the postimplementation of experiments, the mean of exp1 and exp 2 was 22.09 (±1.23) and 21.90 (±1.19), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of leg extension is 2.076 which is not significant at 0.05 level of significance (P = 0.151); hence, it does not show significant difference between the EXP-1 and EXP-2  and 19.25 (±0.83), respectively. In the postimplementation of experiments, the mean of exp1 and exp 2 was 21.43 (±1.16) and 21.24 (±1.08), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of leg press is 4.731 which is significant at 0.05 level of significance (P = 0.030); it shows significant difference between the scores of EXP-1 and EXP-2 (Tables 2The mean of leg press before the implementation of experiments EXP-1 and EXP-2 was 21.82 (±1.19) and 21.90 (±1.17), respectively. In the postimplementation of experiments, the mean of EXP-1 and EXP-2 was 25.04 (±0.88) and 24.82 (±0.87), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of 6MWT is 13.645 which is significant at 0.05 level of significance (P < 0.001); it shows significant difference between the scores of EXP-1 and EXP-2 (Tables 2The mean of 6MWT before the implementation of experiments EXP-1 and EXP-2 was 417.30 (±25.51) and 417.50 (±25.49), respectively. In the postimplementation of experiments, the mean of EXP-1 and EXP-2 was 521.27 (±6.52) and 518.25 (±7.57), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that F value in case of SGRQ (QOL) is 2.370 which is not significant at 0.05 level of significance (P = 0.125); hence, it does not show significant difference between the EXP-1 and EXP-2  of EXP-1 and EXP-2 was 47.37(±1.33) and 47.36 (±1.22), respectively. In the postimplementation of experiments, the mean of EXP-1 and EXP-2 was 50.42 (±1.05) and 50.23 (±1.04), respectively. Further, the posttest scores of both the experimental groups were compared using ANCOVA where pretest scores were covariate. Based on the analysis, comparison between the groups shows that From the above-mentioned findings, this can be concluded that EXP-1 and EXP-2 both had positive effect on the body weight, quality of life SPO2, PImax, and leg extension, although the difference between postexperiment scores between the groups were not significant statistically; hence, it can be said that both the experiments had similar effects on the patients which indicate that EXP-2 (respiratory training with athletic training) appeared to be as effective as the EXP-1 . However, for FEV1, BDI, leg press, and 6MWT, EXP-1 and EXP-2 both had positive effect, and the difference between postexperiment scores between the groups was found statistically significant with EXP-2 (respiratory training with athletic training) having better effect then EXP-1 .Hence, it can be concluded that combining respiratory training with athletic training will be more beneficial for asthma patients compared to conventional treatment method.The results of our study demonstrated for the first time that threshold loading training and LTT are predictors of physical ability in asthma patients. Moreover, our results confirm the effect of IRT with LTST on FEV1, maximum inspiratory pressure (PImax), the quality of-life, baseline dyspnoea, and body weight on the physical capacity of this patient group.The effects of TLT and IRT with LTST on 6MWT are well described in the literature in terms of PImax. The findings in the present study corroborate prior research with asthma patients , 38, demThe present study is the first to describe the effect of TLT and IRT with LTST on 6MWT performance. We observed a marked improvement in both groups. Others have assessed the impact of thoracic and upper limb muscular endurance on patients with respiratory illness maximal exercise capacity but did not use the 6MWT. Nonetheless, a study has described the effect of lower-limb peripheral muscle function on exercise capacity in patients with respiratory disease, including  the impaOur findings are consistent with previous research , demonstAnother indication that asthmatic systemic symptoms impair exercise ability was finding bodyweight as a predictor of 6MWT in our study. We demonstrated a statistically significant beneficial influence of body weight on the 6MWT performance, consistent with other studies . AccordiIt has been shown that TLT and IRT with LTST had a statistically significant effect on 6MWT score and QoL, as measured by the SGRQ activity domain total score. For example, have some trials evaluated pulmonary function, 6MWT performance, respiratory muscle endurance, body composition, and peripheral muscular endurance, and 6MWT was identified as a predictor of SGRQ activity and influence domains . Also, GFurther, the overall effect of threshold loading in the present study is consistent with the recommendations of previous research  in whichFuture studies will be required to estimate the impact of IRT with upper torso training, including specific muscle reconditioning on submaximal exercise capacity in respiratory disease patients. The most effective component of pulmonary rehabilitation is associated with physical conditioning. Therefore, LTST with free weights is possible for muscle overhauling in asthma patients.The effect of TLT and IRT with LTST observed in our study does essentially suggest a significant effect. Both devices with LTST are beneficial to improve inspiratory muscles and exercise capacity in asthma patients.Our findings highlight the importance of inspiratory training and skeletal muscle in exercise capacity in asthma patients. Peripheral muscle endurance, body weight, the sensation of dyspnoea, and inspiratory muscle training all influence the capacity of asthma patients to carry out exercises and physical works. Therefore, the development of treatment strategies that, while considering individual objectives and requirements, aims to interrupt the dyspnoea, dyspnea cycle, and sedentary lifestyle in these patients is warranted.


The purpose of this study was to assess the relationship between exercise-induced hypertension (EIH) and cardiovascular events, and to determine whether exercise blood pressure (BP) improved risk stratification in adults with repaired coarctation of aorta.Retrospective study of patients with repaired coarctation of aorta on antihypertensive therapy that underwent exercise testing and exercise test (2003–2019). BP was measured at rest in 3 different clinical settings and averaged to determine the resting BP. Indices of left ventricular function and afterload were obtained from the echocardiogram. EIH was defined as systolic BP >210  or >190  at peak exercise. Cardiovascular event was defined as atrial fibrillation, ventricular tachycardia, heart failure hospitalization, heart transplant, and cardiovascular death.C statistic, 0.671  to 0.727 ; P=0.01). Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker was associated with a lower risk of cardiovascular events.Of 327 patients (age 35±13 years), 116 (35%) had EIH. Although the resting BP was similar between patients with versus without EIH, the EIH group had higher pulsatile arterial load, more advanced left ventricular remodeling, and were less likely to be on angiotensin converting enzyme inhibitor/angiotensin receptor blocker. EIH was associated with cardiovascular events  independent of resting systolic BP, and improved prognostic accuracy above resting systolic BP (EIH was associated with cardiovascular events independent of resting BP, and patients receiving angiotensin-converting enzyme inhibitor/angiotensin receptor blocker had lower risk of cardiovascular events. These data suggest that exercise BP could be used to assess adequacy of antihypertensive therapy, and to guide titration of antihypertensive therapy. Exercise-induced hypertension was present in 35% of adult with repaired coarctation of aorta treated hypertension and was commonly observed even in the subset of patients with normal blood pressure at rest.Exercise-induced hypertension was associated with cardiovascular events independent of blood pressure at rest. The patients receiving angiotensin-converting enzyme inhibitor/angiotensin receptor blocker were less likely to have exercise-induced hypertension and also had a lower risk of cardiovascular events.Exercise blood pressure can potentially be used to assess adequacy of antihypertensive therapy, and in turn, to guide the titration of antihypertensive therapy4 The diagnosis and monitoring of hypertension in patients with rCOA  is typically based on blood pressure (BP) measurements obtained at rest (office and/or home BP measurement), similar to the management of hypertension in the general population.7 However, recent data show that adults with rCOA have higher arterial load as compared with non-COA patients with similar resting systolic BP (SBP), suggesting that resting SBP may underestimate left ventricular (LV) pressure load in this population.10 The higher arterial load in patients with rCOA is postulated to be due to a combination of endothelial dysfunction, abnormal arterial smooth muscle reactivity, changes in material properties of the aorta leading to increased arterial stiffness, and reduced baroreceptor sensitivity leading to increased sympathetic activation.13 These same factors are also linked to exercise induced hypertension (EIH).16Hypertension is the most common comorbidity in adults with repaired coarctation of aorta (rCOA), and it can persist in up to 40% to 60% of patients after a successful COA repair, even in the absence of hemodynamically significant residual or recurrent coarctation.23 However, it is unknown whether the presence of EIH in rCOA patients that are already on antihypertensive therapy confers a higher risk of adverse outcomes, independent of BP at rest. Such data could be used to improve risk stratification and optimize antihypertensive therapy in this population. The purpose of this study was, therefore, to assess the relationship between EIH and cardiovascular events both of which are common in this population, and to determine whether exercise BP improved risk stratification in this population.EIH, defined as SBP >210 mmHg in males or >190 mmHg in females, occur in 15% to 30% of patients with rCOA, and it is associated with a higher risk of developing chronic hypertension during follow-up.Figure S1 shows a flowchart for cohort selection.The authors declare that all supporting data are available within the article. The Mayo Clinic Institutional Review Board (IRB) approved this retrospective cohort study of adults (age ≥18 years) with rCOA that were treated for hypertension between January 1, 2003 and December 31, 2019. The IRB number for the Mayo Clinic Adult Congenital Heart Disease Registry was IRB #20-007695, IRB Approval Date: 8/14/2020. The inclusion criteria were the following: (1) clinical diagnosis of hypertension (SBP ≥130 and/or diastolic BP [DBP] ≥80 mmHg) requiring antihypertensive therapy ≥1 year prior to the beginning of the study. (2) Cardiopulmonary exercise test and transthoracic echocardiogram performed within 48 hours from the clinic visit. (3) Clinical follow-up ≥1 year from the time of exercise test for time-to-event analyses. The exclusion criteria were the following: (1) concomitant LV inflow disease (Shone complex) defined as having any of the following conditions: mitral valve prosthesis, sub-valvular, valvular, or supra-valvular mitral stenosis (mean gradient >3 mmHg) or ≥moderate mitral regurgitation. (2) Hemodynamically significant residual COA defined as Doppler mean COA gradient >20 mmHg or need for a transcatheter or surgical COA intervention from the exercise test to the last encounter. (3) Aberrant origin of the right subclavian artery. The office BP was measured in 3 different clinical settings: (1) at the time of echocardiogram using a manual BP cuff, (2) at the time of clinic visit using an automated BP cuff, and (3) at the time of exercise test using a manual BP cuff. The BP was measured by trained clinical personnel after 5 minutes of rest in a seated position in all cases. For this study, we used the BP obtained from the right arm, and we averaged the BP measurements from the 3 different clinical settings to determine the average resting BP for each patient. We defined optimal BP control as resting SBP <130 mmHg and resting DBP <80 mmHg.17 BP was measured manually at rest and then every 2 minutes throughout the exercise test. EIH was defined as SBP at peak exercise >210 mmHg in males or >190 mmHg in females.All patients included in the study underwent maximum effort cardiopulmonary exercise test with a treadmill ergometer. Maximal effort was defined as symptom-limited exercise test with a respiratory exchange ratio >1.10 previously described.9 (2) Total arterial compliance index, which is a linear approximation of the pressure-volume relationship of the arterial system, was calculated as Doppler-derived stroke volume index/brachial pulse pressure.9Pulsatile arterial load was assessed using 2 indices: (1) Effective arterial elastance index, which is a lumped measure of the total stiffness of the arterial system, was calculated as 0.9×brachial systolic BP/Doppler-derived stroke volume index.25 The severity of residual COA and LV outflow disease was assessed using standard Doppler techniques. Based on these data, the patients were classified into 2 mutually exclusive groups: (1) Isolated rCOA; (2) rCOA with concomitant LV outflow disease defined as having any of the following conditions: aortic valve prosthesis, sub-valvular, valvular, or supra-valvular aortic stenosis (mean gradient >20 mmHg) or ≥moderate aortic regurgitation.All patients underwent comprehensive 2-dimensional, Doppler and speckle tracking echocardiogram according to contemporary guidelines.26 The occurrence of cardiovascular event was ascertained by review of the electronic health records and the Accurint mortality database.The composite study outcome included incident cardiovascular event defined as new-onset atrial fibrillation, sustained or non-sustained ventricular tachycardia, heart failure hospitalization, heart transplant, and cardiovascular death. Cardiovascular death was defined as death due to myocardial infarction, sudden cardiac death, heart failure, stroke, and cardiovascular hemorrhage.Additionally, the medical records were reviewed at the time of exercise test, and the clinical indices (including antihypertensive therapy) obtained within 3 months of the exercise tests were used to define the baseline characteristics of the cohort. The medical records were also reviewed for all subsequent clinical encounters to determine intensification of antihypertensive therapy defined as increase in dose of antihypertensive medication and/or addition of another antihypertensive medication.2 test for categorical variables, and unpaired t test and Wilcoxon rank sum test for continuous variables. Pearson correlation was used to assess the relationship between continuous variables. Annualized cardiovascular event rates were calculated by dividing the number of patients that experienced the event by patient-years of follow-up.Data were presented as mean±SDS, median (interquartile range), and count (%). Between-group comparisons were performed using χP<0.1 on univariable analysis.Cox proportional hazard models were used to evaluate the association between exercise SBP and cardiovascular events. First, we created a base model using the following covariates: resting BP, demographic indices , comorbidities , antihypertensive therapy , and echocardiographic indices . These covariates were chosen using stepwise backwards selection of covariates with C-statistics and the integrated discrimination index were calculated to assess improvement in prediction accuracy.27 The integrated discrimination index (95% CI) and comparison P were derived from 1000 bootstrap samples. Exploratory analysis was performed to determine whether other exercise BP indices (exercise DBP and exercise pulse pressure [PP]) improved prediction accuracy above the base model.To assess the prognostic power of exercise SBP over the base model, we added exercise SBP to the base model, and P<0.05 was considered to be statistically significant for all analyses.Sensitivity analysis was performed to assess the relationship between exercise SBP and cardiovascular events in different subsets of patients: (1) males versus females; (2) patients with concomitant LV outflow disease versus isolated rCOA; (3) patients with intensification of antihypertensive therapy after exercise test versus patients that remained in the same antihypertensive therapy. All statistical analyses were performed with SAS version 9.4, and BlueSky Statistics software , and There were 327 patients that met the study inclusion criteria. The mean age at baseline assessment was 35±13 years, 201 (62%) were males, and 116 (35%) had EIH. Compared with the patients without EIH, those with EIH had higher LV mass index and LV filling pressures, lower absolute LV global longitudinal strain, and were less likely to be on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) or multiple antihypertensive medications .Of the 327 patients, 215 (66%) had isolated rCOA while 112 (34%) had concomitant LV outflow disease. The most common antihypertensive medications were ACEI/ARB , and beta blockers , and 139 (30%) patients were on 2 or more antihypertensive medications at baseline. Additionally, 89 (27%) patients had intensification of antihypertensive therapy during follow-up  after undergoing exercise test. Of the 41 patients with initiation of additional antihypertensive medication, the most common agent was ACEI/ARB (n=34), followed by calcium channel blocker (n=5).P<0.001 for all), and between BP obtained in the clinic and exercise laboratory . The average SBP was 129±18, and 146 (45%) had optimal SBP control (defined as SBP <130 mmHg). The average DBP was 74±11, and 273 (84%) had optimal DBP control (defined as DBP <80 mmHg). Although, both groups had similar resting SBP, DBP, and PP, the EIH group had higher effective arterial elastance index , and lower TACI , suggesting a higher pulsative arterial load and vascular dysfunction in this group (Table Table S1).The resting BP measurements in all 3 clinical settings  were obtained on the same day in 178 (54%), and within 2 days in 149 (46%).There was an excellent correlation between BP obtained in the clinic and echocardiography laboratory , no correlation between resting versus exercise DBP , and no correlation between resting versus exercise PP . The exercise SBP (by design) and PP was higher in the EIH although both groups had similar effort (as measured by exercise time and respiratory exchange ratio), and peak heart rate (Table Table S1).The mean exercise SBP, DBP and PP was 173±31, 65±14, and 108±27 mmHg, respectively . However, there was no significant difference in cardiovascular event rate between the patients with optimal resting DBP control as compared with those with suboptimal resting DBP control . Table P=0.02). The use of ACEI/ARB was associated with a lower risk of cardiovascular events .The patients were followed for 7.6±3.2 years from the time of exercise test and during this period, 89 (27%) patients had at least one cardiovascular event . The unadjusted incidence of cardiovascular events was 36 per 1000 patient-years. The unadjusted annual incidence of cardiovascular events was lower in patients with optimal resting SBP control as compared with those with suboptimal resting SBP control . Of the 181 patients with suboptimal SBP control at rest, 74 (41%) had EIH, and the incidence of cardiovascular events was also higher in patients with EIH as compared with patients without EIH .Of the 146 patients with optimal SBP control at rest, 42 (29%) had EIH, and the incidence of cardiovascular events was higher in patients with EIH as compared with patients without EIH . EIH was associated with a nearly 2-fold increase in the risk of cardiovascular events  to 0.727 (0.709–0.750); P=0.01, Table P=0.4). Similarly, the addition of exercise PP to the base model did not result in significant improvement in predictive accuracy .Exercise SBP was independently associated with cardiovascular events after adjustment for resting SBP, demographic indices, comorbidities, antihypertensive medications, and echocardiographic indices . However, there was no significant association between exercise SBP and cardiovascular events in patients that received intensification of antihypertensive therapy after exercise test (Table S2).We performed 6 sets of pre-specified sensitivity analyses, and in these analyses, exercise SBP was associated with cardiovascular events in men, women, patients with isolated rCOA, patients with concomitant LV outflow disease, and patients without intensification of antihypertensive therapy  EIH was present in 35% of the cohort, and the patients with EIH had higher arterial load and more advanced LV remodeling as compared with the patients without EIH although both groups had similar resting BP. (2) Exercise SBP (whether modeled as continuous or binary variable) was associated with cardiovascular events independent of BP at rest. (3) The patients with EIH were less likely to be on ACEI/ARB; (4) The use of ACEI/ARB was associated with a lower risk of cardiovascular events.4 SBP measured at rest is the most common BP metric used for the diagnosis and monitoring of hypertension, but it tends to underestimate LV pressure load, and in turn, leads to under-diagnosis and potentially under-treatment of hypertension in patients with rCOA.10 As a result, the American and European guidelines for the management of adults with congenital heart disease endorse the use of alternate BP measurement modalities such as ambulatory BP monitoring and BP assessment during exercise.7 EIH in patients with normal BP at rest is associated with a higher risk for developing chronic hypertension during follow-up, and hence can be used for screening and early diagnosis of hypertension.23 The current study supports a novel application of exercise BP for prognostication and for assessment of adequacy of antihypertensive therapy in adults with rCOA. These findings are consistent with studies conducted in the acquired heart disease population, showing that EIH was a risk factor for cardiovascular mortality, independent of office BP and other atherosclerotic cardiovascular disease risk factors.29Hypertension is common in adults with rCOA, and it is an independent risk factor for adverse outcomes.31 This discordance between resting SBP and central aortic pressure has been attributed to factors such as difference in aortic stiffness, wave reflection from impedance mismatch of the thoracic aorta, and sympathoadrenergic response during activity. We postulate that the EIH group had higher arterial load , and this in turn, led to more advanced LV remodeling , and worse outcomes as compared with patients without EIH.We also observed that patients with EIH had higher Doppler derived arterial load indices  as compared with patients without EIH, although both groups had similar resting BP. This is consistent with previous studies suggesting that SBP measured at rest may not provide an accurate assessment of LV afterload in the rCOA population.The improved prognostic power of exercise SBP  in the current study, suggests that exercise SBP can be used to assess the adequacy of antihypertensive therapy in rCOA patients with hypertension. For instance, 29% of the 146 patients with optimal SBP control had EIH and higher incidence of cardiovascular events , and perhaps, these patients would benefit from more intensive antihypertensive therapy. Of note, exercise SBP was associated with cardiovascular events in all subgroup analyses except in the subset of patients that had intensification of antihypertensive therapy following exercise test demonstrating. This suggests that titration of antihypertensive therapy using exercise BP may improve outcomes in this population.33 Angiotensin II is elevated in patients with hypertension, and the highest angiotensin II levels occurred during exercise in patients with EIH.32 ACEI/ARB has been shown to decrease BP at peak exercise and improve LV diastolic function, without any change in resting BP, further supporting the important role of neurohormonal activation in the pathogenesis of EIH.34 However, similar data are lacking in patients with rCOA.Furthermore, we observed that the patients with EIH were less likely to be on ACEI/ARB, ant that the use of ACEI/ARB was associated with a lower risk of cardiovascular events as compared with other antihypertensive medications. We postulated that this may be related to the role of angiotensin II in the pathogenesis of EIH and adverse LV remodeling .This is a retrospective, observational single-center study and hence it is prone to selection and ascertainment bias, and inferences on causality cannot be drawn. The resting BP used in this study was derived from office BP , and the office BP is the least reliable method for assessing hypertension. However, we tried to mitigate this limitation by using BP measured in 3 different clinical settings and by 3 different trained operators, and this assessment mirrors what is often obtained in everyday clinical practice. Furthermore, we did not measure biomarkers of neurohormonal activation and cardiac remodeling, and hence are unable to provide mechanistic insight into the underlying pathophysiologic interactions between exercise BP, LV remodeling, and the effect of neurohormonal blockade. The association between ACEI/ARB use is prone to confounding due to indication and other measured and unmeasured group differences and must be considered as hypothesis-generating only. However, the present data emphasize the importance of performing adequately powered randomized controlled trials to determine whether treatments to reduce EIH might improve outcomes in patients with rCOA.EIH was present in 35% of adult with rCOA treated hypertension and was commonly observed even in the subset of patients with normal BP at rest. EIH was associated with cardiovascular events independent of BP at rest. The patients receiving ACEI/ARB were less likely to have EIH, and also had a lower risk of cardiovascular events. These data suggest that exercise BP can potentially be used to assess adequacy of antihypertensive therapy, and in turn, to guide the titration of antihypertensive therapy. Further studies are required to determine whether the integration of exercise BP into the clinical decision process would improve clinical outcomes in adults with rCOA.The current study assessed the relationship between EIH and cardiovascular events, and whether exercise BP improved risk stratification in adults with rCOA. The result showed that EIH was present in 35% of adult with rCOA treated hypertension and was commonly observed even in the subset of patients with normal BP at rest. EIH was associated with cardiovascular events independent of BP at rest. The patients receiving ACEI/ARB were less likely to have EIH and also had a lower risk of cardiovascular events. These data suggest that exercise BP can potentially be used to assess adequacy of antihypertensive therapy, and in turn, to guide the titration of antihypertensive therapy. Further studies are required to determine whether the integration of exercise BP into the clinical decision process would improve clinical outcomes in adults with rCOA.A.C. Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grants . The MACHD Registry is supported by the Al-Bahar Research grant. B.A. Borlaug is supported by research grants for the NHLBI (R01 HL128526 and U01 HL160226).None.


Diabetes is a major cause of the progression of acute kidney injury (AKI). Few prediction models have been developed to predict the renal prognosis in diabetic patients with AKI so far. The aim of this study was to develop and validate a predictive model to identify high-risk individuals with non-recovery of renal function at 90 days in diabetic patients with AKI.Demographic data and related laboratory indicators of diabetic patients with AKI in the First Affiliated Hospital of Guangxi Medical University from January 31, 2012 to January 31, 2022 were retrospectively analysed, and patients were followed up to 90 days after AKI diagnosis. Based on the results of Logistic regression, a model predicting the risk of non-recovery of renal function at 90 days in diabetic patients with AKI was developed and internal validated. Consistency index (C-index), calibration curve, and decision curve analysis were used to evaluate the differentiation, accuracy, and clinical utility of the prediction model, respectively.A total of 916 diabetic patients with AKI were enrolled, with a male to female ratio of 2.14:1. The rate of non-recovery of renal function at 90 days was 66.8% (612/916). There were 641 in development cohort and 275 in validation cohort (ration of 7:3). In the development cohort, a prediction model was developed based on the results of Logistic regression analysis. The variables included in the model were: diabetes duration , hypertension , chronic kidney disease , platelet , 25-hydroxyvitamin D3 , postprandial blood glucose , discharged serum creatinine . The C-indices of the prediction model were 0.807 (95% CI 0.738–0.875) and 0.803 (95% CI 0.713–0.893) in the development and validation cohorts, respectively. The calibration curves were all close to the straight line with slope 1. The decision curve analysis showed that in a wide range of threshold probabilities.A prediction model was developed to help predict short-term renal prognosis of diabetic patients with AKI, which has been verified to have good differentiation, calibration degree and clinical practicability. Due to overweight, obesity and unhealthy lifestyles, the global prevalence of diabetes is increasing year by year. There are currently about 537 million adults worldwide with diabetes, and the number is expected to rise to 643 million by 2030 and 783 million by 2045 , 2. DiabAcute kidney injury (AKI) has been recognized as one of the common renal complications of diabetes . DiabeteA nomogram is a user-friendly tool with a graphical representation that can be used to calculate the probability of a specific event for each individual , 13. EarPatients diagnosed with diabetes and AKI in the First Affiliated Hospital of Guangxi Medical University from January 31, 2012 to January 31, 2022 were selected as the research subjects. Inclusion criteria: (1) diabetes was diagnosed before AKI; (2) changes in serum creatinine (Scr) consistent with the diagnostic criteria for AKI; (3) the follow-up time was no less than 90 days. Exclusion criteria: (1) age < 18 years; (2) CKD stage 5 or renal replacement therapy (RRT); (3) death or loss to follow-up within 90 days of AKI diagnosis; (4) patients with missing important baseline data and the Scr values of 90-day following up. This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University [Approval number: 2019(KY-E-028)]. Participants were required to sign (or have a proxy sign) informed consent for data collection. This study was conducted in accordance with the tenets of the Declaration of Helsinki.Using a retrospective cohort study, the patients were followed up from the diagnosis of AKI to 90 days. The observed clinical outcome was the recovery of renal function. All subjects were randomly divided into training cohort and validation cohorts by a ratio of 7:3. The development cohort was used to construct the prediction model, and validation cohort was used to verify the model’s prediction ability to predict non-recovery of renal function at 90 days in diabetic patients with AKI.Demographic data and baseline clinical data were collected, including age, gender, duration of diabetes (months), underlying diseases , body mass index (BMI), blood pressure, blood routine, liver function, renal function, electrolytes, myocardial enzymes, 25-hydroxyvitamin D3 [25(OH)D3], blood glucose, and discharged Scr, dialysis, etc. The baseline Scr was defined as a stable Scr within the last 3 months or longer if none was available within 3 months . The disSeveral steps were used in data preprocessing. Before starting the model building process, we have checked each variable for missing, outliers, or implausible values. As only a small number of missing values were present (< 5% of each variable), the missing data and outliers were removed.AKI was defined referring to the diagnostic criteria of AKI in the Kidney Disease: Improving Global Outcomes guideline: Scr increased by ≥ 26.5 µmol/L within 48 h or increased by > 50% of the baseline value within 7 days. The criteria of AKI stage: stage 1: Scr increase to 1.5–1.9 times of baseline value or increased ≥ 0.3 mg/dL, stage 2: Scr increase to 2.0–2.9 times of base value, stage 3: Scr increase to 3 times or ≥ 4.0 mg/ dL or begin RRT .Diagnosis of diabetes conforms to World Health Organization criteria as follows: (1) random blood glucose ≥ 11.1 mmol/L, (2) fasting blood glucose (FBG) ≥ 7.0 mmol/L, or (3) postprandial blood glucose (PBG) ≥ 11.1 mmol/L .Renal function recovery was defined as a return of Scr to less than 1.25 times the baseline value or Scr decrease to normal lab range  or removal of RRT . Otherwi2 test. The univariate Logistic regression model was used to screen the risk factors, the variables with P < 0.05 were included in the multivariate Logistic regression (the forward LR method). Based on the multivariate Logistic analysis results, a nomogram was constructed based on the odds ratios of risk factors. The concordance index (C-index) and receiver operating characteristic curve (ROC) were used to evaluate the discrimination of the prediction model in the development and validation cohorts. The Hosmer-Lemeshow goodness of fit test was used for the calibration degree to compare the difference between the predicted probability and the actual probability, and P > 0.05 indicated that the model calibration degree was reliable. The Brier score was also calculated to evaluate the calibration degree of the model, and the better the calibration of the model with a Brier score close to 0. The Bootstrap method was used to draw the calibration curve, and the closer the slope is to 1, the higher the accuracy of the prediction model. Decision curve analysis was conducted to determine the clinical usefulness of the nomogram by quantifying the net benefit at different threshold probabilities in the primary dataset. P < 0.05 was regarded as a statistically significant difference.All statistical analyses were performed on SPSS 22.0 and R 3.6.3 software. For continuous variables, data are presented as the mean ± standard deviation; for dichotomous variables, data are presented as whole numbers and proportions [n(%)]. Comparisons among two groups were performed by χTable Compared with the validation cohort, the development cohort had a longer diabetes duration (p < 0.05). There was no significant difference in gender, age, length of hospital stay, history of hypertension, CKD, BMI, blood pressure, white blood cell count (WBC), hemoglobin, platelet (PLT), albumin, 25(OH)D3, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), FBG, PBG, glycated hemoglobin A1c (HbA1c), blood urea nitrogen (BUN), baseline Scr, uric acid (UA), serum potassium level, AKI stage, RRT rate, discharge Scr and renal function non-recovery rate in development and validation cohorts.Logistic regression analysis was used to construct the prediction model, as shown in Table 9/L, 68.75 points for 25(OH)D3 of 50 nmol/L, 18.75 points for PBG of 12 mmol/L, 20 points for discharge Scr of 300 µmol/L. The total score of this patient was 154 points (14 + 10 + 0 + 22.5 + 68.75 + 18.75 + 20), the risk of non-recovery rate of renal function at 90 days in diabetic patients with AKI was about 72.5%.Based on the above results, a predictive model for 90-day renal prognosis risk in diabetic patients with AKI was constructed. The nomogram is shown in Fig. P = 0.326, the Brier score was 0.065, and the calibration curve was a straight line with a slope close to 1 , the area under the ROC curve (AUROC) of the prediction model for predicting 90-day non-recovered renal function in diabetic patients with AKI was 0.809, and the Youden index was 0.619, the sensitivity and specificity were 0.746 and 0.873, respectively Fig. A. The HoDecision curve analysis demonstrated the clinical utility of the prediction model based on a continuous potential risk threshold (x-axis) and the net benefit of using the model to risk stratify patients (y-axis). The black line represents that all patients have recovery of renal function, and the gray line represents that all patients have non-recovery of renal function. The threshold probability of the predictive model in the development cohort was 25–100% to produce the greatest benefit Fig. A, and thIn this study, the influencing factors of short-term renal prognosis were evaluated based on the demographic characteristics and clinical data of diabetic patients with AKI, and a prediction model of prognostic risk was constructed. The results showed that diabetes duration, history of hypertension and CKD, increase of PBG and discharged Scr were the risk factors for non-recovery of renal function at 90-day in diabetic patients with AKI; while decrease of PLT and 25(OH)D3 were the protective factors. The prediction model has good discrimination and accuracy through internal verification of Bootstrapping resampling techniques with 1,000 replications and validation cohort. The decision curve analysis also showed good clinical utility. In addition, the predictors used in this model are readily available at discharge and can be used to predict short-term renal prognosis in diabetic patients with AKI, and patients are individually assessed and followed up using this risk stratification . MoreoveNumerous AKI prediction models have been reported in the previous literature. However, most of prognostic models were developed for specific patient populations  –23. PrevA prospective study showed that, compared with patients with diabetes duration of less than 5 years, patients with diabetes duration of more than 20 years had a faster decline in renal function . PatientAlthough AKI is generally reversible, some patients may experience incomplete recovery of renal function, while others experience subsequent accelerated renal loss leading to an increased risk of CKD . In a 10Incomplete recovery from AKI can lead to chronic dysfunction and progressive decline in renal function, especially in patients with pre-existing CKD . Poorly However, this study has several limitations. First, this is a single-center retrospective study with limited sample size and rather short-term following up. Second, the diagnosis of AKI was only based on changes in Scr, and only cases of AKI with decreased urine output might be missed. Third, Scr values were only collected at baseline and 90 days after AKI, which lacked dynamic variation values. Therefore, it is not possible to determine whether patients develop AKI more than once. Fourth, this study only carried out internal verification and did not include external verification. It is still necessary to further expand the sample size for external verification of the predictive performance of the model.Increase of diabetes duration, history of hypertension, CKD, decrease of PLT, 25(OH)D3, increase of PBG and discharged Scr are independent risk factors for non-recovery of renal function in diabetic patients with AKI within 90 days. Based on the above variables, a nomogram can be used to establish a prediction model to help predict the short-term renal prognosis, which has been verified to have good discrimination, calibration and good clinical practicability.