This study investigated the distribution of characteristics of traditional Chinese medicine syndromes and their association with symptoms in 1027 patients with chronic heart failure (CHF). An observational study was performed by researchers, collecting data from 1036 patients with CHF from 24 Chinese medicine hospitals from May 2009 to December 2014. Due to incomplete information from nine patients, 1027 patients with CHF were analysed. The distribution of syndromes in CHF and association between high-frequency syndromes and symptoms were investigated. The primary syndromes were qi deficiency, blood stasis, fluid retention, yin deficiency, phlegm turbidity, and yang deficiency. The primary sites of disease were the heart, kidney, lung, and spleen. In patients with CHF of differing cardiac function, there was no significant difference in the frequency of yin deficiency (P>0.05). The distribution of yang deficiency was significantly different between New York Heat Association (NYHA) classes II, III, and IV and between classes I+II and III+IV (P<0.05). The frequency of phlegm turbidity was significantly different between NYHA classes II and III, between classes III and IV, and between classes I+II and III+IV (P<0.05). The frequency of fluid retention was significantly different between NYHA classes I and IV, between classes II, III, and IV, and between classes I+II and III+IV (P<0.05). Regarding associations between syndromes and symptoms, qi deficiency was diagnosed in 87.43% of patients with insomnia and spiritlessness; blood stasis in 84.85% of patients with spontaneous sweating + cyanosis of the lips; fluid retention in 75% of patients with a hard pulse and oedema; and yin deficiency in 72.92% of patients with feverish sensation in the chest, palms, and soles and spontaneous sweating. The frequency of yang deficiency and fluid retention was higher and that of phlegm turbidity was lower in classes III and IV than in classes I and II. Chronic heart failure (CHF), which is the name given to symptomatic chronic cardiac insufficiency, mainly refers to abnormal cardiac function caused by various reasons that obstruct the heart's pumping, causing insufficient blood output and finally leading to the insufficient perfusion of organs and tissues, accompanied by stasis of the systemic and/or pulmonary circulation. It is the final stage of heart disease of various causes and the main cause of death; thus, it has a high morbidity and mortality clinically , 2. AlthIn recent years, traditional Chinese medicine (TCM) played an increasingly prominent role in the prevention and treatment of CHF as it focuses on integral syndrome differentiation and adjustment and has the special advantage in promoting the functional recovery of various organs, reducing adverse reactions, and improving the quality of life of patients –10. TreaA total of 1036 patients with CHF treated in 24 Chinese medicine hospitals  from May 2009 to December 2014 were enrolled in the study. The data used to support the findings of this study have not been made available to protect the subjects' privacy. There were 590 (56.95%) male and 446 (43.05%) female patients. The male-to-female ratio was 1.32:1. The average age was 67.54 ± 10.40 years. However, four patients had unknown cardiac function and five had no description of their syndrome. Therefore, 1027 patients with CHF were analysed.(1) Diagnostic Criteria of CHF. CHF was diagnosed according to the Guidelines for the Diagnosis and Treatment of Chronic Heart Failure (2007) in China [in China . Cardiac(2) Diagnostic Criteria of TCM. Qi deficiency, yang deficiency, and yin deficiency were diagnosed according to the deficiency syndrome differentiation criteria established by the Professional Committee of Deficiency Syndrome and Geriatrics, Chinese Association of Integrative Medicine, in 1986 [ in 1986 . Blood s in 1986 . Qi stag in 1986 .(3) Standards for Symptoms. The symptoms were recorded according to the Standard Terminology for Common Clinical Symptoms in Chinese Medicine [Medicine .Inclusion criteria included basic heart disease history; signs and symptoms of CHF; a diagnosis of CHF confirmed using echocardiography; a diagnosis of coronary heart disease confirmed using coronary angiography, coronary artery computed tomography, a previous history of acute myocardial infarction, pathological Q waves on electrocardiogram (ECG), or electrocardiographic stress test and myocardial radionuclide imaging; no history of hypertension or blood pressure <160/100 mmHg on medication; age >18 years and ≤80 years; and provided informed consent.9/L and neutrophil > 85%, or patchy shadows on chest radiographs; severe hepatic insufficiency ; Ccr >20%, Scr >3 mg/dl or >265 μmol/L; haematological primary disease; malignancy; pregnancy or lactation; mental disease; and infectious disease.Exclusion criteria included acute myocardial infarction, acute myocarditis, cardiogenic shock, or severe arrhythmia with hemodynamic changes; current concomitant infection, as evidenced by any one of fever, white blood cell count >10 × 10A clinical epidemiological questionnaire regarding CHF was developed based on previous research  and threResponses were double entered into an EpiData 3.1 database by two separate individuals. Database consistency was checked. Inconsistencies were corrected according to the data source. Statistical analysis with two-sided tests was performed using SPSS 23.0 software. P≤0.05 was considered significant.The relationship between high-frequency syndromes and symptoms was analysed using the Apriori algorithm in SPSS Modeler 14.0. The association rules  try to dAs categorised using the NYHA cardiac function classification, 11 patients (1.06%) were class I, 289 (27.9%) were class II, 611 (58.98%) were class III, 120 (11.58%) were class IV, and five (0.48%) were unknown.Of the 1036 patients, five patients had unknown cardiac function and four had no description of their syndrome. Therefore, 1027 patients with CHF were analysed. The syndromes identified in the 1027 patients, in descending order of frequency, were qi deficiency, blood stasis, fluid retention, yin deficiency, phlegm turbidity, yang deficiency, blood deficiency, qi stagnation, others, cold coagulation, and dryness-heat; the disease sites were heart, kidney, lung, spleen, liver, stomach, and gallbladder. The results are shown in Tables In the 11 patients with class I CHF, in descending order of frequency, blood stasis, qi deficiency, yin deficiency, phlegm turbidity, fluid retention, and yang deficiency syndromes were seen; the disease sites were the heart, kidney, spleen, lung, and liver. In the 286 patients with class II CHF, in descending order of frequency, qi deficiency, blood stasis, phlegm turbidity, yin deficiency, fluid retention, yang deficiency, blood deficiency, qi stagnation, cold coagulation, and dryness-heat syndromes were seen; the disease sites were the heart, spleen, kidney, lung, liver, stomach, and gallbladder. In the 610 patients with class III CHF, in descending order of frequency, qi deficiency, blood stasis, fluid retention, yang deficiency, yin deficiency, phlegm turbidity, blood deficiency, and qi stagnation syndromes were seen; the disease sites were the heart, lung, kidney, spleen, liver, stomach, and gallbladder. In the 120 patients with class IV CHF, in descending order of frequency, qi deficiency, blood stasis, fluid retention, yang deficiency, phlegm turbidity, yin deficiency, and qi stagnation were seen; the disease sites were the heart, kidney, spleen, lung, stomach, liver, and gallbladder. The results are shown in Tables The differences in the distribution of syndromes in patients with CHF between different cardiac function classes were mainly seen in four syndromes: yin deficiency, yang deficiency, phlegm turbidity, and fluid retention. Therefore, the distribution of the four syndromes in different cardiac function classes was compared using a row-by-column chi-square test. In patients with CHF of different cardiac function classes, there was no significant difference in the distribution of yin deficiency (P > 0.05); however, there was a significant difference in the distribution of yang deficiency, phlegm turbidity, and fluid retention (P < 0.05).The distribution of yang deficiency was significantly different between NYHA classes II, III, and IV, and between classes I + II and III + IV (P<0.05). The distribution of phlegm turbidity was significantly different between NYHA classes II and III, between classes III and IV, and between classes I + II and III + IV (P < 0.05). The distribution of fluid retention was significantly different between NYHA classes I and IV; between classes II, III, and IV; and between classes I + II and III + IV (P < 0.05). The results are shown in In order to further investigate the association between syndromes and symptoms, the association rules between the four highest-frequency syndromes  and symptoms were analysed. The top 15 association rules ranked in order of confidence value are shown in Tables 61In patients with CHF and qi deficiency, the common symptoms were insomnia + spiritlessness, thready pulse + shortness of breath, moist tongue coating + spiritlessness, insomnia + shortness of breath, soreness and waist and knee weakness + spiritlessness, insomnia + weak breathing with no desire to speak, insomnia + weakness, thready pulse + weakness, wiry pulse + spiritlessness, and insomnia + palpitation according to the association rules between qi deficiency and symptoms. Among them, the highest confidence was obtained for qi deficiency => insomnia + spiritlessness (87.43%). In other words, qi deficiency was diagnosed in 87.43% of cases where insomnia + spiritlessness were reported. The results are shown in According to the association rules between blood stasis and symptoms, the common symptoms were spontaneous sweating + cyanosis of the lips, night sweats + cyanosis of lips, thready pulse + cyanosis of the lips, oedema + cyanosis of lips, wiry pulse + cyanosis of the lips, chest pain + weakness, chest pain + cyanosis of the nails + spiritlessness, abdominal distension + cyanosis of the lips, and cyanosis of the nails + chest tightness. Among them, the highest confidence was obtained for spontaneous sweating + cyanosis of the lips (84.85%). In other words, blood stasis was diagnosed in 84.85% of cases where spontaneous sweating + cyanosis of the lips were reported. The results are shown in According to the association rules between fluid retention and symptoms, the common symptoms were hard pulse + oedema, difficult expectoration + oedema, hypochondriac distension + spontaneous sweating, nausea + hypochondriac distension, hypochondriac distension + inability to lie flat, hypochondriac distension + oedema, thirst without desire to drink + thready pulse, oliguria + thready pulse, nausea + oedema, and thirst without desire to drink + insomnia. Among them, the highest confidence was obtained for hard pulse + oedema (75%). In other words, fluid retention was diagnosed in 75% of cases where hard pulse + oedema were reported. The results are shown in According to the association rules between yin deficiency and symptoms, the common symptoms were feverish sensation in the chest, palms, and soles + spontaneous sweating, red tongue + thready pulse, red tongue + dry mouth, feverish sensation in the chest, palms, and soles + night sweats, feverish sensation in the chest, palms, and soles + dysphoria, fissured tongue + dry mouth, tongue red + wiry pulse, feverish sensation in the chest, palms, and soles + dizziness, feverish sensation in the chest, palms, and soles + thready pulse, feverish sensation in the chest, palms, and soles + dry mouth, and feverish sensation in the chest, palms, and soles + insomnia. Among them, the highest confidence was obtained for feverish sensation in the chest, palms, and soles + spontaneous sweating (72.92%). In other words, yin deficiency was diagnosed in 72.92% of cases where feverish sensation in the chest, palms, and soles + spontaneous sweating were reported. The results are shown in Identification of the pathological nature of the disease based on syndrome differentiation is the core of treatment in TCM .The syndromes identified in this study, in descending order of frequency, were qi deficiency, blood stasis, fluid retention, yin deficiency, phlegm turbidity, yang deficiency, blood deficiency, and qi stagnation. The most frequent disease site was the heart, followed by the kidney, spleen, lung, and liver. A review of the last 10 years of literature  on the dMoreover, the distribution of syndromes in patients with CHF of different cardiac function classes suggested that qi deficiency and blood stasis are always involved in the pathological process of CHF. This is related to the distribution of syndromes in coronary heart disease, the underlying cause of CHF. A questionnaire survey conducted by Liu  in 2013 This study shows that the frequency of syndromes in patients with CHF varied with cardiac function class. Specifically, yang deficiency and fluid retention occurred at a higher frequency in classes III and IV than in classes I and II, whereas the opposite was true for phlegm turbidity. Moreover, the frequency of yang deficiency, phlegm turbidity, and fluid retention was significantly different between the different cardiac function classes at a statistically significant level. Obviously, the syndrome in the CHF patients changed with the deterioration of cardiac function. In patients with heart failure, long-term qi deficiency impairs yin and, in severe cases, yang. The insufficient generation or excessive consumption of heart-yang results in pathological changes, including heart-qi deficiency, insufficiency of heart-yin, heart-yang deficiency, heart-blood stasis, phlegm turbidity, and fluid retention. Hence, the symptoms and signs of yang deficiency are more obvious in late heart failure. Therefore, there were certain syndromes and pathogenetic characteristics at different stages of heart failure. The more severe the disease, the worse the heart-qi (yang) deficiency .The disease sites were basically the same among patients of different cardiac function classes. The primary disease site was the heart, and other common disease sites included the kidney, spleen, and lung. The disease sites dynamically changed with the cardiac function class. This is consistent with the assertion of Tietao Deng that “all five viscera, not only the heart, can lead to heart failure” . SpecifiSyndromes are the basic elements of syndrome differentiation. In recent years, many scholars have conducted in-depth research on syndrome differentiation methods and proposed a new syndrome differentiation method system using syndrome combinations for syndrome differentiation, which provides a new method to reveal the law, essence, and characteristics of syndrome differentiation, as well as the standardization of syndrome differentiation. However NeiJing, there are elaborations on “insufficiency of qi” and “qi deficiency”. For example, people with qi deficiency often feel tired and weak, having a low faint voice, lack of energy, shortness of breath, pale complexion, inappetence, head and limbs oedema, borborygmus and loose stools, dyspepsia, hidrosis and spontaneous sweating, weak pulse, pale tongue fat, or tooth marks, which are all signs of qi deficiency [ Nan Jing, he said, “qi is the root of the human”. If the promoting effect of qi is weakened, there will be underproduction and obstruction of the distribution of fluid-blood.Qi deficiency is one of the important pieces of evidence and a common TCM syndrome differentiation type, which generally refers to a series of manifestations caused by weak constitution or long illness. As early as inficiency . In patiBlood stasis mainly refers to various factors causing stasis, such as qi stagnation, qi deficiency, phlegm retention, cold coagulation, blood heat, and trauma, leading to poor blood flow and blocked arteries. Its clinical manifestations are characterized by dull tongue, petechiae or ecchymosis, sublingual varices, cyanosis of the lips, dryness, and thin pulse . In chroFluid retention refers to the pathological products of water and liquid metabolism disorder formed in the body. Common symptoms include dizziness, chest distress, vomiting water, salivation, greasy hair, and thready and slippery pulse. Fluid retention occurs in different places, which has different effects . Accordi The Su-Wen · The Theory of Natural Gas, “Yang qi is rooted in yin, and yin qi is rooted in yang. Yang is not born without yin, and yin does not change without yang.” Because yin and yang are mutually rooted, qi and blood depend on each other. Therefore, yin blood deficiency means that the blood does not support the heart; heart qi no longer functions, leading to heart failure.Yin deficiency refers to deficiency of blood or body fluid. Clinical manifestations mainly include hot flushes; red cheeks; night sweating; feverish sensation in the chest, palms, and soles; haemoptysis; blurred vision; emaciation or insomnia; dysphoria; spermatorrhea; hypersexuality; red tongue; and dry mouth . In chroAccording to the clinical manifestations related to chronic heart failure, most scholars believe that heart failure belongs to the root deficiency and enrichment of symptoms. In recent years, many doctors  have supIn this study, the distribution of syndromes in patients with CHF of different cardiac function classes was investigated. The results reflect the distribution pattern of TCM syndromes in CHF. Moreover, the correlation between high-frequency syndromes and symptoms was explored in terms of association rules, which provide guidance for the diagnosis and treatment of CHF in clinical Chinese medicine practice. The main limitations of this study are that the number of patients in each cardiac function classes varied greatly and that CHF was complicated by other diseases in most patients, which might cause some errors in the survey results. Therefore, a large-sample, standardized clinical epidemiological study of syndromes is required.In terms of correlation with NYHA cardiac function classification, the frequency of yang deficiency and fluid retention was higher and that of phlegm turbidity was lower in classes III and IV than in classes I and II. This is the basic pattern observed in the evolution of syndromes in patients with CHF as cardiac function changes.


Subjects were 40 to 74 years old  with median 3.6 years follow-up period, and patients with and without chronic kidney disease were analyzed separately . Cardiovascular disease mortality, comprising coronary heart diseases and stroke as entered in the national death registry using ICD-10 coding, was examined. Among all subjects, 346 deaths (96 in chronic kidney disease and 250 in non-chronic kidney disease) due to cardiovascular disease occurred. Compared with cardiovascular disease mortality in chronic kidney disease patients with untreated normal blood pressure, the multivariable adjusted hazard ratio was 3.08  for those with untreated hypertension, 2.30 (1.31–4.03) for those who became normotensive after treatment, and 3.28 (1.91–5.64) for those who remained hypertensive despite treatment. In non-chronic kidney disease subjects, the ratios were 1.90 (1.33–5.41), 1.95 (1.35–2.80), and 1.77 (1.18–2.66), respectively. These results from a nationwide cohort could be one of representative demographics of controlling blood pressure and cardiovascular disease deaths when treating patients with chronic kidney disease in Japan in recent years. Even after development and spread of anti-hypertensive drugs, preventing development of hypertension is preferable, because any hypertension treatment status comparing untreated normal blood pressure was a risk of cardiovascular mortality at baseline year.Several recent clinical trials and meta-analyses have shown that lowering blood pressure reduces the risk of cardiovascular disease. However, current evidence that describes general demographics in blood pressure and mortality with chronic kidney disease is sparse in Japan. Using a population-based longitudinal cohort that received annual health checkups in Japan in 2008, hypertensive status, self-reported use of antihypertensive drugs, and prognosis were examined through 2012. Chronic kidney disease was defined as positive proteinuria or estimated glomerular filtration rate <60 ml/min/1.73 m High blood pressure (BP) confers a risk of cardiovascular disease (CVD) –3. CompaNumerous observational studies focused on general populations have found that, for a given baseline BP, the risk of CVD is higher for people who use antihypertensive medications than for those who do not ,9–14. HoThe present study evaluated a longitudinal, general-population cohort of 227,204 persons who received annual health checkups, including examinations for proteinuria and renal function according to “The Specific Health Check and Guidance in Japan” program in 2008, and followed their prognosis and cause of death through December 2012. In subpopulations with and without CKD diagnosed based on the presence of proteinuria and renal function, risks for all-cause and CVD mortality were examined among various categories of BP control. This analysis provides information about the representative status of BP control and CVD mortality of Japanese people with CKD in recent years.This longitudinal cohort study was conducted according to the guidelines of the Declaration of Helsinki and was granted ethics approval by the relevant institutional review boards . Original Ethics Committee approval was obtained from Fukushima Medical University .The study was performed as part of the prospective ongoing “Research on the Positioning of Chronic Kidney Disease in Specific Health Check and Guidance  in Japan” project . Other dThe duration of follow-up of the subjects was 1 to 4 years . The net subject population comprised 227,204 people  aged from 40 to 74 years and for whom all of the data necessary for our research purposes were available. The data included information about age, sex, body mass index (BMI), systolic BP, diastolic BP, smoking habit, use of antihypertensive, lipid-lowering, and hypoglycemic drugs (obtained by self-reported questionnaire), and the results of dipstick urinalyses for proteinuria and blood tests for glucose levels, creatinine concentration, and lipid status.The underlying causes of death were coded according to ICD-10. Follow-up was conducted through December 2012. Incidents of CVD death were defined by ICD coding as I20-29 and I60-69.http://jccls.org/) recommends that all urine dipstick results of 1+ correspond to a urinary protein level of 30 mg/dl; proteinuria was defined as 1+ or greater. Serum creatinine was measured using the enzymatic method. The glomerular filtration rate (GFR) was estimated using the formula of the Japanese Society of Nephrology Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: NoReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: NoReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: In the present study, Kei Nagai et al. examined mortality due to cardiovascular disease (CVD) among subjects who underwent annual health check in Japan. Study population was approx. 220 thousand and the follow up period was 4 years. The health check participants were separated into chronic kidney disease (CKD) and non-CKD subjects. They were also divided by their blood pressure/hypertension treatment categories. The following was one of the major findings: in CKD patients, compared with CVD mortality in patients with untreated normal blood pressure, the multivariable adjusted hazard ratio was 3.08  for those with untreated hypertension and 2.30 (1.31–4.03) for those who became normotensive after treatment, and 3.28 (1.91–5.64) for those who remained hypertensive despite treatment. They concluded, among subjects with CKD, patients who become normotensive during treatment have a lower risk of CVD than those who remain hypertensive, suggesting the effectiveness of BP reduction in preventing CVD death in CKD patients. Unfortunately, findings presented in this work do not support this conclusion.[Major Points]1) Since CVD mortality in CKD patients with normotensive/hypertension treated category (0.35%) was lower than that with hypertensive/untreated category (0.39%), the authors interpreted that the findings support treatment of hypertension in CKD patients to reduce CVD death. However, this is an observational study and cause/result relationship and speculation for prospective interventional benefits cannot be obtained, since patients in these 2 categories may have different basal backgrounds. For instance, patients with untreated hypertension may have lower socioeconomical conditions and may be less concerned about their health. Normotensive patients under hypertension treatment may have a better chance to be diagnosed other disorders during their periodical hospital visit and receive better care. There is no guarantee that untreated subjects remain untreated for 4 years.2) Indeed, CVD mortality in non-CKD subjects were 0.21% for normotensive/hypertension treated category and 0.17% for hypertensive/untreated category (Table 3). Furthermore, CVD mortality in overall population (including CKD and non-CKD) were 0.27% for normotensive/treated category and 0.22% for hypertensive/untreated category . These findings prove that authors’ logic is inconsistent to established effects of hypertension treatment to reduce CVD death in CKD and non-CKD subjects.3) As the authors described, previous studies reported CVD mortality among subjects with reduced renal function. The present study is distinct in that not only reduced renal function but also proteinuria was analyzed.4) Median follow up period should be described in the abstract.5) CVD mortality in CKD and non-CKD subjects should be described in the abstract.[Minor Points]1) A term “hypertensive category” is often used in the manuscript but it implies the extent of hypertension: for instance, 140, 160 and 180 mmHg. Other term, such as hypertension treatment categories, should be appropriate.2) Line 138: >5 years should be replaced by 5.5 years.Reviewer #2: Nagai et al reported the association between antihypertensive treatment and CVD mortality in patients with CKD who received annual health checkups. This study is a longitudinal general-population cohort with a large number of subject and showed the clear results of an increased mortality in those with hypertension or with hypertensive treatment, thus the data is of clinical importance. However, this manuscript has some major problems.1)In Fig2, authors showed hazard ratio of hypertensive group or treated groups, referencing untreated normal blood pressure. Authors conclusion is the effectiveness of BP reduction in preventing CVD in CKD patients, however, in this manuscript, it is unclear whether hazard ration between untreated hypertensive people, treated normal BP people and treated hypertensive people in CKD is statistically different. Authors should clearly show this point.2)In Fig2, authors showed hazard ration of CVD mortality in non-CKD people. These data revealed the CVD risk of hypertension, however did not show the effectiveness of hypertensive treatment for the prevention of CVD risk in non-CKD people. Is BP control not effective for the CVD reduction in non-CKD hypertensive subjects in this study? Authors should describe the results although this manuscript targets CKD patients.3) Table3 showed CVD mortality in those with CKD and without CKD. In conclusions, authors described “…CVD mortality risk seems to be higher in CKD patients than in non-CKD patients.”. Authors should show statistical significance.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool, Attachmentcomment to authors PONE-D-19-26343.docxSubmitted filename: Click here for additional data file. 30 Oct 2019To the reviewers;Reviewer #1: [Major points]1-1) Since CVD mortality in CKD patients with normotensive/hypertension treated category (0.35%) was lower than that with hypertensive/untreated category (0.39%), the authors interpreted that the findings support treatment of hypertension in CKD patients to reduce CVD death. However, this is an observational study and cause/result relationship and speculation for prospective interventional benefits cannot be obtained, since patients in these 2 categories may have different basal backgrounds. For instance, patients with untreated hypertension may have lower socioeconomical conditions and may be less concerned about their health. Normotensive patients under hypertension treatment may have a better chance to be diagnosed other disorders during their periodical hospital visit and receive better care. There is no guarantee that untreated subjects remain untreated for 4 years.---Thank you for your comment and we recognize this observational study cannot show the interventional effect of BP control on CVD mortality and hard to discuss magnitude of HRs due to unadjustable factors among hypertension treatment categories before baseline year such as socioeconomical status and hospital visiting. Therefore, we would like to add limitation in the second last paragraph of the discussion and deleted description to compare HRs between two hypertension treatment categories other than reference group.1-2) CVD mortality in non-CKD subjects were 0.21% for normotensive/hypertension treated category and 0.17% for hypertensive/untreated category (Table 3). Furthermore, CVD mortality in overall population (including CKD and non-CKD) were 0.27% for normotensive/treated category and 0.22% for hypertensive/untreated category . These findings prove that authors' logic is inconsistent to established effects of hypertension treatment to reduce CVD death in CKD and non-CKD subjects.---Thank you for your thoughtful comment. Related to your 1st major point, we recognized that it is hazardous to compare HRs each other between two hypertension treatment categories other than reference group . We would like to correct the conclusions from “effect of hypertension treatment on mortality” into “current demographics of hypertension treatment in Japan”. Please approve to mix up discussion and conclusion sections in order to keep context fluency .1-3) As the authors described, previous studies reported CVD mortality among subjects with reduced renal function. The present study is distinct in that not only reduced renal function but also proteinuria was analyzed.---Thank you for your suggestion, we highlighted strong point of our study to deal with proteinuria, in the fourth paragraph of the revised discussion. 1-4) Median follow up period should be described in the abstract.---Thank you for your comment. We added follow-up period in the revised abstract and method section.1-5) CVD mortality in CKD and non-CKD subjects should be described in the abstract.---Thank you for your comment. We added description regarding CVD mortality in the revised abstract.[Minor points]2-1) A term "hypertensive category" is often used in the manuscript but it implies the extent of hypertension: for instance, 140, 160 and 180 mmHg. Other term, such as hypertension treatment categories, should be appropriate.---Thank you so much for your suggestion and we agree with you. We used “hypertension treatment category” throughout this manuscript.2-2) Line 138: >5 years should be replaced by 5.5 years.---Thank you for comment. Please make sure it in the revised version.Reviewer #2: 1) In Fig2, authors showed hazard ratio of hypertensive group or treated groups, referencing untreated normal blood pressure. Authors conclusion is the effectiveness of BP reduction in preventing CVD in CKD patients, however, in this manuscript, it is unclear whether hazard ration between untreated hypertensive people, treated normal BP people and treated hypertensive people in CKD is statistically different. Authors should clearly show this point.---Thank you for your thoughtful comment. As another reviewer and you pointed out, we recognized that it is hard to compare HRs each other between two hypertension treatment categories , other than reference group . We would like to correct the conclusions from “effect of hypertension treatment” into “current demographics of hypertension treatment in Japan”. Please approve to mix up discussion and conclusion sections in order to keep context fluency .2) In Fig2, authors showed hazard ration of CVD mortality in non-CKD people. These data revealed the CVD risk of hypertension, however did not show the effectiveness of hypertensive treatment for the prevention of CVD risk in non-CKD people. Is BP control not effective for the CVD reduction in non-CKD hypertensive subjects in this study? Authors should describe the results although this manuscript targets CKD patients.---Related to your 1st point, we should not have compared HRs between untreated hypertension and treated normal BP, among CKD subjects as well as among non-CKD. We appropriately deleted description regarding effectiveness of BP control and just touched on the previous works in CKD cohort and implication of marked CVD mortality risk in patients with positive proteinuria in the fourth paragraph of the revised manuscript. 3) Table3 showed CVD mortality in those with CKD and without CKD. In conclusions, authors described "...CVD mortality risk seems to be higher in CKD patients than in non-CKD patients.". Authors should show statistical significance.---Thank you for your thoughtful comment. Related to your former comments, we revised conclusion, because it is difficult to compare HRs among hypertension treatment categories. Please make sure the last paragraph of the revised discussion section. To the editorial;We deeply recognized your journal office has been afraid of overlapping contents in our current and previous manuscripts. In advance of launching this cohort study using health checkups before 2008, our committee determined “one project, one publication-policy”. It means that each researcher has been analyzed based on the standard analytical file exactly for the purposes of testing his or her original scientific interest - in chronic kidney disease (CKD), clinical relevance of dipstick proteinuria for general population and distribution of hypertension and its treatment in Japan, etc. – with prior consultation. And then, the steering committee (SC) has supervised and carefully checked possibility of overlapping each other before submitting manuscript. In other words, our policy secures independence of each project and helps to avoid any double publications.This project focused on demographics of hypertension and its treatment, while the previous one (PLoS One 14: e0223005) focused on sequential results of CKD diagnosis  and its mortality risk. Therefore, we would like to propose obvious independence between these two projects.Please refer our position paper shown below and you can see the list (attached in the end of this letter) and find “Antihypertensive treatment and risk of CVD death (Kunihiro Yamagata)”. Unfortunately, though the most updated list of our projects including “Cause-specific mortality in the general population with transient dipstick-proteinuria (PLoS One 14: e0223005)” is not published yet, SC authorized “Cause-specific mortality...” as independent project of “Antihypertensive treatment and risk of CVD death”.*Clin Exp Nephrol. 2017 Dec;21(6):978-985. doi: 10.1007/s10157-017-1392-y. Epub 2017 Mar 3.Mortality risk among screened subjects of the specific health check and guidance program in Japan 2008-2012.Iseki K, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, Narita I, Konta T, Kasahara M, Shibagaki Y, Yoshida H, Moriyama T, Kondo M, Iseki C, Watanabe T; “Design of the comprehensive health care system for chronic kidney disease (CKD) based on the individual risk assessment by Specific Health Check”.AttachmentRtoRs-2019-10-POne-r1.docxSubmitted filename: Click here for additional data file. 14 Nov 2019Antihypertensive treatment and risk of cardiovascular mortality in patients with chronic kidney disease diagnosed based on the presence of proteinuria and renal function: A large longitudinal study in JapanPONE-D-19-26343R1Dear Dr. Yamagata,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. 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Later stage (stage 3b–5) CKD patients with DR had significantly higher CKD progression compared with patients without DR (OR (odds ratio) 1.66 (1.36–2.02)). Patients with proliferative DR had significantly higher CKD progression events compared to patients with non-proliferative DR (OR 2.18 (1.71–2.78)). The presence and severity of DR is a risk factor for CKD progression among our Taiwanese CKD patients with diabetes. Prevention and early detection of DR are important and DR should be routinely screened as early as possible among diabetic CKD patients.It has rarely been studied whether the presence and severity of diabetic retinopathy (DR) could influence the renal disease progression among all chronic kidney disease (CKD) diabetic patients. This study investigates the characteristics of diabetic patients, with different stages of chronic kidney disease (CKD), according to the occurrence of diabetic retinopathy and determines the influence of retinopathy in the deterioration of renal function. We conduct a multicenter, longitudinal cohort study based on the Epidemiology and Risk Factors Surveillance of the CKD project (2008–2013) and the National Health Insurance Research Database (NHIRD) (2001–2013). A total of 4050 diabetic patients with CKD, 20–85 years of age, from 14 hospitals and the community are included in this study. As compared to CKD patients without DR, CKD patients with DR have a lower baseline estimated glomerular filtration rate (eGFR) (39.17 ± 30.36 mL/min per 1.73 m Chronic kidney disease (CKD) is a serious global health problem with a high global prevalence 11%–13%) [1%–13% 1 and ESRDClinically, both CKD and DR share common risk factors, such as aging, poor glycemic control, and systolic hypertension, etc. . In thesIn a previous population-based study, diabetic retinopathy is found to be closely related to microalbuminuria and overt nephropathy among Korean patients with DM . HoweverWe conducted a multicenter, longitudinal cohort study from 14 medical centers and the community, collecting questionnaire and biochemistry data to establish the Epidemiology and Risk Factors Surveillance of the CKD database (2008–2013) by our core Laboratory and the Bureau of Health Promotion, Ministry of Health and Welfare, Taiwan. A total of 16,206 patients with and without CKD from 14 hospitals and the community, ranging from 20 to 85 years of age, were recruited in this study. End-stage renal disease (ESRD) was defined either as receiving maintenance dialysis or having a kidney transplant during this period. Patients with under 1-year of follow up, non-CKD, and missing or incomplete data were excluded. After exclusion, a total of 8537 participants who followed up for at least one year were included. We then linked the biochemical laboratory data to the National Health Insurance Research Database (NHIRD) from 2001 to 2013. During data analysis we further excluded 4487 patients without diabetes mellitus. Finally, 4050 patients with diabetes mellitus were included in the study analysis . Among t2) = 141 × min α × max  −1.209 × 0.993Age × 1.018  and × 1.159 (if black), where sCr denotes the serum creatinine level (mg/dL), ƙ = 0.7 (for women) and 0.9 (for men), α = −0.329 (for women) and −0.411(for men), min denotes the minimum of sCr/ƙ or 1, and max denotes the maximum of sCr/ƙ or 1 [2 and the presence of any kidney damage  ≥ 30); stage 2, eGFR = 60–89 mL/min/1.73 m2 with any kidney damage ; stage 3a, eGFR = 45–59 mL/min/1.73 m2; stage 3b, eGFR = 30–44 mL/min/1.73 m2; and stage 4, eGFR = 15–29 mL/min/1.73 m2; and stage 5, eGFR < 15 mL/min/1.73 m2 [2 per year was defined as CKD progression [Data on patient demographics and health were collected using standardized questionnaires. These questionnaires included questions about age, sex, cigarette smoking, alcohol consumption, betel nut chewing, personal and family comorbid conditions, and medication use. Physical examinations were done especially on anthropometry, blood pressure (BP) and pulse rate (PR), and local and systemic examinations. Body height was measured by using a wall-mounted measuring tape (centimeters) and weight was measured by a digital scale in kilograms . Diabetic retinopathy was diagnosed and staged clinically by dilated fundus examination and fluorescein angiography of the retina was used, if required. Staging of DR after the examination was done as follows: No apparent signs of DR was regarded as normal; microaneurysms, hard exudates, intraretinal hemorrhages, venous beading, or prominent intraretinal microvascular abnormality was regarded as early stage, non-proliferative DR (NPDR); and retinal or optic disk neovascularization, vitreous hemorrhage, or preretinal hemorrhage was regarded as late stage, proliferative DR (PDR) . Proteinr/ƙ or 1 . The var/1.73 m2 . An averp < 0.05 was considered to be statistically significant.The odds ratio (OR)  of CKD was calculated for the overall, the non-proliferative DR, and the proliferative DR groups. We then explored the confounding and effect modification data in stratified analyses. After adjustments for all covariates, a multivariate logistic model with stepwise variable selection models was used to evaluate the relationship between DR and CKD progression. All statistical tests used the SAS statistical package . The value This study was reviewed and approved by the institutional ethical committees of Taipei Medical University—Shuang Ho Hospital (TMU-JIRB 201204036), Tri-Service General Hospital (TSGHIRB100-05-197), Cardinal Tien Hospital (TMU-JIRB 201204035), Changhua Christian Hospital (CCHIRB 20405), Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUHIRB 20120019), Kaohsiung Chang Gung Memorial Hospital (101-1096B), National Cheng Kung University Hospital (A-ER-101-117), and China Medical University Hospital (DMR101-IRB2-273(CR-1)). Written informed consent was obtained from all participants after a detailed explanation of the study protocol. Clinical and biological samples were collected by our trained surveyors and research assistants after patients’ informed consent was obtained.p < 0.01) and blood pressure >130/85 mmHg  than the non-DR group. There is significantly higher fasting glucose (AC glucose) 142.85 ± 64.63 mg/dL in the DR group vs. 129.09 ± 46.62 mg/dL in the non-DR group (p < 0.01). A total of 58.82% of the DR group vs. 43.96% of the non-DR group had higher glycated hemoglobin (HbA1c) ≧7% (p < 0.01). A significantly higher number of patients had UPCR > 1000 mg/dL . Up to 18.9% of the DR patients had severe UPCR > 3500 mg/dL, however, only 6.99% of non-DR patients had severe UPCR > 3500 mg/dL. The mean baseline estimated glomerular filtration rate (eGFR) was significantly lower, 39.17 ± 30.36 mL/min per 1.73 m2 in the DR group compared to 54.38 ± 33.67 mL/min per 1.73 m2 in the non-DR group. More CKD progression events were noted in the DR group than in the non-DR group . There was significantly lower hemoglobin (Hb) (11.22 ± 2.43 g/dL in the DR group vs. 12.39 ± 3.85 g/dL in the non-DR group (p < 0.01)), hematocrit (Hct) (32.84 ± 6.43% in DR group vs. 36.49 ± 6.48% in the non-DR group (p < 0.01)), and serum albumin (3.88 ± 0.95 g/dL in the DR group vs. 4.16 ± 1.74 g/dL in the non-DR group (p < 0.01)), respectively   . A previ < 0.01) . This re < 0.01) , model 3We note in our study that the DR severity is related with renal function decline in late CKD stages, independent of hypertension or diabetic status. Both proliferative and non-proliferative DR are significantly associated with CKD progression in unadjusted models, however, after adjustments for baseline eGFR, hypertension, HbA1c, and BMI, this relationship has been noted only in proliferative DR , model 3Our study has several limitations. In this study, since we used the prevalent CKD cohort, the effects of retinopathy on incident CKD were not determined. The personal identities of the study participants were linked to the national health care (NHI) databases. As the NHI database did not include the population that was not under medical health care it did not represent the whole population. However, in 2016, nearly 99.9 percent of Taiwanese population were under NHI coverage ,49. ThusIn conclusion, the presence and severity of retinopathy intimately associates with CKD progression among all diabetes patients with chronic kidney diseases. Routine follow-up and management of ocular and retinal disorders in CKD patients with diabetes would be important for aggressive management of diabetic retinopathy and prevention of CKD progression among these patients.


Kidney transplantation (KT) is the most obvious method of treating a patient with end-stage renal disease. In the early stages of KT, urine production is considered a marker of successful reperfusion of the kidney after anastomosis. However, there is no clear conclusion about the relationship between initial urine output after KT and 1-year renal function. Thus, we investigated the factors that affect 1-year kidney function after KT, including urine output.This retrospective study investigated the relationship between urine output in the 3 days after KT and transplanted kidney prognosis after 1-year. In total, 291 patients (129 living-donor and 162 deceased-donor transplant recipients) were analyzed; 24-h urine volume per body weight (in kilograms) was measured for 3 days postoperatively. The estimated glomerular filtration rate (eGFR), determined by the Modification of Diet in Renal Disease algorithm, was used as an index of renal function. Patients were grouped according to eGFR at 1-year after KT: a good residual function group, eGFR ≥60, and a poor residual function group, eGFR < 60.P = 0.03), weight (P = 0.00), and body mass index (P = 0.00). Donor factors affecting 1-year eGFR include age (P = 0.00) and number of human leukocyte antigen (HLA) mismatches (P = 0.00). The urine output for 3 days after KT  was associated with 1-year eGFR in deceased-donor . And, postoperative urine output was associated with the occurrence of delayed graft function (area under curve (AUC) = 0.913; AUC = 0.984 and AUC = 0.944).Recipients’ factors affecting 1-year eGFR include height .Clinical Research Information Service of the Korea National Institute of Health in the Republic of Korea ( The incidence of end-stage renal disease (ESRD) is increasing with the prolonged life span and raised prevalence of chronic diseases, such as diabetes and hypertension . Kidney Early detection and prevention of renal functional decline are important for the maintenance of normal graft function. Several tests, including urine-based measurements, can be used to evaluate the function of the kidneys. Urine tests are suitable for clinical applications because the necessary samples are easy to obtain. They involve the measurement of specific substances in the urine, such as kidney injury molecule-1 , or meas2) to overcome some limitations [In general, it is known that the glomerular filtration rate (GFR) is an excellent indicator of overall kidney function . GFR meaitations .Transplanted kidneys are known to produce large amounts of urine in the initial stage after transplantation . No critThis single-center retrospective cohort study was conducted using the electronic medical records of Chonnam National University Hospital. This registry retrospectively collects data regarding recipients’ characteristics and outcomes. Adult patients (age ≥ 20 years) who underwent KT in our center during the 10-year period between 1 January 2008 and 31 December 2017 were included.The institutional review board of Chonnam National University Hospital approved the study protocol (CNUH-2019-018), and the study was registered with the Clinical Research Information Service of the Korea National Institute of Health in the Republic of Korea (KCT0003571), which belongs to the World Health Organization Registry Network.In total, 303 kidney transplants, including re-transplantations, were performed during the study period. Patients were excluded from the analysis if they lacked medical records for the first year after surgery, due to death or loss to follow-up; patients aged < 20 years were also excluded. The preoperative information collected was age, sex, height, weight, body mass index (BMI), duration of dialysis, method of dialysis, eGFR, diabetes mellitus (DM) status, hypertension (HTN) status, hepatitis B virus status, hepatitis C virus status, and type of donated kidney. eGFRs were estimated using the MDRD equation. In addition, the characteristics of donated kidney such as age, Creatinine, DM, HTN, and human leukocyte antigen (HLA) mismatch, incidence of delayed graft function (DGF) were also investigated. DGF was defined as hemodialysis performed within 1 week after surgery. Nephropathy was defined as primary kidney disorder, such as IgA nephropathy or autosomal polycystic kidney, but not secondary kidney disorder due to HTN or DM. Our hospital usually measures the amount of urine for 24 h during the 3 days after KT; those data were used in the present study. The total volume (in milliliters) of urine collected over 24 h was divided by the body weight (in kilograms) of the patient. Follow-up data  were collected at 1 year after KT. Graft rejection episodes were defined as biopsy-proven rejection or clinically suspected acute rejection that was improved by empirical steroid pulse therapy. Patients were considered to be positive for viral infection when cytomegalovirus (CMV), Epstein–Barr virus (EBV), or BK polyomavirus (BKV) was detected after KT.2 for 3 months or more [Chronic kidney disease (CKD) is defined as GFR < 60 mL/min/1.73 m or more . This cr or more  and, the or more . The patP values <.025 was considered as statistically significant. The analysis of usefulness of postoperative urine output for the prediction of delayed graft function and residual renal function at 1 year after transplantation used receiver-operating-characteristic (ROC) curve techniques. The statistical analysis was performed using R version 3.6.0 .For demographic data, the independent two sample t-test for normal continuous data or the Wilcoxon rank-sum test for non-normal continuous data were used as appropriate. The normality was verified by Shapiro-Wilk test. The categorical data was analyzed by the Chi-squared test or Fisher’s Exact test. A subgroup analysis according to the type of transplanted kidney was performed. A bonferroni correction was used to adjust type I error for multiple comparisons in subgroup analysis and During the study period, 303 kidney transplants were performed. Four patients aged < 20 years were excluded. Eight patients who were lost to follow-up or who died within 1 year after KT were also excluded. Finally, a total of 291 patients were included in the analysis  administered for 3 days and 1 year eGFR Tables  and 6.TPostoperative day 2 urine output was the highest in the correlation between 3 days postoperative urine output and DGF development Table .Table 7The relationship between postoperative urine output at 3 days and 1 year eGFR was analyzed by ROC curve Fig. .Fig. 2RGood residual function group was associated with fewer rejection episodes in all patients; subgroup analysis yielded similar findings Table .Table 8Good residual function group was also associated with fewer viral infections in all patients; subgroup analysis yielded similar findings Table . The cohEarly diuresis after KT is a good indicator of transplanted kidney function . HoweverP < .02; angiotensin II, 62.8 vs. 48.5 pg/mL, P < .01). In addition, Oberbauer et al. [In this study, deceased-donor kidney recipient was associated with postoperative urine output and 1-year eGFR. Urine production begins as blood moves to the glomerulus and is filtered out of the glomerular barrier. The renin–angiotensin–aldosterone system (RAAS) regulates renal blood flow and the GFR by modulating resistance of the renal afferent and efferent arterioles. Regardless of the type of fluid, when a sufficient volume of fluid enters the blood vessel, the amounts of renin and aldosterone decrease and urine volume increases . Renin ar et al.  reportedGlobally, the 1-year graft survival rate of overall KT is > 90%, and this rate is gradually improving for deceased-donor KT . HoweverIn this study, postoperative viral infection was associated with the 1-year eGFR. There may be several types of viral infections after KT, but CMV and BKV are common. Viral infections may affect acute or chronic rejection episodes. Reportedly, 72% of CMV-positive recipients developed rejection, whereas CMV-negative recipients had only a 17% rejection rate . The mecFinally, the results of this study show a correlation between the occurrence of rejection episodes and the 1-year eGFR. Esteve et al.  reportedIn the present study, most KT were carried out by one surgeon and there were few variables due to surgery. However, this study has the following limitations. First, this study was retrospectively conducted in a single institution. Therefore, the sample size was small and there was no direct measurement of renin and aldosteron. However, it is known that renin and aldosterone levels are raised in deceased donor KT. Second, demographic data are different between the groups (for example BMI), so we tried to compensate for this difference by using urine volume per weight rather than post-operative urine output itself. Third, The incidence of DGF in this study was lower than in other studies . This maSufficient urine output after immediate KT reflects proper blood supply to the transplanted kidney and the absence of stenosis or leakage at the anastomosis site. Early postoperative urine output was associated with 1-year postoperative graft function in deceased-donor kidney recipients, but not in living-donor kidney recipients. This difference may be caused by activation of the RAAS due to prolonged cold ischemic time during the preparation of deceased-donor kidneys. Therefore, we recommend that the approach to achieving proper urine volume after KT be adjusted depending on the type of transplanted kidney.


Blood pressure variability (BPV) is an independent cardiovascular risk factor in hypertensive patients. The best method for quantifying BPV is still an object of debate. The existence of different BPV patterns, particularly age and arterial stiffness related, is postulated. Our aims were:i)to compare BPV using different blood pressure (BP) measurement methodsii)to compare different calculation approachesiii)to analyze the predictors of BPV.Cross-sectional study in 108 elderly hypertensive hospitalized patients. Each patient underwent blood pressure measurements with 5 different modalities: 24 hour BP and pulse wave velocity (PWV) monitoring (24hBPM), measurement by nurses or physicians, self-measurement and beat-to-beat monitoring. Differences between maximum and minimum values (ΔBP), averages of the absolute differences between consecutive values (ARV) and coefficients of variation (CV) were calculated.P <.05). 24hBPM ΔSBP in a multivariate analysis was significantly associated with age  and PWV . Calcium antagonists were associated with a lower ΔSBP  while diuretics and alpha-blockers with a significant increase .ΔBP showed the wider values’ dispersion (Δ systolic blood pressure (SBP): 66.4 ± 22.9 and Δ diastolic blood pressure [DBP]: 45.0 ± 13.5 mmHg). ARV and CV were highest with nurses’ measurements . The strongest correlation was found comparing physicians’ SBP measurements and 24hBPM ARVs (R2 0.23, Age, PWV, diuretics, alpha-blockers, but also measurements obtained by nurses, increase BP variability while calcium antagonists reduce it. BP profiles in elderly in-hospital patients potentially provide important information; they should, however, be interpreted cautiously. Furthermore, it has been shown that BPV is associated with the development and severity of target organ damage .,5A large and increasing number of studies support the evidence that blood pressure variability (BPV) represents a strong and independent risk factor for cardiovascular diseases (CVD),,7 Autonomic, humoral, neural, vascular, and environmental mechanisms influence in turn BPV. Sustained BPV could also reflect alterations in regulatory mechanisms such as impaired sympathetic drive and baroreflex function .,10Fluctuations in blood pressure (BP) can be classified as short-term , mid-term , and long-term  variability. Independently from the modality of assessing it, several factors can affect BPV, including in particular gender, age, diabetes, some antihypertensive medications, and obviously the mean blood pressure. ARV has the advantage of taking into account the temporal order of BP measurements, and therefore the BP time series variability. Another parameter frequently used is the coefficient of variation (CV), which is the standard deviation divided by the corresponding mean. However, even if CV provides a good intra-individual estimate of BPV, it does not take into account the order of BP measurements. Lastly, with the intention to quantify the extremes of BP excursions, it was proposed to calculate the difference between the maximum and the minimum BP values (ΔBP), which has the advantage of being independent from the mean.Knowing that BPV is not only a “background noise” of blood pressure (BP), but an independent risk entity and that evidence is lacking on the best quantitative method for measuring it; more and more questions on BPV reliability arise. Different methods to estimate BPV have in fact been proposed during the last years; among them, the most commonly applied is the average real variability (ARV), which is the average of the absolute differences between consecutive BP readings.,15 which could produce different patterns of BPV. In this complex panorama, specific BP measurement technique predictor factors for BPV are not available.The majority of studies on BPV have been focused on the results of 24-hour ambulatory BP monitoring (ABPM), and comparisons of BPV on other modalities of measurement are lacking. Moreover, BP fluctuations reflect the complex interactions of several, and at least in part, dynamic factors , Hence, the best antihypertensive therapy management should be planned not only considering the mean BP but also taking into account the intra-individual BP fluctuations.This point is potentially relevant, knowing that, in some studies, the association between CVD mortality and BPV was stronger than between the same and mean BP.In addition, most studies have evaluated factors associated with BPV in young subjects; while in the inpatient real life, elderly are mainly represented; inpatient dynamic in which, at least in the internal medicine wards, the antihypertensive home therapy is often reassessed. Hospitalization per se represents an environmental factor, which could largely affect BP, primarily through the stressful experience of adapting to the new setting, which could increase both BP and BP variability. Furthermore, the arterial stiffness increase seen in the elderly, predisposes, in the presence of state of stress, to an excessive pressure response with related large BP fluctuations.Elderly is a heterogeneous group in which chronic conditions are strongly represented; among those hypertension concerns about 60% of the subjects.Considering the important number of variables potentially affecting BPV in the internal medicine hospital setting, we designed a real-world cross-sectional study aimed at evaluating BPV using different estimation methods  and different BP measurement strategies: obtained by physicians or nurses; obtained by self-measurement; registered by a 24 hour automated monitor; obtained using a beat-to-beat. The objectives were: i) to compare BPV using different BP measurement methods, ii) to compare different calculation approaches, and iii) to analyze the predictors of BPV, in an elderly in-hospital population.22.1Single center, cross-sectional study in elderly patients consecutively hospitalized at the internal medicine ward of the teaching Hospital “La Carità”  between June 2014 and March 2015. Eligibility criteria for enrollment included:i)age older than 70 years;ii)hospitalization in the internal medicine ward not motivated by the hypertension itself.The exclusions criteria were:i)inability to understand and to sign the informed consent;ii)mental illness;iii)inability to perform BP self-measurements.The study was carried out according to the Helsinki Declaration and was approved by the Swiss Ethics Committee. All of the participants gave written informed consent.2.2One hundred and eight elderly hospitalized patients were investigated. Each patient underwent 5 modalities of BP measurement:1)performed by nurses’ staff2)performed by physicians’ staff3)performed by the patient himself4)Performed by a physician using a beat-to-beat5)Performed over 24 hours by an automated device measuring BP and estimating pulse wave velocity (PWV).Nurses, physicians, and patients used the same electronic device to measure BP. A Finometer was chosen to register beat-to-beat BP fluctuations. The BP values of the first 2 days of the hospital stay were not considered for the analysis. BP measurements by nurses, physicians and self-measurements by patients were carried out 3 times per day during daytime.On the 4th day of hospitalization, a 24-hour BP and PWV monitoring using an automated device  was performed. See Figure 2.3BP measurements were performed by physicians and nurses using a, validated and calibrated, automatic oscillometric device . The upper non-dominant arm was measured and then, a small cuff was used by circumferences of less than 24 cm, a medium cuff by circumferences between 24 and 34 cm, and a large cuff by circumferences of 35 cm or more. Blood pressure measurements were performed after a comfortable resting of 5 minutes in the seated position. Measurements were performed before taking the medication and without consuming caffeine or tobacco in the preceding 30 minutes. Measurements were performed during daytime at 08h00, 12h00 and 18h00. Recorded systolic blood pressure (SBP) and diastolic blood pressure (DBP) values represented the lowest of 3 different readings measured at 5-minute intervals.2.4Patients were asked to measure their seated BP thrice, at 08h00, 12h00, and 18h00; after more than 5 minutes of rest each time. BP was measured using the same oscillometric device used by nurses and physicians. Patients were asked to record the results over a 3-day period. The mean of all measurements was calculated for each patient and used for the analysis.2.5The Finometer is a device allowing a non-invasive continuous beat-to-beat BP measurement, with a real-time display of the arterial pressure. A calibration of the finger BP on the basis of the brachial BP using an integrated brachial cuff system was performed for every patient. The beat-to-beat blood pressure was registered thanks to small cuffs applied to the fourth finger of the non-dominant hand, which accordingly to a continuous Doppler flow monitoring, inflated and deflated rhythmically extrapolating BP values. After the first 2 minutes dedicated to familiarization, parameters were recorded at 30 seconds, 1, 2, 4, and 6 minutes. At the end of the procedure a “stress induction test” based on standardized questions was performed.2.6The 24 hour Blood Pressure Monitoring (24hBPM) was performed using a Mobil-O-Graph ; an electronic blood pressure and pulse wave velocity monitor equipped with an arm cuff validated for clinical use. The 24hBPM was applied the fourth day of the study. The cuff was fixed to the non-dominant arm and the device was set to automatically obtain readings every 30 minutes during the day (06:00 AM–10:00 PM) and every hour during the night (10:00 PM–06:00 AM). Eight Mobil-O-Graphs were employed for the study. The supplying company guaranteed the calibration.2.72. The diagnosis of diabetes was considered by the presence of hypoglycemic medications  or if their fasting blood glucose levels reached 7.0 mmol/L or more. Dyslipidemia was defined by total cholesterol >5.18 mmol/L, triglycerides >1.70 mmol/L, low-density lipoprotein >3.37 mmol/L, high-density lipoprotein <1.04 mmol/L or if the patient was on a lipid-lowering treatment at home. Participants who smoked at least one cigarette per day were classified as current smokers and those who had stopped smoking for more than 3 years were classified as former smokers. Hypertension was defined based on patient's medical history or if the patient was on BP lowering medications over the last 15 consecutive days. Antihypertensive medications in use at home were recorded at admission and categorized into the following groups: renin angiotensin aldosterone system inhibitors (RAAS-I), alpha-adrenergic blocking agents (α-block), calcium channel blockers (Ca-antag), diuretics, beta-adrenergic blocking agents (β-Block), and others. Controlled BP was defined as systolic BP less than 140 mm Hg and diastolic BP less than 90 mm Hg in patients under BP-lowering medications.Demographic data for each patient were recorded, as well as height, weight, body mass index (BMI), smoking status, patients’ chronic conditions  and medications in use at home. The weight, in Kg, of the patient was collected with the help of a scale and the height, in cm with a stadiometer. The BMI was calculated with the formula: weight in Kg/(height in m)2.82 statistics, respectively.Variables were shown as median  or mean ± Standard Deviation (SD); or value and relative frequencies (%) as appropriate. We compared continuous variables and proportions by standard parametric tests and χFor each measurement method, BPV was estimated for both SBP and DBP, using 3 indices of variability:I)delta-systolic and diastolic blood pressure (ΔSBP and ΔDBP), expressing for both the difference between maximum and minimum blood pressure values;II)average real variability (ARV), computed as the average of the absolute differences between consecutive BP measurements;III)coefficient of variation (CV) obtained by dividing the SD by the average BP level and multiplying by 100.P value).Correlations between BP obtained with the different measurement methods and the calculated indices of variability were quantified with the Pearson coefficient  by BP-measurement strategy, and differences among groups were investigated.Subjects were classified in 2 groups of high and respectively low variability, based on the 50P value for the null hypothesis. To explore a possible departure from linearity of the age effect, we repeated the analysis using restricted cubic splines with 3 internal knots.Stepwise multiple linear regression analyses were performed in order to explore the covariates associated with BPV. As covariates we considered: gender, age, BMI, dyslipidemia, diabetes, serum creatinine, history of cardiovascular disease, current smoking, pulse wave velocity, height, hypertension, anti-diabetic medication, antihypertensive medication. In the tables, we report the β regression coefficients with their asymptotic standard errors and the associated 2-sided P values <.05 (2 tailed) were considered significant.All statistical analyses were performed using Stata Statistical Software, Release 14, College Station, TX, STATA Corp LP and SPSS 20, SPSS Inc., Chicago, IL. 32 (22.6–30.3) and 48.2% of the patients had a history of CVD. Patients’ first diagnosis at admission was as follows, n (%): cardiovascular diseases 24 (22.2); pneumonia 20 (18.5); other infectious diseases 15 (13.9); neurological diseases 15 (13.9); gastrointestinal diseases 11 (10.2); oncological diseases 5 (4.6); syncope 4 (3.7); nephrological diseases 3 (2.8); endocrinological diseases 3 (2.8); fractures 3(2.8); falls 2 (1.9); miscellaneous 3 (2.8).A total of 108 patients completed the study and were included in the analysis. Baseline demographic and clinical characteristics of the study population are summarized in Table 2 0.72, P <.001) and self-assessed  showed the highest degree of correlation with 24hBPM. The weakest correlation, on the contrary, was found between SBP obtained by Finometer and 24hBPM . Finometer and 24hBPM showed, however, the highest correlation coefficient for DBP   . ΔBP was significantly associated for SBP obtained by nurses and 24hBPM  and for DBP obtained by patients and 24hBPM  (Table P <.05) and pulse wave velocity . Although not statistically significant, age and creatinine were lower in the low-variability group, with respectively 86.3 ± 6.0 vs 84.2 ± 6.2 years, P = .077 and 102.2 ± 59.1 versus 96.5 ± 56.6 μmol/L, P = .089. Pulse wave velocity values significantly differed also for ΔDBP in 24hBPM  (Table P <.05)  were calculated for each BP measurement method Table . 24hBPM BP R2 0.5; P <.001BP R2 0.5; P <.001BP R2 0.5; P <.001P <.001) and with PWV . Similar associations were found for ΔSBP obtained with Finometer, with significant values for age  and for PWV . In addition, antihypertensive drugs were significantly associated with Finometer ΔSBP, although in opposite directions: calcium antagonists, with a significant reduction  while diuretics with a significant increase . ΔSBP calculated on the basis of physicians’ measurements was significantly associated with age  and with PWV . Although not statistically significant, we found a trend towards an association between physicians’ ΔSBP and alpha-blockers . Patient ΔSBP was on the contrary significantly associated . Considering other determinants of variability we found that ARV-SBP based on nurses’ measurements was significantly associated with the use of beta-blockers . ARV-SBP and ARV-DBP based on physicians’ measurements were respectively significantly associated with a positive cardiovascular history  and age . No other significant associations were found for ARV-SBP and ARV-DBP (Table P <.05); and nurses’ SBP measurements . DBP CV based on physicians’ measurement was also significantly associated with age and PWV: β −0.75, SE 0.30, P <.05; β 2.70, SE 1.38, P = .05. DBP CV based on nurses’ measurements was significantly associated with BMI  . Furthermore, in previous studies, younger populations in heterogeneous environmental circumstances and potentially with several factors influencing punctual BP fluctuations were evaluated.,24 Finally, our study is the first one aimed at comparing BPV, also analyzing values obtained with a continuous beat-to-beat noninvasive monitoring system (Finometer).Our proof of concept study is the first one comparing several approaches to calculate blood pressure variability in a specific and distinctive population composed of over 70-year-old in-hospital hypertensive patients. Previous findings did already analyze the topic, highlighting a poor correlation between methods used for variability estimation and investigating the variability agreement between ABPM and beat-to-beat and between ABPM and self-measurements.,26Our choice to calculate 3 different determinants of short-term variability arises from the attempt to highlight peculiarities of the within-individual differences; peculiarities that can only partially be investigated by BPV determinants dependent on the mean BP.In our population, variability calculated on the basis of BP measured by beat-to-beat showed the better systolic and diastolic correlation with values obtained from the 24hBPM. Similarities and differences between BPV determinants were highlighted by the fact that some of them only showed a significant correlation.–28 Furthermore, a strong association between arterial stiffness, estimated with a beat-to-beat analyzer in a hypertensive population, and Systolic BPV was shown.Recently, findings of observational studies showed an association between ABPM-BPV and arterial stiffness. This association was more evident focusing on short-term BP variability determinants such as ARV and CV.Our study confirms, in an in-hospital elderly population, the association between high beat-to-beat BPV and the magnitude of vascular damage measured by pulse wave velocity obtained with an independent method (24hBP and PWV monitor). The fact that arterial stiffness confirms a correlation with the amplitude of BP fluctuations, does not, however, tell us in which way BPV itself impacts on the progression of vascular damage. In our data, moreover, PWV was significantly higher in the High-BPV group. Finally, a rise in PWV correlates with an increase in BP variability for both 24hBPM and measurements obtained by physicians. Diuretics and, as recently shown, alpha- blockers, confirm on the contrary an association with higher BPV values.Recently, great interest was shown in exploring the contribution of different classes of antihypertensive medications on BPV. In our study, we attempt to provide an estimation of the impact of calcium antagonists, diuretics, alpha-blockers, beta-blockers, and renin angiotensin aldosterone system inhibitors on BPV. As suggested from previous findings, we confirm the association between the use of calcium antagonists and low BPV values. Interestingly, the effect of calcium antagonists on beat-to-beat BP variability was not previously highlighted. Furthermore, increasing the interest in the topic, it was shown in a previous study, that BPV reduction related to calcium antagonist treatment was associated with a concomitant improvement in baroreflex sensitivity, suggesting this mechanism as one of the components of BP stabilization.,33 However, in our study, due to the limited number of patients admitted for the cited diagnoses, we were unable to conduct a targeted sub-analysis. For the same reason, even if some diagnoses justifying hospital admission, especially infections, could impact BPV, we did not investigate their potential role.Moreover increasing evidence suggests a relationship between BPV and, falls, symptomatic hypotension and syncope, mostly in elderly people. Moreover, our study was conducted in hospitalized patients; in a setting far from the patient's everyday life in which blood pressure shows a peculiar pattern, related to several influencing factors , susceptible to impact on reliability and variability and associated with a higher prevalence of symptomatic and asymptomatic orthostatic hypotension.We have to acknowledge some limitations of our study. Firstly, the observational design, which does not allow to conclude definitively about causality. Moreover, some strong associations found in our data could not be recognizable in younger patient or in population samples with other characteristics. As a consequence of structural vessel changes, diminished baroreflex sensitivity and enhanced response to sympathetic activation related to increased arterial stiffness, elderly patients represent, in fact, a population with a non-linear and extremely variable pattern of arterial aging and BP behavior. Finally, even if we did not consider the BP values of the first 2 days, to reduce in particular the impact on BP of the adrenergic response to environmental adaptation and the magnitude of white coat hypertension, we cannot exclude a residual hospital mediated “stress-response”.In this fascinating but still cloudy research field, we can conclude on 1 hand that, individual characteristics and antihypertensive treatments are susceptible to producing peculiar blood pressure variability patterns and on the other that, the way blood pressure is measured and variability is calculated play a significant role. Age, PWV, diuretics, alpha-blockers, but also measurements obtained by nurses, increase blood pressure variability while calcium antagonists reduce it. The cited factors of variability are highly prevalent in the in-hospital internal medicine population; setting in which antihypertensive treatments are often readapted. Blood pressure profiles obtained on the wards, potentially provide important information; they are however difficult to interpret and influenced by numerous biases. A unique consensus about the way of measuring blood pressure variability and their significance as a function of the patients’ characteristics would be helpful.We would like to thank Anna Zasa MSc for data managing.Conceptualization: Rosaria Del Giorno, Lorenzo Balestra, Pascal Simon Heiniger, Luca Gabutti.Data curation: Rosaria Del Giorno, Lorenzo Balestra, Pascal Simon Heiniger, Luca Gabutti.Formal analysis: Rosaria Del Giorno, Luca Gabutti, Lorenzo Balestra.Investigation: Pascal Simon Heiniger, Luca Gabutti, Lorenzo Balestra.Methodology: Rosaria Del Giorno, Luca Gabutti.Writing – original draft: Rosaria Del Giorno, Lorenzo Balestra, Pascal Simon Heiniger.Writing – review & editing: Rosaria Del Giorno, Lorenzo Balestra, Luca Gabutti.


Background: Patients with subclinical hypothyroidism (SCH) have elevated blood pressure, but the effect of levothyroxine (LT4) therapy on blood pressure among those patients is still unclear. This study aimed to assess whether LT4 therapy could reduce blood pressure in SCH patients through a systematic review and meta-analysis.Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched. Randomized controlled trials (RCTs) assessing the effect of LT4 therapy on blood pressure or prospective follow-up studies comparing the blood pressure level before and after LT4 treatment were included, and the mean difference of systolic blood pressure (SBP) or diastolic blood pressure (DBP) was pooled using random-effect meta-analysis.Results: Twenty-nine studies including 10 RCTs and 19 prospective follow-up studies were eligible for the analysis. Meta-analysis of 10 RCTs suggested that LT4 therapy could significantly reduce SBP in SCH patients by 2.48 mmHg . No heterogeneity was observed among these 10 RCTs (I2 = 0%). Meta-analysis of the 19 prospective follow-up studies found that LT4 therapy significantly decreased SBP and DBP by 4.80 mmHg  and 2.74 mmHg , respectively.Conclusion: The findings suggest that LT4 replacement therapy can reduce blood pressure in SCH patients, which needs to be validated in more clinical trials with larger samples. Subclinical hypothyroidism (SCH) is a state with elevated thyrotropin  level and normal free thyroxine fT4) level . Compare level . Many studies have revealed that both overt hypothyroidism and SCH can increase the risk of cardiovascular disease –13. SomeSome studies suggested that LT4 therapy could offer benefits for SCH patients through decreasing TSH level, such as the lipid-lowering effect , 22. FinThis systematic review was done by the Preferred Reporting Items for Systematic Review and Meta-analysis statement (PRISMA)  and was The systematic review question was whether LT4 replacement therapy could reduce blood pressure among SCH patients. Studies eligible in this meta-analysis must meet the following inclusion criteria which were formulated by the five terms of systematic review question, namely population, interventions, comparators, outcomes, and study designs (PICOS). The inclusion criteria were showed as follows: (1) they were randomized controlled trials (RCTs) assessing the effect of LT4 treatment on blood pressure or prospective observational studies comparing the blood pressure levels before and after LT4 treatment (S); (2) participants were adult patients with SCH (P); (3) the intervention was thyroid hormone replacement alone with LT4 (I); (4) the comparator for RCTs was placebo or no LT4 treatment, while the comparator for prospective observational studies was the blood pressure before LT4 treatment (C); (5) they reported the difference in systolic blood pressure (SBP) or diastolic blood pressure (DBP) between LT4-treated groups and controls without LT4 treatment, or the changes in the levels of SBP or DBP before and after LT4 treatment (O). Studies recruiting adolescents (under 18 years of age) or pregnant women or using combination of LT4 with other drugs as interventions were excluded. Studies without usable data on the effect of LT4 treatment on blood pressure or containing overlapping data were all excluded.The following information was extracted independently by two investigators: first author, year of publication, study design, country, sample size, ethnicity, definition of SCH, treatment dosage of LT4, mean TSH level at baseline, change in TSH during treatment, TSH measurement methods, hypertension status of SCH patients, treatment duration as well as blood pressure before and after treatment. Two authors independently assessed the risk of bias of included RCTs using Cochrane risk of bias tool, which mainly included randomized sequence generation, treatment allocation concealment, blinding, outcome data completeness, and selective outcome reporting . The risQ-test and the I2 statistic, and heterogeneity was considered to be substantial when I2 was more than 50% . Meta-analysis of the 10 RCTs suggested that LT4 therapy could significantly reduce SBP , but not DBP , but not DBP . Sensitivity analysis with sequential omission of single trial found obvious changes in the pooled mean difference of DBP, but not in the pooled mean difference of SBP .No heterogeneity was observed among those 10 RCTs I = 0%. MeP = 0.015), and it was not significant among those with lower mean TSH level , and meta-regression analyses also suggested that it had little possibility to cause substantial influence on the treatment effect , but not for SBP (I2 = 13.1%). Meta-analysis of these 19 studies found that LT4 therapy significantly decreased SBP  and DBP of SCH patients  and DBP , and LT4 therapy was more effective in lowering SBP of SCH patients with higher baseline SBP than those with lower SBP , suggesting that SCH patients with more TSH change had more reduction in SBP after LT4 therapy than those with less TSH change  and TSH change during treatment  were important influential factors of DBP-lowering effect of LT4 therapy , and the effect was modest in those with lower mean TSH level  and DBP  than those with lower blood pressure (Supplementary Tables P = 0.04) than those receiving initial LT4 dose <50 μg daily (Supplementary Tables P < 0.05).Subgroup analyses in the meta-analysis of prospective follow-up studies suggested that the pooled mean differences for both SBP and DBP were statistically significant in most stratified analyses despite of some difference in the magnitude of the treatment effect Figure , 4. For P-values of Egger's test for SBP and DBP were 0.30 and 0.26, respectively. In addition, possible risk of publication bias was found in the meta-analysis of prospective follow-up studies on SBP . Moreover, analysis using trim and fill method found no obvious change in the pooled mean difference of SBP.Both funnel plot and Egger's test found no publication bias in the meta-analysis of RCTs Figures . The P-vAlthough many trials have been published to evaluate the possible benefits of LT4 therapy in SCH patients , 65, 66,P = 0.038), suggesting that LT4 therapy was more effective in reducing SBP in patients with higher baseline SBP than those with lower SBP.In the present meta-analysis, all included RCTs showed no statistically significant effect of LT4 therapy on blood pressure except for the study by Chen et al. . HoweverBecause SCH has an obviously adverse impact on cardiovascular function, it has been proposed that restoring TSH level to the normal range through LT4 therapy may reverse its negative impact on cardiovascular function , 9, 66. Several cross-sectional studies suggested an obviously positive relationship between TSH level and hypertension among euthyroid individuals –18. Two Since the new ACC/AHA guidelines have lowered the definition of high blood pressure to 130/80 mmHg, more SCH patients will have concurrent hypertension , 77. BecThose studies included in our meta-analysis recruited patients with distinct degrees of SCH Tables , 2, whicOne important limitation in this meta-analysis was the inconsistency across included studies, such as differences in the extent of elevated TSH level, baseline blood pressure, races and mean ages of patients, which could possibly result in the distinct findings in those included studies. However, the inconsistent characteristics across included studies are very common in meta-analyses of clinical trials, and meta-analyses of RCTs with different drug dosages, different ages of patients, different races and different treatment duration are both reasonable and feasible –83. TherP > 0.05, P = 0.04, Supplementary Table Despite of the obvious differences across those studies included in the meta-analysis, subgroup analyses and meta-regression analyses suggested that most of those baseline characteristics had little influence on the blood pressure-lowering effect of LT4 therapy. For instance, there were obvious differences in both the mean LT4 dosages and treatment duration across those included studies Tables , 2, but Several other limitations should be noted in interpreting our findings. Firstly, obvious difference existed in the hypertension status of patients across those included studies. However, subgroup analysis and meta-regression analysis suggested that it was unlikely to result in distinct treatment effects across those included studies. Secondly, it was possible that misclassification of participants may have occurred owing to variations in TSH measurement methods and TSH cut-off values to diagnose SCH across those included studies. Though subgroup analyses by TSH cut-off values to diagnose SCH suggested that it had no obvious influence on the blood pressure-lowering effect of LT4 therapy , the defIn conclusion, our meta-analysis provided some evidence for the effect of LT4 therapy on blood pressure among SCH patients. However, owing to the limited number of included RCTs, the evidence for the effect of LT4 therapy on blood pressure is still not strong, which highlights a clear need for more high-quality RCTs with larger sample size.WH and XL designed the study. WH, SL, J-aZ, JZ, KM, and XL contributed to the literature search, interpretation, writing, and proofreading of the manuscript. WH, SL, J-aZ, and KM extracted data and performed data analyses.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.