Cardiovascular autonomic dysfunctions (CAD) are prevalent in Parkinson’s disease (PD). It contributes to the development of cognitive dysfunction, falls and even mortality. Significant progress has been achieved in the last decade. However, the underlying mechanisms and effective treatments for CAD have not been established yet. This review aims to help clinicians to better understand the pathogenesis and therapeutic strategies. The literatures about CAD in patients with PD were reviewed. References for this review were identified by searches of PubMed between 1972 and March 2021, with the search term “cardiovascular autonomic dysfunctions, postural hypotension, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension, and nondipping”. The pathogenesis, including the neurogenic and non-neurogenic mechanisms, and the current pharmaceutical and non-pharmaceutical treatment for CAD, were analyzed. CAD mainly includes four aspects, which are OH, SH, postprandial hypotension and nondipping, among them, OH is the main component. Both non-neurogenic and neurogenic mechanisms are involved in CAD. Failure of the baroreflex circulate, which includes the lesions at the afferent, efferent or central components, is an important pathogenesis of CAD. Both non-pharmacological and pharmacological treatment alleviate CAD-related symptoms by acting on the baroreflex reflex circulate. However, pharmacological strategy has the limitation of failing to enhance baroreflex sensitivity and life quality. Novel OH treatment drugs, such as pyridostigmine and atomoxetine, can effectively improve OH-related symptoms via enhancing residual sympathetic tone, without adverse reactions of supine hypertension. Baroreflex impairment is a crucial pathological mechanism associated with CAD in PD. Currently, non-pharmacological strategy was the preferred option for its advantage of enhancing baroreflex sensitivity. Pharmacological treatment is a second-line option. Therefore, to find drugs that can enhance baroreflex sensitivity, especially via acting on its central components, is urgently needed in the scientific research and clinical practice. Parkinson’s disease (PD) patients are suffered by both motor and non-motor symptoms -3. CardiOrthostatic hypotension (OH) is a physical finding defined as a reduction of either a systolic blood pressure (BP) decreases of at least 20 mm Hg or a diastolic blood pressure decrease of at least 10 mm Hg within 3 minutes of an upright tilt with at least 60°or standing time , 5. OH iThe mechanisms underlying the development of OH in PD remain largely elusive. At present, the pathophysiological mechanisms are mainly composed by two parts: non-neurogenic and neurogenic parts. Non-neurogenic mechanisms include reduced intravascular volume, cardiac impairment and drug-induced hypotension. Neurologic mechanisms included cardiac and extra-cardiac noradrenergic denervation accompanied with impaired baroreflexes, which were called the “triple whammy”  5, 23]., 23.5, 2The decrease of effective circulating blood volume is one of the causes of OH in PD patients. Dysphagia, which is a common situation in advanced PD patients, is closely associated with insufficient fluid and poor nutrition intake, decline of intravascular blood volume and occurrence of OH -28.Cardiac dysfunction, especially heart failure, was frequently found in PD patients and considered to be a risk factor for OH . The preAntiparkinsonian drugs had long been listed as main suspects for OH in PD. The suspected anti parkinsonism drugs contain Levodopa and dopamine receptor agonists such as pramipexole, ropinirole and rotigotine. Antiparkinsonian drugs with the possibility to cause or exacerbate OH were summarized in Levodopa: Levodopa is one of the most effective symptomatic treatment options for Parkinsonism with a favorable safety and tolerability profile. However, it was found to be possibly responsible for postural hypotension. Kondo, M. reported that a case of Parkinson’s disease showed orthostatic hypotension due to levodopa administration with a dose of 500mg per day . HoweverDopamine receptor agonists (DAs): Non-ergot DAs, such as pramipexole, rotigotine and ropinirole, is another large group of drugs which are often used to control the motor and non-motor symptoms in PD patients. DAs was considered having the possibility to exacerbate OH by stimulating baroreceptors and causing peripheral venous and arteriolar dilatation , 38.Pramipexole,one of the wildly used Dopamine receptor agonists in clinic, was reported to worse OH. In Pramipexole On Underlying Disease (PROUD) study, 535 PD patients were included and 261 received pramipexole (1.5mg/d). After 6-15 moths’ treatment, 2 patients developed drug-related postural hypotension . HoweverRopinirole, another dopamine receptor agonist, has also been reported to be at risk of orthostatic hypotension. In a study from Titlic M, et al, 50 PD patients were included and one female patient was reported to have OH after the administration of ropinirole . In anotRotigotine transdermal system was often applied in patients with advanced PD. Of 90 patients with advanced PD who received rotigotine 8mg/24h for 8 weeks as well as levodopa and oral DA , 9 (10%) was reported with OH . In anotFrom all the research above, it seems that the PD patient’s age, disease duration, disease severity as well as drug dosage may all related to the occurrence of antiparkinsonian drugs- induced OH.Cardiac and extra-cardiac sympathetic noradrenergic denervation and baroreflex failure existed in virtually all PD patients with OH detected by neuroimaging, neurochemical, and neuropharmacological studies -48. ThesMore than one study confirms that PD patients have a loss of sympathetic innervation of the heart, as demonstrated by low myocardial concentrations of radioactivity after injection of the sympathoneural imaging agents, 123I-metaiodobenzylguanidine or 6-[18F] fluorodopamine -51. CardBesides cardiac noradrenergic innervation, the extra cardiac noradrenergic innervation is also related to the occurrence of OH in PD patients. Study found that the decrease of 6-[18F] fluorodopamine-derived radioactivity was most prominent in the heart but was also detectable in extracardiac organs, such as renal cortex, and thyroid . Extra-cCardiac denervation alone will not lead to OH in PD patients. Baroreflex response and sympathetic reflex, which buffers blood pressure against excessive fluctuations, plays critical role in the occurrences of OH in PD patients. Baroreflex circulation consists of afferent and efferent pathways. Through the afferent pathway, the information of vascular pressure is transmitted from the baroreceptors of arteries and veins to the nucleus tractus solitarius (NTS) in the dorsal medulla oblongata. The efferent pathways are mainly composed by two parts: vagal and adrenergic pathway. The vagal baroreflex pathway runs from the NTS to the nucleus ambiguus (NA) and sends efferent signal to the sinoatrial node (SA), which normally controls the activation of the heart and is closely related to heart rate and rhythm. The adrenergic pathway runs from the NTS to the caudal ventrolateral medulla (CVLM), rostral ventrolateral medulla (RVLM), intermediolateral thoracic spinal cord, autonomic ganglia and to the heart, skeletal muscle and splanchnic vessels, ultimately affecting the total peripheral resistance, cardiac output and the control of arterial pressure.A change of position from supine to an upright position leads to nearly 25-30% of total blood volume accumulated in the skeletal muscle and splanchnic vessels. PD patients mainly involve the nucleus tractus solitarius, rostral ventrolateral medulla, caudal ventrolateral medulla and the sympathetic efferent pathway, which is also known as the central injury mechanism . PD patiThe ideal treatment strategy for OH includes three elements: 1) Minimizing the pulse pressure difference related to postural changes; 2) Avoiding supine hypertension as much as possible; 3) Relieving orthostatic hypotension associated symptoms; 4) Decreasing the morbidity and mortality of patients with symptomatic OH. The efficacy and limitation of both Non-pharmacological and pharmacological measures are summarized as follows and some clinical trials are listed in Non-pharmacological management is the preferred intervention for OH because it can improve baroreflex sensitivity impairment which is consistently associated with supine hypertension. Non-pharmacological treatment intervenes OH through multiple mechanisms, including ensuring sufficient blood volume, reducing the amplitude and speed of posture change, decreasing the accumulation of blood in peripheral vascular bed, and enhancing baroreflex sensitivity.Water-drinking treatment is an effective way to enhance baroreflex sensitivity. Drinking water of 16 ounces in 3 to 4 minutes is an emergency treatment to raise systolic BP and reduce orthostatic symptoms . DrinkinTreadmill gait training was another way to enhance baroreflex sensitivity. A controlled open-label study evaluating the cardiovascular benefits of partial weight supported treadmill gait training in PD showed that the training stabilized the BP, and enhanced baroreflex sensitivity by 80.4% .About 25-30% of total blood volume was accumulated in the splanchnic-mesenteric capacitance bed, which is a large volume, low-resistance system . Ways toWaist-high and custom-fitted thigh compression stockings and sequential application of pressure ranging from 30 to 40 mmHg by abdominal binders, may decrease venous pooling in the lower body -70. UnfoPhysical counter-maneuvers may cut down blood accumulation in lower limbs and prevent standing BP from falling to fatal levels or prevent the occurrence of syncope , 72. HowPD patients with OH should avoid some situations that may cause OH, including a sudden change in position, staying in bed for a long time, standing for a long time, high-temperature environments, excessive intake of alcohol, low salt diets, insufficient fluid intake, high-glycemic index carbohydrates intake , 74. In When non-pharmacological methods are unable to effectively control OH, it is necessary to adopt pharmacological treatment, which is regarded as a second-line treatment strategy because they may cause or aggravate supine hypertension . HoweverNorepinephrine replacement therapy is more effective in PD patients with neurodegeneration of peripheral noradrenergic fibers. Midodrine, droxidopa and metoclopramide are representative drugs acting on noradrenergic and adrenergic pathway.Midodrine exerts its actions via activation of the alpha1-adrenergic receptors of the arteriolar and venous vasculature, enhancing vascular tone. Midodrine has long been used in clinic and approved for treatment of OH by US Food and Drug and in some European countries . In 1981Droxidopa  is a norepinephrine prodrug which increases the levels of norepinephrine in postganglionic sympathetic neurons and has been used in PD patients with OH since 1989 , 88. DroMetoclopramide or domperidone has been reported to be a potential OH intervention as a dopamine receptor antagonist, because presynaptic dopamine receptors of sympathetic nerve endings contribute to the release of norepinephrine , 99. SomFipamezole, an α2-adrenergic receptor antagonist, can bind to α-adrenergic 1A and 1B receptors, dopamine and norepinephrine transporter . A previEnhancing residual sympathetic tone is another way to prevent OH. Representative drugs are pyridostigmine and atomoxetine. This treatment is suitable for patients with spared postganglionic fibers.Pyridostigmine, which is an acetylcholinesterase inhibitor, is found to enhance standing blood pressure in patient with OH by inhibiting acetylcholinesterase, augmenting sympathetic traffic at the level of the autonomic ganglia (as preganglionic sympathetic neurons are cholinergic), and enhancing baroreflex function. Due to its novel mechanism, pyridostigmine had no effect on supine hypertension . To furtIn recent years, the advantages of atomoxetine in the treatment of OH have been concerned by scholars -110. AtoFlucortisoneFlucortisone reduces the deficiency of plasma renin and aldosterone when standing as a synthetic mineralocorticoid with little glucocorticoid activity, so it can be used to treat OH. Studies have shown that low-dose flucortisone (0.1 mg/day) improve OH combined with a high pillow position and a high-salt diet at night , 112. HoIndomethacin is a nonsteroidal drug with anti-inflammatory and antipyretic properties. The mechanism of indomethacin on OH intervention is unclear. Indomethacin may reduce the drop in BP via increasing reflex vasoconstriction due to promoting the release of endogenous angiotensin II and noradrenaline from remaining nerve ending , 114. ThSupine hypertension (SH) is another CAD in patients with PD and About one half of patients with autonomic failure also suffer from supine hypertension. SH is defined as the systolic BP ≥150 mmHg and the diastolic BP ≥90 mmHg when in the supine position . SH can The cause and mechanisms of supine hypertension remain still unknown. Supine hypertension in PD patient with autonomic failure may be mediated by an increase in peripheral vascular resistance due to residual sympathetic tone. In PD wThe treatment goal of supine hypertension is to regulate dysfunction of target organs and the risk for OH. The indications for beginning the management of supine hypertension are patient’s BP persistence greater than 180/110 mmHg (systolic and diastolic), and the treatment should be individualized for systolic blood pressure (SBP) 160-180 mmHg and diastolic blood pressure (DBP) 90-110 mmHg . Supine There is need to create educate patients with supine hypertension that they should not stay in supine position when taking anti-hypotensive drugs or using compression stockings or abdominal belts. One recent research also showed that passive heating of the pelvis and abdomen with a commercial heating pad can reduce BP in patients with supine hypertension and autonomic nervous failure .When non-pharmacological treatment cannot be effective, pharmacological interventions may be considered to be used in supine hypertension. Because supine hypertension is often combined with OH, it is clinically difficult to treat supine hypertension, and antihypertensive drugs should be able to control BP overnight, while not causing OH in the morning. Clonidine, as an α2-adrenergic agonist, is a central antihypertensive drug suitable for patients with severe supine hypertension. Residual sympathetic tone acts on the adrenergic receptors during hypertension, but it is a possible mechanism for PD patients to develop supine hypertension, allowing clonidine to be used for severe supine hypertension. However, BP should be closely monitored during this time .Short-acting nifedipine and nitroglycerin transdermal patchesNitroglycerin transdermal patches are highly maneuverable, but their antihypertensive effects may be unstable . The lowNitroglycerin transdermal patch and nifedipine lower BP, but these two drugs have no effect on stressful diuresis at night . NifedipSildenafil citrate enhances the function of nitric oxide as an effective vasodilator , 129. InNebivolol, a third-generation selective β1-adrenergic receptor blocker, has unique vasodilatory actions which is dependent on increasing the bioavailability of endothelium derived nitric oxide. Although nebivolol has a strong effect on lowering BP, it does not worsen OH in the morning. One study showed that nebivolol significantly reduced nocturnal BP (about 40 mmHg) in patients exhibiting good response to 25 mg sildenafil citrate . NebivolEplerenone (at 50mg), as a selective mineralocorticoid receptor antagonist, has been showed to reduce maximum BP by about 32mmHg in supine hypertension . The mec1 receptor blocker (ARB), decreased fluid loss and pressure natriuresis. After taking 50 mg losartan for 6 hours, the BP of 11 patients with severe autonomic nervous failure decreased by 32 mmHg, what’s more, losartan had minimal effects on morning NOH . T. T1 receve drugs .Postprandial hypotension is considered among the earliest events of CAD in PD. Postprandial hypotension may be misdiagnosed as a state of dyskinesia, accompanied by worsening stiffness and bradykinesia -140. PD Yohimbine which activates adrenergic receptors and promotes the production of norepinephrine from peripheral sympathetic nerve endings , 152. YoDipping" refers to a 10-20% decrease in BP at night . NondippPD is a common cause of autonomic dysfunction -162, and


There is no clear evidence for the target value of blood pressure control after Percutaneous coronary intervention (PCI). Therefore, our study was designed to explore the relationship between blood pressure after PCI and major adverse cardiac events (MACE) during 3-year follow-up.This study is a prospective study. We included the patients who were diagnosed with acute coronary syndrome and underwent PCI stent implantation operation. The study initially collected information of 552 patients. The start and end times of the study are from January 1, 2017 to December 31, 2020. The independent variables of this study are the average systolic blood pressure and the average diastolic blood pressure after PCI. The dependent variable is the occurrence of MACE events in patients within 3 years after PCI. MACE is defined as acute myocardial infarction, recurring chest pain, heart failure, stroke, revascularization and cardiac death.P = 0.029). The impact size and 95% CI at the right inflection point were 1.00 and 0.98–1.02(P = 0.604), respectively.A total of 514 subjects met the inclusion criteria. The average age of the study subjects is 61.92 ± 9.49 years old, of which 67.12% are male. 94 subjects had a MACE event within 3 years, and the occurrence rate was 18.29%. There is no significant non-linear or linear relationship between diastolic blood pressure and MACE events. There is a curvilinear relationship between the average systolic blood pressure of patients after PCI and MACE events within 3 years and the inflection point is 121. On the left side of the inflection point, the effect size and 95% CI are 1.09 and 1.01–1.18, respectively (There is a curvilinear relationship between systolic blood pressure and prognosis of patients after PCI. Under the premise of ensuring the safety of patients, maintaining lower blood pressure after surgery is beneficial to improve the prognosis of patients. Hypertension is one of the important risk factors of coronary atherosclerosis –3. The gThis study is a prospective study. The purpose of this study is to explore the relationship between the systolic and diastolic blood pressure after surgery and the occurrence of MACE events within 3 years of patients undergoing PCI in China. The independent variables of this study are the average systolic blood pressure and the average diastolic blood pressure after PCI.The patients in this study were non-selectively and consecutively collected from patients who were diagnosed with acute coronary syndrome and underwent PCI stent implantation operation from January to December 2017 in the Affiliated Hospital of Jining Medical University, Jining City, Shandong province, China. The information obtained by the research does not contain the patients’ private data. All patients participating in the study signed the study informed consent form. This study was approved by the Medical Science Research Ethics Committee of the Affiliated Hospital of Jining Medical University (Ethics Number: 2021C030).The study initially collected information of 552 patients. The start and end times of the study are from January 1, 2017 to December 31, 2020. The inclusion criteria were: (1) the patients who were diagnosed with acute coronary syndrome; (2) the patient underwent PCI stent implantation operation. The exclusion criteria were: (1) the patients who lost in follow-up due to change of mobile phone number, refused to answer the phone or other reasons; (2) death in the hospital; (3) the patient refused to answer questions during the follow-up process and withdrew from the study.We collected the blood pressure values of patients after PCI and recorded them as continuous variables. We recorded the patient's blood pressure 9 times, including immediately after surgery, 30 min after surgery, 1 h after surgery, 1.5 h after surgery, 2 h after surgery, 4 h after surgery, 6 h after surgery, 12 h after surgery, and 24 h after surgery. We calculate the average value of the patient's 9 systolic and diastolic blood pressures as the independent variable of this study. The blood pressure of the patients was measured with a Mindray ECG monitor. Before the measurement, keep the patient in a quiet state for 10–20 min, and prohibit smoking, tea and coffee. All of the patients wear the same uniform and measure the left upper extremity. During the measurement, the patient was placed in a supine position and align with the fourth intercostal space.The dependent variable of this study is a binary variable. According to previous studies, we regard the occurrence of MACE within 3 years as the clinical outcome of the patient. The definition of MACE events in this study is as follows: follow-up by telephone and ask patients whether they have acute myocardial infarction, recurring chest pain, heart failure, stroke, revascularization, and cardiac death within 3 years after discharge. MACE events were first reported by the patients through telephone follow-up by the researchers. Then we identify the MACE event type through the medical system records. If any of the above outcomes occur, it is deemed that the patient has had a MACE event.−, Creatinine, Cysteine protease inhibitor C, free triiodothyronine (FT3), Free thyroxine (FT4), Thyroid Stimulating Hormone (TSH), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), Lipoprotein, K+, left ventricular ejection fraction (LVEF), Na+, total cholesterol (TC), triglyceride (TG), uric acid (UA)and urea.The variables included in this study include the following three aspects: (1) socio-demographic data of the subjects; (2) variables that may be related to MACE or blood pressure; and (3) other variables collected based on our clinical experience. Therefore, we used the following variables to construct a fully adjusted model: (1) the categorical variables included sex, smoking history, drinking history, education level, atrial fibrillation, diabetes, heart failure, myocardial infarction, myocardial bridge, cerebral infarction, number of stents implanted and medication after discharge; (2) continuous variable: body mass index (BMI), ClThe follow-up method in this study was telephone follow-up. The outcome of the MACE event was determined by the patients’ self-report. The follow-up was carried out by 5 members of the research group who had received standardized training. This study was followed up for 3 years. During the three-year period, follow-up visits were made every year.2 (classified variable), one-way ANOVA test  or Kruskal-Whllis H test (skewness distribution) to test the differences of systolic blood pressure and diastolic blood pressure among three groups. The data analysis process of this study is based on three aspects: (1) the relationship between blood pressure and MACE events in patients after PCI (linear or nonlinear); (2) which factors interfere with the relationship between blood pressure and MACE events in patients after PCI; (3) what is the real relationship between blood pressure and MACE events in patients after PCI after stratified analysis. Therefore, the data analysis in this study is divided into two steps. Step 1: univariate and multivariate bivariate logistic regression were used. We build three models: model 1, a crude model with no covariates adjusted; model 2, adjusted social demographic data; and model 3, adjusted social demographic data and other covariables that may affect MACE events. Step 2: explain the nonlinear relationship between blood pressure and the occurrence of 3-year MACE events. Cox proportional hazard regression model using smooth curve fitting. If nonlinearity is detected, we first use a recursive algorithm to calculate the inflection point, and then construct a two-segment binary logic regression on both sides of the inflection point. Finally, the logarithmic likelihood ratio test is mainly used to determine which model is more suitable to fit the correlation between the target independent variable and the result variable. For continuous variables, we first convert them into classified variables according to tangent points. The likelihood ratio test was carried out after the effect adjustment test of the subgroup index. In order to ensure the robustness of data analysis, we carried out sensitivity analysis. We convert blood pressure into classification variables and calculate the P value of the trend. The aim is to verify the results of blood pressure as a continuous variable and to observe the possibility of nonlinearity. All the analyses were conducted using statistical software packages R  and EmpowerStats . P values less than 0.05 (two-sided) were considered statistically significant.The continuous variables in accordance with the normal distribution are expressed by the mean ± standard deviation. The continuous variable of the skewness distribution is expressed by the median . Classification variables are expressed in frequency or percentage. We used χP > 0.05). The group with the highest systolic blood pressure had the oldest average age, the highest incidence of myocardial infarction, the highest BMI, Cysteine protease inhibitor C, TSH, and Na+ values, but the lowest incidence of cerebral infarction. No statistically significant differences were detected in Sex, Alcohol consumption, Smoke, Degree of education, AF, DM, heart failure history, Myocardial bridge, number of stents, Cl−, creatinine, Cysteine protease inhibitor C, FTH, HDL-C, LDL-C, Lipoprotein, K + , LVEF, Na + , TC, TG, Urea, ACEI, Aspirin, b-blocker, Clopidogrel, Nitrates, Ticagrelor among different DBP groups (P > 0.05). The group with the highest diastolic blood pressure had the lowest average age, the highest incidence of myocardial infarction, and the highest BMI, TSH, and UA values.A total of 514 subjects met the inclusion criteria . The impact size and 95% CI at the right inflection point were 1.00 and 0.98–1.02 (P = 0.820), respectively (Table P = 0.029). The impact size and 95% CI at the right inflection point were 1.00 and 0.98–1.02, respectively (P = 0.820). Only to the left of the inflection point, there is a statistical correlation between systolic blood pressure and the occurrence of MACE events. In addition, we did not find a clear statistical correlation between the diastolic blood pressure and the occurrence of MACE events.Our study found that there is a curvilinear relationship between the average systolic blood pressure of patients after PCI and MACE events within 3 years. At the same time, we found the inflection point of systolic blood pressure at 121. On the left side of the inflection point, the effect size and 95% CI are 1.09 and 1.01–1.18, respectively (Josephine et al.  measuredPrevious studies have not conducted relevant studies on blood pressure control in the short-term after PCI. However, previous studies have explored the relationship between the admission blood pressure of patients with myocardial infarction and the prognosis in the hospital. But there are some studies inconsistent with the results of our study. For example, Shiraish et al.  conducteOur research has the following three advantages. First of all, our study provides the target direction for blood pressure control after PCI for the first time. Early postoperative blood pressure control is a key clinical concern for doctors and nurses. This is not explored in previous studies. Secondly, our research separately explored the curve relationship between systolic and diastolic blood pressure and long-term prognosis, and found the inflection point of systolic blood pressure. This has important guiding significance for clinical practice. Third, this observational study adjusted multiple confounding variables to more clearly describe the relationship between blood pressure and the long-term prognosis of patients after PCI.However, our study also has some limitations. First of all, our research is only a single-center study, and the subjects are all from the same hospital in Shandong Province, China. Second, our study only explored the impact of blood pressure on the prognosis of patients after PCI. In the future, the blood pressure of patients after discharge can be monitored and observed to find the long-term blood pressure target value of patients after discharge, so that the patients can get the maximum benefit. At last, MACE events were first reported by the patients through telephone follow-up by the researchers. Then we identify the MACE event type through the medical system records. However, the possibility that the patient may seek treatment in other medical institutions cannot be ruled out. If the patient’s medical treatment information cannot be retrieved, the patient’s self-reported outcome shall prevail. This is also one of the limitations of this study.There is a curvilinear relationship between systolic blood pressure and prognosis of patients after PCI. Under the premise of ensuring the safety of patients, maintaining lower blood pressure after surgery is beneficial to improve the prognosis of patients. In the future, the blood pressure of patients after discharge can be monitored and observed to find the long-term blood pressure target value of patients after discharge, so that the patients can get the maximum benefit.


A patient subgroup analysis showed that changes in FEF25-75% values were higher in patients with a baseline peripheral blood eosinophil count ≥400 cells/μL and oral corticosteroid use. Mepolizumab significantly improves small airway function. This effect correlates with clinical benefits and may represent an accessible parameter through which to evaluate therapeutic response. This study provides novel insights into the phenotypic characteristics associated with the improved functional outcome provided by mepolizumab treatment.Severe eosinophilic asthma (SEA) is associated with high peripheral blood and airway eosinophilia, recurrent disease exacerbations and severe airflow limitation. Eosinophilic inflammation is also responsible for small airway disease (SAD) development. SEA patients experience poor disease control and response to standard therapy and are prime candidates for anti-IL5 biologicals, such as mepolizumab, but the effect of treatment on SAD is unclear. We investigated the effect of mepolizumab on lung function in SEA patients, focusing on SAD parameters, and searched for an association between patients’ phenotypic characteristics and changes in small airways function. In this real-life study, data from 105 patients with SEA were collected at baseline and after 6, 12 and 18 months of mepolizumab treatment. Along with expected improvements in clinical and lung function parameters brought by Mepolizumab treatment, FEF2525-75% values showed a highly significant, gradual and persistent increase (from 32.7 ± 18.2% at baseline to 48.6 ± 18.4% after 18 months) and correlated with ACT scores at 18 months (r = 0.566;  Asthma is a chronic respiratory disease characterized by airway inflammation, variable airflow limitation and bronchial hyperresponsiveness. This widespread airway disorder affects over 300 million people worldwide and its prevalence is increasing. Although the majority of asthmatic patients can achieve good control over their symptoms using standard treatments, a minority of patients experience poor disease control, characterized by low quality of life (QoL) and high rates of exacerbations, hospitalizations and mortality ,2. AsthmEosinophils are very sensitive to the anti-inflammatory action of glucocorticoids (GC) through direct and indirect mechanisms, including the inhibition of the expression of eosinophilic cytokines and chemokines . HoweverEosinophilic inflammation is also closely related to small airway disease in asthma. Small airway dysfunction is highly prevalent in the asthmatic population, across all degrees of severity, particularly in patients with severe disease . PatientMepolizumab, a fully humanized anti-mouse IgG1/k monoclonal antibody, targets the eosinophilic subtype of severe asthma. The pharmacological efficacy of mepolizumab is due to the neutralization of the biological activity of IL-5, which prevents the terminal differentiation of eosinophil progenitors and reduces the output of eosinophils from bone marrow, resulting in a normalization of blood eosinophilia . In largThe main purpose of this study was to investigate the potential effect of mepolizumab on forced expiratory flow at 25%–75% (FEF25-75) of forced vital capacity (FVC), and whether this effect is related to other clinical benefits. With this aim, we explored the potential usefulness of FEF25-75, a measure of small airway dysfunction widely performed in everyday clinical practice, as an adjunctive tool to assess response to mepolizumab therapy. Furthermore, we also assessed the possible phenotypic characteristics associated with a better functional outcome.This was a retrospective study that analyzed 105 patients with severe eosinophilic asthma treated with mepolizumab and referred to four centers in southern Italy. All the patients received a diagnosis of severe asthma according to the European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines  and wereThe following data were recorded at baseline: demographic characteristics, smoking history, BMI, duration of asthma, age of asthma onset, atopic status, presence of rhinitis, sinusitis, nasal polyposis and other comorbidities , blood eosinophil count, total IgE level, fractional exhaled nitric oxide (FeNO) and pulmonary function tests, Asthma Control Test (ACT) score, number of exacerbations and asthma medications.The clinical, biological and functional outcomes were collected 6, 12 and 18 months after the first injection of mepolizumab.Clinical Outcome: ACT score, number of exacerbations, need of maintenance systemic corticosteroid. Exacerbations taken into account were those with worsening of symptoms, requiring oral corticosteroids for at least three days.Biological outcome: blood eosinophils count and FeNO.Pulmonary function tests: FEV1%, FVC%, FEV1/FVC% and FEF25-75%.The statistical analysis was performed using Prism Version 8.2.1 . The data were reported as mean and standard deviation (SD) for normally distributed data and median and interquartile range (IQR) for non-normally distributed data. The categorical variables were considered as the number of cases and percentages. The comparisons of continuous variables were performed using the t-test or the Wilcoxon signed-rank test, as appropriate, in order to assess the difference between the patient’s status before and after treatment. The comparisons between different sub-groups of patients were performed using Mann–Whitney-U test. The categorical variables were compared using Fisher’s exact test. Spearman’s rank correlation coefficient was calculated to assess the association between variables and a linear regression analysis was developed. Probability values of <0.05 were considered to be statistically significant.Our retrospective observational study included 105 adult patients with severe eosinophilic asthma, according to the ERS/ATS definition , treated2. According to the ERS/ATS definition of severe asthma, all the patients required high dosages of inhaled corticosteroids (ICS) and long-acting beta agonist (LABA) combinations. Furthermore, 60% of the patients received additional bronchodilator treatment consisting of long-acting muscarinic antagonist (LAMA), 51.43% required continuous intake of oral corticosteroids (OCS) and 3.8% used leukotriene receptor antagonists (LTRA). Despite maximal therapy, most patients (84%) had uncontrolled asthma defined by a baseline ACT score <20 (according to GINA defined criteria). Moreover, they had a history of asthma complicated by frequent exacerbations (mean SD 4.2 ± 2.5). All the patients had eosinophil counts in peripheral blood of at least 150 cells/μL at baseline or at least 300 cells/μL within the previous 12 months, with a median (IQR) eosinophil count at baseline of 500 (350–717). Among all the enrolled patients, 55% were defined as allergic based on skin prick test (SPT) positivity and the most reported comorbidity was chronic rhinosinusitis (49.5%) with or without nasal polyposis (33.3%). Regarding lung function, the mean (±SD) baseline FEV1 and FEF25-75 was 63.7 ± 17.9 and 32.7 ± 18.2 of predicted value respectively.The patients were more frequently female , with a mean age of 58.5 ± 11.0 years old and a mean BMI above the normal range of 27.4 ± 4.2 kg/cmp = 0.005), while no correlation was found between blood eosinophils and ACT score  and FEF25-75% of predicted  at baseline  (Median (IQR)) to near-threshold value for control of 19  after 6 months (ACT score for asthma control is >20), crossing the control threshold at 18 months’ follow-up, reaching a value of 23  , Panel aAfter 6 months of add-on mepolizumab therapy, blood eosinophil count dropped from 500 cells/μL (350–717) [median (IQR)] to 80 cells/μL (40–130). This expected effect was sustained over time, reaching 50 cells/μL (30–100) after 18 months of treatment , Panel aTreatment with mepolizumab determined a positive impact on lung function. Significant effects were already measurable according to all spirometric parameters after 6 months of add-on therapy. In particular, the mean percentage value for FEV1, FVC and FEV1/FVC increased almost to their maximal improvement level after 6 months of therapy, without further significant improvement over the course of the observation period , Panel d% at baseline  and at 18 months’ follow-up , FVC% at baseline  and at 18 months’ follow-up ; FEV1/FVC% at baseline  and at 18 months’ follow-up , FEF25-75% at baseline (r = 0.347 p = 0.0007) and at 18 months’ follow-up  , while the comparison between FEF25-75 correlation with ACT on baseline and after 18 months was statistically significant .We also evaluated correlations between clinical scores (ACT) and pulmonary function tests  with reg<0.0001) . A PearsWe then evaluated the study outcomes in different subgroups of patients according to age of asthma onset, allergic phenotype, baseline eosinophilic count and need for maintenance oral corticosteroids (mOCS). No difference was found in terms of treatment-related improvement in clinical, biological and pulmonary function outcomes according to age of asthma onset (<40 or ≥40 years), allergic phenotype defined on the basis of SPT results (data not shown), and obesity.To evaluate the response to mepolizumab according to baseline blood eosinophil level, we chose a cut-off of 400 cells/μL ,17, basep = 0.04) (p = 0.03). In this high-eosinophils subgroup, the improved symptom control after 12 months of treatment with mepolizumab was paralleled by a greater improvement both in FEV1 (12 (6.3–19) vs. 7 (0–12)% of predicted, p = 0.01) (p = 0.04)  vs. 5 (1–8)  = 0.04) , Panel a = 0.01) , Panel b = 0.04) , Panel c = 0.04) p = 0.01)  of add-on therapy with mepolizumab  vs. 400 (330–600), olizumab .Our data provide novel insights into the established beneficial effects of mepolizumab on lung function, showing significant improvements in airflow in the small airways (FEF25-75), as well as in the large airways (FEV1), and the association of mepolizumab with specific subgroups of SEA patients with high eosinophil counts and OCS use.Overall, our study aligns with findings reported by previous RCTs and recent real-life observations ,21,22,23Although data regarding the clinical efficacy of mepolizumab in terms of symptoms, exacerbation rate and OCS sparing effect are strong, currently available findings regarding its therapeutic action on lung function are less evident. A recent Cochrane analysis  reportedValidated treatment response criteria to mepolizumab remain are yet to be defined precisely. According to the recommendations of the British National Institute for Health and Care Excellence (NICE), an adequate therapeutic response can be provided by a reduction = in asthma exacerbation rates of at least 50%, or by a clinically significant decrease in continuous OCS use . AlthougWe also planned to identify possible baseline features associated with better functional and clinical responses to mepolizumab treatment. These characteristics included age of asthma onset, atopic trait, blood eosinophil count and need for maintenance OCS. Interesting differences between OCS-dependent subjects and non-OCS dependent subjects were found. At baseline, the OCS-dependent subjects presented a greater blood eosinophil count and degree of peripheral airflow limitation than the non-OCS-dependent subjects. These results may suggest that the OCS-dependent patients, despite treatment with systemic steroids, had a more severe form of the disease. These data appear to be similar to the data obtained in previous research . Both alAnother interesting finding observed in our study was the progressively increasing improvement in FEF25-75, detected in the subgroup of patients requiring OCS maintenance therapy, when compared to subjects not needing regular OCS treatment. It is also noteworthy that the patient subgroup under continuous OCS therapy demonstrated higher baseline blood eosinophil counts, despite OCS treatment. For this cluster of patients, it can be proposed that the reduction of peripheral blood eosinophil numbers, observed at every time point of our study, could have been related to the anti-IL-5 activity exerted by mepolizumab within the context of glucocorticoid-resistant eosinophilic inflammation, and was thus not modifiable by OCS.This study did feature some limitations. Given its retrospective and multicenter design, some datasets were smaller due to different clinical record-taking across participating centers. Furthermore, as a functional marker of peripheral airflow limitation, we used FEF25-75% predicted, whose role in identifying small airway dysfunction has been thoroughly debated in terms of reproducibility and sensitivity and can be operator-dependent, since flows at percentages of FVC strictly depend on the correct spirometric maneuver .Our data indicate that despite these limitations, FEF25-75% predicted can be a valuable asset as a first-level assessment for SAD, since it is routinely performed in common clinical practice and could be used as a treatment response parameter. Moreover, these data appear to be even more significant, since they do not come from an RCT. Improvements in FEF25-75% predicted by Mepolizumab in a real-life context highlight the relevance of distal airways as targets for asthma control, since data in recent research showed that SAD affects 50–60% of individuals across the range of persistent asthma severity .Even though mepolizumab has already proven to be very effective and well tolerated, results from real-life experiences show that this drug can induce better therapeutic effects than those reported by RCTs. Consistently with such findings, in this study we demonstrated that mepolizumab elicited long-lasting improvements in lung function, especially with regard to relevant increases in small airway caliber. This effect, closely related to the mepolizumab-mediated attenuation of eosinophilic inflammation, probably contributes in a decisive manner to persistent clinical benefits. It is difficult to reliably predict which patients will benefit the most from mepolizumab based on their baseline features. However, we identified subgroups of patients with SEA for whom the lung functional benefits appeared to be more significant, thus providing potentially important insights into our understanding of the phenotypic features associated with a better response in terms of clinical and functional outcomes.


To investigate the association between sex differences and end-stage kidney disease (ESKD) in patients with biopsy-confirmed diabetic kidney disease (DKD).2 or initiation of renal replacement therapy. The association between sex differences and ESKD was assessed using the log-rank test and Cox regression.We performed a retrospective cohort study. A total of 336 patients with biopsy-confirmed DKD who were followed up for at least 12 months were enrolled. Baseline clinical and pathological data at the time of biopsy were collected. ESKD was defined by an estimated glomerular filtration rate of <15 ml/min/1.73 mP >0.05). Univariate [male: hazard ratio (HR) [95% confidence interval (CI)], 1.005, (0.702–1.439)] and multivariable , 1.164, (0.675–2.007)]. Cox regression further showed that sex difference was not significantly associated with ESKD.There were 239 (71%) male and 97 (29%) female patients in our cohort. Female patients had higher systolic blood pressure, total cholesterol and low-density lipoprotein cholesterol levels compared with male. There were a lower proportion of female patients in the very high risk grade according to the chronic kidney disease categories . During a median follow-up time of 20 months, 101 (57.7%) male and 43 (44.3%) female entered into ESKD, with no significant difference by the log-rank test (Female patients had the higher systolic blood pressure, total cholesterol, LDL-C, compared with male patients. However, there was no significant association observed between sex difference and ESKD in our study. Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes. Despite improvements of management in basic research and clinical practice, DKD remains the leading cause of end-stage kidney disease (ESKD) worldwide , 2. In oThe association between sex differences and the incidence or progression of DKD has been investigated in several studies, but not been well established with disparate conclusions . DiffereTherefore, in the current study, we aimed to investigate sex differences of clinical and pathological characteristics in patients with biopsy-confirmed DKD. We also aimed to evaluate the association between sex difference and ESKD.We performed a retrospective cohort study. The study was approved by the ethics committee of West China Hospital of Sichuan University and all patients have signed a written informed consent form.2.Patients with biopsy-confirmed DKD from January 2010 to December 2018 in our hospital were reviewed. Baseline data were collected from the hospital information system at the time patients received a kidney biopsy. The inclusion criteria were as follows: a. type 2 diabetes; b. biopsy-confirmed DKD; and c. follow-up for longer than 12 months . Type 2 diabetes was diagnosed in accordance with the 2018 American Diabetes Association criteria . Renal pP-value of less than 0.05 was considered statistically significant.Continuous variables were described as mean ± standard deviation (SD) or median and quartiles on the basis of a normality test. Categorical variables were presented as counts with ratios. Differences of baseline data between male and female patients were evaluated appropriately by the Student’s t test or the Mann–Whitney test. The prognosis of the kidney was compared by the log-rank test and shown using the Kaplan–Meier curve. Univariate and multivariate Cox analysis were applied to determine the risk factors of ESKD. All analyses were conducted using SPSS software 22.0 and GraphPad Prism 7.0. A two-sided 2 and the median proteinuria was 4.3 (2.0–7.8) g/24 h. There were 239 (71.1%) male and 97 (28.9%) female in our cohort; compared to male, female had the higher level of systolic blood pressure and lipid metabolism. Moreover, a significantly higher proportion of female patients received renin–angiotensin–aldosterone system (RAAS) inhibitors therapy. Male had the higher level of serum creatinine compared with female. There were no significantly differences in age, diastolic blood pressure, the duration of diabetes, the incidence of diabetic retinopathy, blood glucose, proteinuria, triglyceride, medical insurance, insulin use, statins and fibrates use. With regard to pathological lesions, 16 patients had glomerular class I, 77 had class IIa, 33 had class IIb, 153 had class III, and 52 had class IV. However, there were no significant differences in glomerular class, interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation and arteriolar hyalinosis between male and female patients.A total of 336 patients were enrolled in the study. Baseline clinical and pathological characteristics are shown in 2 vs. 25.4 (23.2–27.5) kg/m2, P >0.05) and triglyceride  were not significant different between male and female. However, compared with male patients, female patients had the significantly higher total cholesterol , LDL-C , HDL-C , but lower uric acid  mmol/L vs. 354 (311–391) mmol/L, P <0.05).With regard to metabolic characteristics, the body mass index  kg/mTo evaluate the risk distribution between male and female patients, we used the CKD category heat map as recommended by the Kidney Disease Improving Global Outcomes . PatientDuring a median follow-up period of 20 (14–35) months, a total of 144 (57.1%) patients developed ESKD. Specifically, there were 101 (57.7%) male, 18 (52.9%) premenopausal female, and 25 (39.7%) menopausal female suffered from ESKD during the follow-up time. There was no significant difference in kidney survival between male and female, and no difference between premenopausal and menopausal female (P = 0.978), which indicated there was no association between sex and ESKD. The higher levels of systolic blood pressure, proteinuria, total cholesterol, LDL-C, HDL-C, advanced class of glomerular lesion, IFTA, interstitial inflammation, arteriolar hyalinosis, incidence of diabetic retinopathy, and the lower levels of serum albumin and eGFR were associated with ESKD. Moreover, when we adjusted for essential clinical and pathological indices, sex was still not associated with ESKD . However, a higher levels of interstitial inflammation , and the lower serum albumin  and eGFR  were independently associated with ESKD.To evaluate risk factors of ESKD in patients with DKD, we performed univariate and multivariable Cox regression analyses . Similarly, several studies showed that African American, Hispanic and Pima Indian female had a higher risk of DKD and disease progression (Increasing studies have investigated the effect of sex differences on DKD development and progression, however, but different cohorts have reported conflicting findings. In studies that enrolled patients with type 2 diabetes, it seems that more results indicated female has greater risk of DKD progression . A studygression –15. Nevegression . This prgression , 18. OurThe recognition of underlying mechanism of sex differences in diseases remains limited. Sex hormones are considered to be the main driver of sex disparities in the incidence and progression of CKD. A meta-analysis that included 11,345 patients clearly indicated that male was associated with a faster progression of nondiabetic CKD . HoweverThere are other possible mechanisms contribute to sex differences. Studies have suggested that more adolescent female with diabetes had hyperfiltration in the early stage of DKD , 29. AddThere were several limitations should be addressed. First, this was a retrospective cohort study, and we only observed the relationship between sex differences and kidney prognosis. therefore, prospective studies are warranted to determine the underlying causative relationship. Second, our study only included Chinese patients, various genetic backgrounds might have affected our results. Third, we had no opportunity to evaluate the levels of sex hormones at baseline owing to the study design. Fourth, the sample size was limited and patients were in a relatively severe disease stage because we only enrolled patients with biopsy-confirmed DKD. Therefore, further prospective and large sample size DKD cohorts are required to investigate the issue.In patients with biopsy-confirmed DKD, female patients had the higher systolic blood pressure, total cholesterol, LDL-C levels, compared with male patients. However, there was no significant association was observed between sex difference and ESKD in our study.Sex differences play an important role in many diseases including cancers or chronic diseases. However, the association between sex differences and the incidence or progression of DKD has not been well established with disparate conclusions. Therefore, we investigate the issue in patients with biopsy-confirmed DKD. We found that female patients had the higher systolic blood pressure, total cholesterol, LDL-C levels. However, there was no association between sex difference and ESKD in our study. The study provides relatively strong evidence to illustrate the associations.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by ethics committee of West China Hospital of Sichuan University. The patients/participants provided their written informed consent to participate in this study.YTW, JZ, and FL planed, analyzed and wrote the manuscript. JLZ, YCW, RZ, and HR collected data, check analysis and gave some suggestions. MC revised the manuscript and gave lot of suggestions. All authors contributed to the article and approved the submitted version.This study was supported by Grant 8197031494 from the National Natural Science Foundation of China.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Given the potential impacts of household air pollution (HAP) exposure from burning solid fuels on cardiovascular health during pregnancy, we sought to determine whether baseline exposures to particulate matter with an aerodynamic diameter ≤2.5 μm , mother's education, household wealth, gestational age, and season. At the time of measurement, women were between 9- and 20-weeks of gestation.Multivariable linear regression models were used to examine the association between 24-h personal exposure to PM3 increase in CO exposure was associated with 0.36 mmHg higher DBP . The effect was stronger in pregnant women with higher CO exposures (in the 3rd [2.5 exposures in the highest quartile (3) had a borderline significant association (p = 0.054) with DBP compared to those who had PM2.5 exposures in the lowest quartile (3). No evidence of association was observed for BC exposure and blood pressure.We found that systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher in pregnant women exposed to higher levels of HAP, though only the result for CO and DBP reached conventional statistical significance (p < 0.05). We observed a positive association between CO and DBP among the entire study cohort: a 1-log μg/m2.5 and CO from solid fuel use are associated with higher blood pressure in pregnant women during their first or second trimester.This study contributes to limited evidence regarding the relationship between HAP exposure and blood pressure among women during pregnancy, a critical window for both mother and child's life-course health. Results from this cross-sectional study suggest that exposures to PM •Pregnant women using solid fuels are exposed to high household air pollution levels.•Blood pressure was higher among pregnant women exposed to higher levels of PM and BC.•Household air pollution exposure may increase blood pressure in pregnant women. The most recent Global Burden of Disease (GBD) study reported that household air pollution (HAP) generated from solid fuel use contributed an average of 82.8 μg/m3 PM2.5 in Indian households  through an imbalance of lung autonomic nerve function, systematic oxidative stress, inflammation, and endothelial dysfunction  reported a 10% prevalence of hypertension among Indian women, which increased to 22.5% in NFHS-5 . A study on preeclampsia estimated the hypertensive disease of pregnancy was 10.3% in South India  and anotTo the best of our knowledge, five studies have investigated the association between HAP exposure and blood pressure among pregnant women, although these analyses differ in study design, types of solid fuels, and methods of HAP exposure assessment. 2.5, BC, and CO and measures of gestational blood pressure at baseline for the 799 pregnant women enrolled in the Household Air Pollution Intervention Network (HAPIN) trial.The gaps and inconsistencies in the current body of evidence highlight the need for additional investigation into the relationship between HAP exposure and blood pressure during pregnancy, with more accurate characterization of personal exposure and adequate adjustment of potential confounders. To our knowledge, no studies have examined the association between HAP exposure and gestational blood pressure using personal exposure assessment among rural women during early pregnancy who were exclusively using biomass in India. Here, we analyze data on personal exposure to PM22.1ClinicalTrials.gov Identifier: NCT02944682) is an international multi-center study  assessing the impact of a liquefied petroleum gas (LPG) cookstove and fuel intervention on health. The rationale, study design, and methods of the HAPIN trial have been described elsewhere . Briefly, at each of the four IRCs, approximately 800 pregnant women from households using biomass fuel were identified and enrolled. Half of the households were randomly assigned to receive the intervention: a locally available LPG cookstove as well as 18-month supply of free LPG. The other half act as controls who continue to primarily use traditional cookstoves fueled with biomass. Mothers and children in both intervention and control groups were followed until the child reached one year old.The current analysis utilizes baseline data collected from 799 pregnant women enrolled in the HAPIN trial at the India Intervention Research Center (IRC). The HAPIN Trial  and Nagapattinam (NP). These study sites were chosen based on multiple criteria, including low rates of LPG penetration, low anticipated uptake of LPG among primary biomass fuel users over the 5 years of the trial, high exposure contrasts, and absence of major air pollution point sources. The hilly Villupuram study site is located at an altitude of approximately 10–165 m above sea level, while the Nagapattinam study site, a coastal area, is located at an average elevation between 10 and 50 m above the sea level . Study sPregnant women who participated in the study met a number of eligibility criteria: 1) confirmed pregnancy, 2) 18 to <35 years of age, 3) cook primarily with biomass stove, 4) live in the study area, 5) 9 to <20 weeks’ gestation with a singleton pregnancy confirmed by ultrasound, 6) continued pregnancy at the time of randomization and 7) agree to participate with informed consent . Eligible pregnant women were excluded if they currently smoked, planned to move permanently outside the study area in the next 12 months, or planned to use a clean fuel stove predominantly in the near future . Enrollment and data collection for HAPIN participants in the India IRC started in May 2018. Participants in the current analysis include pregnant women who had completed baseline assessment and randomization (n = 799). One participant was withdrawn due to an eligibility information error. Ethical approval for all HAPIN Trial activities in India IRC were obtained from the Institutional Ethics Committee at Sri Ramachandra Institute of Higher Education and Research (IEC-N1/16/JUL/54/49), Institutional Review Board of Emory University , and the Indian Council of Medical Research–Health Ministry Screening Committee (5/8/4–30/(Env)/Indo-US/2016-NCD-I).2.22.5, BC, and CO were assessed for all pregnant women. Real-time and integrated gravimetric personal PM2.5 exposures were measured using the Enhanced Children's MicroPEM™ (ECM) . Real-time PM2.5 concentrations were estimated with ECM's nephelometer (light-scattering sensor); average 24-h exposures are estimated using gravimetric PM2.5 samples collected by drawing air through an impactor attached to a cassette containing a 15-mm Teflon® filter  (2.5 filters placed in ECMs were assessed for BC with SootScan™ Model OT21 Transmissometers (Magee Scientific) at Sri Ramachandra Institute of Higher Education and Research (SRIHER). Real-time personal exposures to CO were measured with EL-USB-300 monitors (Lascar Electronics), a lightweight, data-logging monitor the size of a large pen that runs on ½ AA batteries and has a sensing range between 0 and 300 ppm. Lascar monitors use an electrochemical cell to measure CO and record the concentration at the user-specified interval of 2.5 s.Details of the exposure assessment methods employed in the HAPIN trial are described elsewhere . At baseoration) . ECMs al2.5 exposures are gravimetric exposure concentrations. When gravimetric concentrations were not available – due to missing or damaged filters, or instrument failures, like flow faults – a device-specific corrected nephelometric average concentration was utilized  . The average of the three readings was used in the analysis. Blood pressure measurements were taken after ensuring that the pregnant woman had not smoked, consumed alcohol or a caffeinated beverage , or cooked using biomass in the 30 min prior to the measurement. If the participant had done any of above activities, she would be asked to refrain from these activities for 30 min before starting the blood pressure measurement .If a participant was found to have a SBP 2.42.5, BC, and CO) and blood pressure. Average SBP and DBP of the three baseline measurements were the two outcome variables in separate models. Given the medium to high correlation between PM2.5 and BC exposures  on SBP or DBP, holding other covariates constant; Z represents a matrix of potential covariates (described below); and All data analyses were conducted using R version 4.0.3 . Descrip = 0.55) , exposurions Eq.  can be g2.5, BC, or CO) and blood pressure levels or (2) for the blood pressure outcome. We identified covariates based on prior evidence and using a directed acyclic graph (DAG) generated using DAGitty v3.0 (Covariates considered in the model are risk factors for (1) both personal exposure  specifically constructed for India based on the ownership of various household assets. Physical activity quartile was calculated based on the total MET  minutes per week using the World Health Organization Global Physical Activity Questionnaire (GPAQ). A MET is the ratio of the rate of energy expended during an activity to the rate of energy expended at rest . Factors that may influence blood pressure level  and personal exposure  were also recorded by questionnaire.Gestational age was determined by ultrasound at study enrollment. Maternal weight and height were recorded as part of baseline prenatal health exams, along with blood pressure measurements. Then, body mass index (BMI), defined as weight divided by the square of height, was calculated based on recorded measurements. Medical history and previous adverse pregnancy/birth events were obtained by questionnaire. Demographic and socioeconomic covariates, such as maternal age, mother's highest level of education, occupation, household size, and household wealth were recorded by questionnaires during baseline household visits. We calculated the relative household wealth using the EquityTool   personal exposures in all models. As sensitivity analyses, we fit a generalized additive model (GAM) to assess the potential nonlinear trends between HAP exposures and SBP/DBP. A smooth function was applied to exposure variables with an optimized smoothing parameter via restricted maximum likelihood. Various values of the basis dimension (k) were tested with gam.check. Additionally, we tested potential effect modification by study site in the log linear models by including an interaction term between PM2.5/BC/CO exposure and study site. Finally, we reproduced the analysis after excluding the highest 1% of exposure observations.Personal exposure to PM3Baseline Characteristics. In Exposure. Compliance with the exposure monitoring is considered good. Only 22 (3%) participants were observed not wearing the equipment nor having the equipment nearby when field workers arrived at the household. Among all baseline personal HAP exposure measurements, 89% (N = 715) of pregnant women had valid PM2.5 samples, 87% (N = 699) had valid BC measurements and 93% (N = 745) had valid CO samples. 2.5, BC and CO exposures of pregnant women. Distributions of exposures are visualized in 2.5 exposures of 86% of the participants were above the World Health Organization's Interim Target 1 for annual mean concentrations of 35 μg/m3. The PM2.5, BC, and CO personal exposures were all significantly higher in Villupuram than in Nagapattinam. The median (IQR) 24-h personal exposure to PM2.5 was 75.5 (82.2) μg/m3 . The overall median (IQR) of 24-h personal exposure to BC was 9.6 (10.7) μg/m3 . For 24-h CO exposure, the overall median (IQR) level was 0.8 (1.8) ppm . The higher 24-h HAP exposures at the Villupuram site were likely due to more fuel consumption, longer stove use time, differences in kitchen configurations, and other indoor and outdoor exposure sources. The 24-h personal exposures to PM2.5, BC and CO are also examined after removing the highest 1% of the measurements. The results are presented in Blood Pressure. All participants had valid blood pressure measurements at baseline and were largely normotensive (SBP <120 and DBP <80) (95%). The mean (SD) of SBP was 104.5 (9.1) mmHg and the mean (SD) of DBP was 61.5 (7.6) mmHg (.6) mmHg . DistribStatistical Analysis. Regression analyses for each HAP-gestational blood pressure pair were restricted to participants with valid exposure and blood pressure measurements. This resulted in a sample size of 715 for PM2.5-gestational blood pressure analysis, 699 for BC-gestational blood pressure analysis, and 730 for CO-gestational blood pressure analysis . The adjusted estimates for the effects of PM2.5, BC, and CO exposure on SBP and DBP are presented in 2.5 exposures in the highest quartile had a marginal significant association with DBP  compared to those who had PM2.5 exposures in the lowest quartile. There was also some evidence of a log-linear trend for DBP . No evidence of an association was observed for BC exposure and gestational blood pressure. For the CO-gestational blood pressure relationship, adjusted mean DBP was 0.36 mmHg higher  per unit increase in natural log-transformed personal CO exposure. Results were stronger with CO exposure levels in the 3rd and 4th quartile, compared to those with exposure levels in the lowest quartile.In adjusted models, we found that pregnant women with PM2.5-gestational blood pressure, BC-gestational blood pressure, and CO-gestational blood pressure relationships, using a smooth term for exposures while controlling for other covariates. No model showed significance with a smoothed exposure term. 2.5/BC/CO. Although the associations between BC/CO and DBP appeared to be some deviations from linearity at high levels of exposure, very few observations were at these levels and the confidence intervals were wide. The result suggests that there is some complexity in the relationship between BC/CO and DBP; however, the shape and direction of those effects is uncertain. Outputs of GAMs analysis are provided in Supplementary Information.In sensitivity analyses, we used GAMs to assess the PM2.5/CO and gestational blood pressure. However, a marginally significant association was observed for BC and DBP in both log linear exposure and categorical exposure models after removing the highest 1% of exposure measurements  compared to those who had exposures in the lowest quartile (3).This is the first study to examine the relationship between HAP and gestational blood pressure using quantitively measured personal exposures and blood pressure among pregnant Indian women using solid fuels in their early pregnancy. This cohort of pregnant women does not have common risk factors for elevated blood pressure or hypertension; they are predominantly young, with relatively low BMI and socioeconomic status. However, we found that SBP and DBP were higher in pregnant women exposed to higher levels of PMOur finding supports evidence from prior studies conducted in pregnant women. In a similar baseline assessment of a cookstove intervention study with Ghanaian pregnant women of early gestation (average 16 weeks), a significant positive association was also found between CO exposure and DBP (an increase of 0.43 mmHg DBP for each 1 ppm elevation in CO exposure), while a non-significant positive trend was observed for SBP . In anot2.5 and blood pressure in non-pregnant Chinese women  and 0.5 mmHg higher DBP  and the estimated effects were stronger among women >50 years of age  and blood pressure (a 1-log-μg/m3 increase in BC was associated with 4.3 mmHg higher SBP) was observed in 2.5 or BC and BP; in Nicaragua, Our results are not entirely consistent with findings from similar studies conducted in non-pregnant women. Unlike the strong association observed between personal exposure to PMse women , we did The varying direction and scale of the effects of HAP on blood pressure in the above studies compared to ours may be a result of the differences in the type of solid fuels being used, cooking practices, age, BMI, basal blood pressure levels, and, more importantly, pregnancy, a factor known to influence blood pressure. In clinically healthy pregnant women, blood pressure steadily decreases up to the middle of gestation and increases up to the day of delivery, with final blood pressure values similar to those found early in pregnancy in the same women . HoweverAs other studies have noted, the observed small size of the blood pressure changes induced by HAP exposure are not likely to have significant clinical relevance for individuals, especially among our young and low risk cohort, However, even small changes in blood pressure at the population level can translate into significant health burdens globally, given the large number of populations exposed to HAP on a daily basis. For example, depending on age, a 5 mmHg lower than usual DBP was associated with 19%–50% lower total stroke risk and 11%–41% lower ischemic heart disease risk . In addition, blood pressure levels are different between complicated and uncomplicated pregnancies as early as in the first trimester of gestation . UnderstAn important limitation of this study is its cross-sectional design. Burning solid fuels is a long-term behavior and air pollution-triggered changes in blood pressure can occur both acutely and over long periods of time, such as days or months . A 24-h timeanddate.com) and we have controlled for season in all HAP-gestational blood pressure models.We also did not have data on some important potential covariates that might confound or modify the association between HAP exposure and gestational blood pressure, such as sodium intake and ambient temperature . However2.5, BC, and CO, major constituents of HAP from solid fuels burning, simultaneously. This allows us to understand the relationship between these different household air pollutants and examine their association with blood pressure individually.Despite these limitations, our study has several notable methodological strengths and innovations. To our knowledge, this is the first study in India that has established the association between HAP and blood pressure using quantitively measured personal exposure and blood pressure among pregnant women. The extensive measurements in such a large cohort permit us to understand the ‘usual’ daily HAP exposures of pregnant women using solid fuels, the blood pressure distribution during early- and mid-pregnancy, and the relationships between the two. Furthermore, we measured PMElevated blood pressure is recognized as one of the most important independent risk factors for cardiovascular disease in India and presents a special concern for pregnant women. Our study contributes to the limited evidence on the association between HAP and blood pressure among pregnant women and suggests that interventions that reduce HAP exposures may improve blood pressure, and subsequently, reduce the incidence of gestational hypertension that could contribute to the risk of adverse pregnancy outcomes and hypertension later in life. More broadly, our characterization of the unique HAP exposure profiles among women using solid fuels in South India may be useful to better understand the magnitude of health effects attributable to air pollution in this region and inform interventions and policies aimed at reducing HAP exposure and associated health effects in India and other developing countries.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Hypertension is a major cause of morbidity and mortality in the world. This study aimed to evaluate an intervention based on the Health Belief Model regarding the whole family's salt consumption and blood pressure among hypertensive patients in rural areas in Iran. n = 100 in each group) were selected via multistage random sampling. The intervention included a two-day workshop on blood pressure and reducing salt consumption based on HBM structures for health personnel and an eight-session workshop on how to reduce salt intake and blood pressure for mothers who were responsible for the families' diets. Participants completed the questionnaires before and immediately after the intervention.  This clinical multicenter trial  with a control and an intervention group was conducted on the residents of 14 villages covered by 14 health houses. Totally, 200 hypertensive patients . The results also revealed a significant decrease in blood pressure in the intervention group.  The results showed that the mothers' model-based education could effectively improve the diet of the whole family members and, as a result, reduce the associated diseases. The main advantage of this study was the involvement of the rural health personnel, which helped run longer and larger-scale health-promotion programs in the communities. This lack of accurate information has been reported as a worrying matter in rural areas [Hypertension is one of the most prevalent health issues among adults worldwide . Hyperteal areas . Therefoal areas . CHWs aral areas . In termal areas . Consideal areas , 27, a sn = 14) were first randomly divided into seven interventions and seven control areas irrespective of their geographic locations. Next, according to the list of hypertensive patients and proportion of the population covered by each health house, 100 patients were randomly selected from the health houses in the intervention group, and 100 ones were randomly selected from those in the control group  and followed for monitoring urine sodium and creatinine concentrations as well as blood pressure. High blood pressure was defined as a systolic blood pressure higher than or equal to 140 mmHg and a diastolic blood pressure higher than or equal to 90 mmHg. It should be noted that the study population and patients were the residents of Sarvestan, a rural area in Fars province in 2017. Considering the power of 80% and error of 5%, the participants were selected through multistage cluster random sampling. In doing so, the rural health houses  were defined. Secondly, a two-day workshop was held. The HBM constructs and salt reduction program were explained for 12 CHWs in 7 health houses of the intervention group in the first and second sessions, respectively. In addition, eight sessions were held for mothers (who were responsible for the families' diets) in terms of diet and harms of consuming a high amount of salt. In this way, the CHWs from the intervention area attended a two-day workshop on the effects of salt on blood pressure and the circulatory system. The CHWs were then asked to deliver the information to mothers via a course containing eight sessions (one session per week) based on the HBM constructs see . PatientThe 24-hour urinary excretion was measured before and after the intervention. Blood pressure monitoring was also done routinely according to the national hypertension screening program irrespective of the patients' locations. Moreover, a researcher-made questionnaire based on the HBM was designed and applied to obtain information regarding the participants' salt consumption before and after the eight-week intervention.The questionnaire was used to collect the data based on the HBM via a Likert scale. To determine the face and content validity of the questionnaire, 30 hypertensive patients were requested to fill it out. Then, the questionnaire was given to 10 experts. Based on the qualitative content validity and according to the recommendations of the experts as well as the ambiguities raised by the patients, changes were applied to the questionnaire items. Mean CVR and CVI values were 0.93 and 0.9, respectively.Afterwards, the reliability of the questionnaire was assessed using Cronbach's alpha. The components of the HBM included perceived susceptibility , perceived severity , perceived benefits , perceived barriers , and self-efficacy . The total Cronbach's alpha questionnaire was 0.81.Blood pressure was measured twice with a 10-minute interval using a Mercury sphygmomanometer (ALP K2 Brand of V300) on the patients' right arms while they were sitting. The two measurements were performed in the morning, and the average blood pressure was recorded. Moreover, a 24-hour urinary excretion (measured via flame photometry) was measured in order to determine the urine creatinine level (mg/dL) and sodium level (mEq/l). The sodium and creatinine levels were measured in the laboratory of Shohada Hospital in Sarvestan. Additionally, height (cm) and weight (kg) were measured in the health centers using a measuring tape and a digital scale, respectively. All the centers in both intervention and control groups used similar instruments, which were calibrated at the opening hour of each working day. The 24-hour urine collection was done from 7 AM to 7 AM on the next day, and the patients were instructed to collect their urine samples even at night. After eight weeks , participants in two groups (control and intervention) were again asked to go to the health houses, and blood pressure, weight, 24-hour urinary sodium, and HBM constructs were measured in two groups under the same conditions. After obtaining the ethical approval of the Ethics Committee of Shiraz University of Medical Sciences, the participants' written informed consents were gathered.t-test and independent sample t-test were applied, and the significance level was set at 0.05.The data were analyzed using the SPSS software (version 16). Paired sample p > 0.05).All the 200 hypertensive patients were over 30 years of age, with the mean age of 60.92 ± 12.05 years. The patients had similar dishes shared with their families  before and after the intervention. The demographic characteristics of the study participants have been presented in t-test, the mean scores of the constructs increased in the treatment group after the intervention (p < 0.05). However, the changes in the mean scores of the constructs were not significant among the control group participants (p > 0.05).As shown in t-test regarding the impact of education in the control and treatment groups have been shown in p < 0.05).The results of paired sample This study was performed to evaluate salt consumption and blood pressure in rural hypertensive participants, a community filed trial. The results of the present study showed that HBM-based educational intervention significantly improved the mean scores of HBM variables  in patients. This results were consistent with those of other studies in the field –31. StilAccording to the results, the mothers' education program effectively reduced salt consumption and the patients' blood pressure. However, no significant changes were observed in control group. In some studies, educational intervention based on HBM has led to a reduction in patients' blood pressure, which is in line with our study , 33. But, and Diabetes control [The results of the current study showed that the CHWs could be involved in simple but effective community-based health programs to reduce the communities' health problems. This was in line with the results of other interventional studies emphasizing the participation of community health personnel in dealing with different health issues including managing hypertension , 27, tub control . Thus, bDespite many interventions in reducing blood pressure and salt consumption, one of the strengths of this study is performing a community-based intervention in a relatively large number of patients living in rural areas.There were limitations in this study. The first was the short time interval between intervention and follow-up of samples, and the second was that the study was performed on patients covered by rural health centers, so it is not possible to generalize the results to urban areas.The reduction in blood pressure in the intervention group in this study may have occurred because the development of health beliefs can help patients pay more attention to blood pressure . On the The results of this field trial suggested that simple but well-designed educational programs by CHWs could promote the healthy behaviors of families so effectively. Using theory-based models, health personnel can act as good facilitators who can help communities get involved in recognizing and improving their health issues, particularly in rural areas.