Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole-body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular mass were reduced in the two congenic strains consistent with the congenic segments harbouring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole-genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl with adipocyte volume, systolic blood pressure and cardiac mass, respectively. Comparative genome analysis showed a marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole-body phenotypes associated with the SHR chromosome 12 and 16 insulin-resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.We previously mapped hypertension-related insulin resistance quantitative trait loci (QTLs) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified  Summary: Comparative genome analyses identify candidate genes for hypertension and insulin resistance on rat chromosomes 12 and 16, and marked enrichment of insulin resistance genes in the syntenic regions of the human genome. High blood pressure and type 2 diabetes affect over 1 billion people worldwide and the two conditions frequently co-exist . AlthougGenetic studies in animal models provide important opportunities for identifying the genes and mechanisms underlying disease traits. Experimental crosses in rats and mice, including mapping studies in congenic strains, have been used to identify hundreds of physiological and pathophysiological quantitative trait loci (QTLs) for complex traits such as blood pressure, left ventricular (LV) mass and type 2 diabetes . Whilst Cd36 as the major determinant of SHR hypertension and insulin resistance in this chromosomal region, a result followed by the demonstration of associations between CD36, hypertension and related metabolic traits in mice and humans (The spontaneously hypertensive rat (SHR), the most widely studied model of human essential hypertension, also manifests insulin resistance and LV hypertrophy – traits that commonly coexist with human hypertension . Using cd humans .in silico comparative genomic analysis across 42 rat strains, and between rats and humans. We demonstrate strong linkage between blood pressure, LV mass, in vivo insulin action and the congenic regions of SHR chromosomes 12 and 16, and show significant enrichment for genes associated in human GWAS with insulin action in the regions of the human genome that are syntenic to these rat congenic regions.The aims of the present study were to pursue the linkages to hypertension and insulin-related metabolic traits on SHR chromosomes 12 and 16 by generating and characterising new SHR congenic lines and testing candidate genes by analysis of gene expression and Fig. S1A-C). SHR.W12 energy expenditure and food intake was lower than in SHR , while the other congenics had similar energy expenditure and food intake to SHR. Circulating leptin levels were similar across strains .Body masses across congenic strains were similar, except for SHR.W16, which, on average, weighed 14 g less than SHR . WKY ratKITT) to assess each strain's ability to remove blood glucose in response to insulin   A,B. WKY than SHR B. KITT ithan SHR B.Fig. 2P>0.05). We found no significant differences in skeletal muscle triglyceride content; although SHR.W4 and SHR.W12 tended towards WKY levels .The triglyceride content of the liver was not significantly different across parental and congenic strains, although WKY and SHR.W16 tended to be lower than SHR, SHR.W4 and SHR.W12  was significantly lower than in SHR .Relative LV mass in WKY, SHR.W12 and SHR.W16  and SHR.W12 significantly lower (−20 bpm) heart rate than SHR . Heart rP<0.05).We used 2-lead ECG to detect alterations in ventricular polarisation related to cardiac hypertrophy. WKY had significantly shorter corrected QT interval (QTc-B), QT dispersion (QTD) and ST interval (ST-I) than SHR . SHR.W12cis-eQTLs or to have gene expression that correlated across the BXH/HXB recombinant inbred strain panel, in one or more tissues, with hypertension or insulin resistance-related traits. We selected 14 of these 64 genes that showed a QTT correlation in adrenal, kidney or left ventricle, related to hypertension; or showed a QTT correlation in fat, liver or skeletal muscle related to whole-body glucose homeostasis or tissue-specific metabolic phenotypes, for differential expression analysis in the relevant tissue, between the SHR, WKY and the chromosome 12 and 16 congenic strains (data not shown). Four genes – three on chromosome 12 and one on chromosome 16 – showed differential expression between SHR and WKY, and in addition showed similar expression between the relevant congenic strain and WKY, indicating cis-regulated control of gene expression from within the congenic segment (Thirty-two genes within the chromosome 12 congenic region and 32 genes in the chromosome 16 congenic region were found from previous expression quantitative trait locus (eQTL) and quantitative trait transcript (QTT) data  to be ei segment .Table 3Zkscan5 (zinc finger with KRAB and SCAN domains 5), a transcript inversely correlated with systolic blood pressure in the kidney, was 1.25-fold lower in abundance in kidney tissue in SHR.W12 and WKY compared with SHR (Table S4). Two transcripts, adrenal ubiquitin-specific peptidase 42 (Usp42) and hepatic heat shock protein β1 Hspb1 (inversely correlated to adipocyte volume), were elevated in SHR.W12 and WKY  compared with SHR (Table S4).Pdgfrl), which correlates with ‘delta captopril effects’ in the left ventricle, was differently expressed in SHR.W16 and WKY compared with SHR; WKY expression was reduced, whereas in SHR.W16, expression was increased. However, expression of Pdgfrl in adipose tissue was more closely matched in SHR.W16 to WKY  than to SHR (Table S4).On chromosome 16, platelet-derived growth factor receptor-like , for those SNVs with P<0.01 .In order to identify deleterious single-nucleotide variants (SNVs) present in the SHR congenic regions on chromosomes 12 and 16 (and absent in WKY), that were associated with insulin resistance, hypertension and LV hypertrophy, we used the PLINK tool  to integP<1×10−4 were considered most likely to affect the phenotypes of interest in SHR, causing a predicted deleterious amino acid substitution .To investigate whether the chromosomal segments of the human genome that are syntenic to rat chromosome 12 and 16 congenic regions contain genes identified as human GWAS hits for relevant cardio-metabolic traits  we mined the syntenic regions in the human genome for reported GWAS hits (Table S5). This represents a significant enrichment for GWAS hits in these chromosomal regions  (SLC12A9 (chromosome 12), CACNA1D and CSMD1 (chromosome 16), were associated with both blood pressure and insulin resistance-related metabolic traits (Table S5).GWAS hits associated with blood pressure were identified in two genes in the chromosome 12 congenic strain synteny regions and two genes in the chromosome 16 congenic strain. GWAS hits for LV mass were not identified in the chromosome 12 synteny regions but were identified in two genes in the chromosome 16 synteny region, one of these also being associated with blood pressure. Syntenic segments of neither region were significantly enriched for genes or GWAS hits for blood pressure-related traits, but the syntenic regions of the chromosome 16 region were significantly enriched for GWAS hit genes for left ventricular (LV) mass (.7×10−4) . Three gHypertension and insulin resistance frequently co-occur in the same individual. Pathologically increased blood pressure leads to increased myocardial load, while insulin resistance affects myocardial metabolism and vascular reactivity, leading to compensatory LV hypertrophy and failure .Cd36, a fatty acid translocase, as the gene underlying both insulin sensitivity and blood pressure QTLs on SHR chromosome 4  has been the most studied and is involved in numerous cellular processes, including protection from oxidative stress  contain SNVs that were significantly associated across 42 rat strains with both hypertension and insulin resistance. Deltex 2 E3 ubiquitin ligase (Dtx2), acts as a negative regulator of Notch signals in mature T-cells , is a minor component in the asymmetric unit membrane of the urothelium  and Upk3icardium . Howeverblastoma .Our human-rat comparative analysis of the chromosome 12 and 16 congenic segments indicated a significant enrichment for insulin resistance-related GWAS hit genes on the regions syntenic to both congenic segments, with 5 and 10 GWAS hit genes for these traits within the syntenic regions to the chromosome 12 and 16 congenic segments, respectively. We also found an enrichment, although less significant, for GWAS hit genes for cardiac hypertrophy in the regions syntenic to the chromosome 16 congenic strain.SLC2A9, CACNA1D and CSMD1), one in the chromosome 12 and two in the chromosome 16 synteny groups, harboured SNPs significantly associated with both blood pressure and insulin resistance/type 2 diabetes in humans. SLC2A9 encodes an electroneutral inorganic cation-chloride co-transporter whose function has yet to be fully established  has unknown function; however, one study in the rat showed downregulation of neuregulin receptor signalling in the transition from hypertrophy to failure in rats , our study, of congenic strains on chromosomes 12 and 16, was carried out in linkage regions to adipocyte insulin resistance that we had defined previously. Sedova carried out a limited appraisal of SNVs between the two parental strains in the chromosome 16 congenic region. Our study may have more plausibility, as it drew upon extensive gene expression and QTT data, as well as linkage disequilibrium data across 42 rat strains, to filter and select candidate genes within the congenic regions.Our study provides a complementary view to a recently published study by The genes and mechanisms underlying hypertension and insulin resistance, in humans and rats, are yet to be fully elucidated. Here, we combined genetic, physiological and comparative genomic analyses to define chromosomal regions underlying SHR blood pressure, insulin sensitivity and left ventricular mass, identifying candidate genes and finding human orthologues of rat genes in these regions that associate with these traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.Cd36 was generated for comparative purposes. Microsatellite marker analysis was carried out at each backcross (Tables S2 and S3), and progeny heterozygous for relevant congenic segments with the lowest proportion of WKY background genotypes were selected as breeders. Once all background microsatellites were confirmed as homozygous SHR, each of the chromosome 4, 12 and 16 lines were intercrossed. Offspring that were homozygous for WKY in the congenic interval (using microsatellites in Table S3) were brother-sister mated to fix the congenic interval. The lines were designated SHR.W4-(D4rat143-D4rat10)/Tja (SHR.W4), containing a congenic segment of 24.2 Mb; SHR.W12-(D12rat1-D12mit3)/Tja (SHR.W12), containing a congenic segment of 28.6 Mb; and SHR.W16-(D16rat88-D16rat15)/Tja (SHR.W16), containing a congenic segment of 79.2 Mb. All animals were maintained under 12 h:12 h light-dark cycle with free access to food and water. Experimental procedures were approved by the UK Home Office under the Animals (Scientific) Procedures Act 1986.Congenic lines containing regions of WKY chromosomes 12 and 16 on an SHR background were constructed with a speed congenic approach using SHR/NCrl as recipient genome and WKY/NCrl  as donor genome . A chrom−1 h−1) (n=6 per group) was measured by ELISA .Indirect calorimetry, food intake and activity were assessed using the Oxymax Lab Animal Monitoring System  for 72 h  with free access to water and chow. Energy expenditure was calculated according to McLean and Tobin  . Serum l−1, previously used to reliably assess whole-body response to insulin  was calculated from the log(glucose) disappearance curve 5-30 min  was measured by glucometer , in venous blood drawn from the tail vein of overnight-fasted rats with free access to water, 5-30 min following an intravenous insulin bolus, according to  insulin . Rats we insulin , 1993. B5-30 min A as 0.69t1/2×100 .n=4 per group) according to manufacturer's instructions and analysed using the Triglyceride Quantification Kit .Lipid was extracted from liver and soleus muscle  and presented as mean values over this time period. Rate pressure product was calculated as systolic blood pressure×heart rate×10−2 . Blood pressure, heart rate and QT interval were measured for 5 min hate×10−2 . Bazett'0−2  with sequences verified for absence of single nucleotide polymorphisms using SHR and WKY whole-genome sequences and the Integrated Genomics Viewer (http://www.broadinstitute.org/igv/). qPCR was carried out on the 7900HT Fast Real-Time PCR System (Thermo Fisher Scientific). CT values were analysed using the 2−ΔΔCT method normalising to β-actin gene, with SHR used to compare strains.We used two approaches to identify candidate genes for the SHR traits investigated in this study: first, we used previously generated eQTL  and quanhttp://rgd.mcw.edu/wg/phenotype-data13). We then generated .map and .ped input files for the PLINK program from a .vcf file containing all SNVs of the 42 strains (http://www.ensembl.org/info/docs/tools/vep/script/index.html).Second, we used PLINK to rank SHR SNVs within the congenic intervals on chromosome 12 and 16, with the closest relationship to each trait of interest , allowing us to compare deleterious SNVs present in SHR and absent in WKY . We obta strains . The oriThe VEP analysis was based on rat genome assembly Rn0r_5.0 and Ensembl release 78 annotations. The PLINK analysis was performed as standard case/control association analysis. We used the additional PLINK options ‘–assoc’ and ‘−allow-no-sex’.P=5×10−7) using the NHGRI-EBI GWAS catalogue (https://www.ebi.ac.uk/gwas/) connected to the following search terms: blood pressure, blood pressure (age interaction), blood pressure (anthropomorphic measures interaction), blood pressure (smoking interaction), blood pressure measurement (cold pressor test), blood pressure measurement (high sodium and potassium intervention), blood pressure measurement (high sodium intervention), blood pressure measurement (low sodium intervention), blood pressure response to hydrochlorothiazide in hypertension, blood pressure variability, cardiac hypertrophy, cardiac muscle measurement, cardiac repolarisation, cardiac structure and function, cardiovascular disease risk factors, cardiovascular heart disease in diabetics, diabetes-related insulin traits, diastolic blood pressure, diastolic blood pressure , fasting glucose-related traits, fasting glucose-related traits (interaction with BMI), fasting insulin-related traits, fasting insulin-related traits (interaction with BMI), fasting plasma glucose, heart rate, hypertension, hypertension (young onset), insulin-related traits, left ventricular mass, QT interval, systolic blood pressure, systolic blood pressure  and type 2 diabetes.Using the Virtual Comparative Map (VCMap), we located regions of the human genome orthologous to the chromosome 12 and 16 congenic intervals . With thTo test whether the congenic regions were enriched for orthologues to cardio-metabolic GWAS hits in humans, we used the above GWAS search results and information gathered from Ensembl, to establish the total number of genes within and outside the congenic regions.P-values in the PLINK analysis were considered significant with a nominal P-value <1×10−4. SNV and GWAS enrichment analyses were performed by chi-squared analysis. Values are expressed as mean±95% confidence intervals (CI), with values of P<0.05 considered significant.Data were analysed using Minitab 17 . All physiological and qPCR data were analysed by one-way ANOVA followed by Fisher's least significant difference test.


Background. To assess whether the visit-to-visit variability in blood pressure (BP) is a risk factor of peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM) 10 years after diagnosis. Methods. The electronic medical records of 825 patients, who were diagnosed with type 2 diabetes mellitus (T2DM) during 2000–2002 and regularly followed for 10 years, were retrospectively reviewed. A total of 53,284 clinic visit records, including analysis of BP, BMI, serum glycohemoglobin, and lipid profile, were analyzed. Results. Patients were categorized into two groups according to their visit-to-visit variability in systolic and diastolic BP . The high-risk group included patients with high SBP and DBP visit-to-visit variability; this group had a 1.679-fold  increased risk of PAD compared with patients in the low-risk group. Cox regression analysis also demonstrated that the age at which the patients were diagnosed with T2DM, smoking status, and mean creatinine level was significantly associated with increased risk of PAD with a hazard ration of 1.064 , 1.803 , and 1.208 , respectively. Conclusions. High SBP and DBP visit-to-visit variability is correlated with PAD in the first decade following a diagnosis of T2DM. In patients with diabetes mellitus, peripheral arterial disease (PAD) is a major risk factor for lower-extremity amputation . HoweverIdentifying the biomarkers for PAD is important for development of prevention modalities in diabetic patients, especially given that the 5-year cardiovascular event rate, including nonfatal myocardial infarction (MI) and stroke, for PAD patients with T2DM was 20% and the mortality rate was 30% . MoreoveA diagnosis of PAD can identify patients who have higher risk of subsequent MI or stroke, and treating hypertension in PAD patients reduces the risk of MI, stroke, heart failure, and death . DiagnosAlthough mean BP values are largely considered the cause of the adverse cardiovascular consequences associated with hypertension, the possible role of increased BP variability has also been reported in observational studies and clinical trials –17. SpecThe association between BP visit-to-visit variability and cardiovascular events generally considers BP measurements at a few time points and in a short to medium follow-up period, limiting the appreciation of the full impact of BP variability on PAD, especially for diabetic patients. Therefore, we evaluated the long-term relationship between BP visit-to-visit variability and the occurrence of PAD in patients from the beginning of their diagnosis with type 2 DM (T2DM).We retrospectively collected the following 10-year measurements obtained at every outpatient clinic visit of 825 patients who were first diagnosed with T2DM during 2000–2002 at Chang Gung Memorial Hospital, Keelung: blood pressure, body weight, body height, and laboratory data. T2DM was diagnosed in accordance with the criteria of the American Diabetes Association . Body maThis study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital; informed consent was waived.1c was assayed using high-performance liquid chromatography and expressed with the unit defined by the National Glycohemoglobin Standardization Program.BP measurements at every visit were recorded throughout the follow-up period till PAD was diagnosed. All outpatient clinics used automated sphygmomanometers operated by trained medical assistants after 10–15 minutes resting, with repeated measurements performed as needed by physicians using aneroid sphygmomanometers . FastingBP visit-to-visit variability and the coefficient of variation (standard deviation (SD) of mean BP divided by mean BP) of SBP and DBP were determined . The BP 1c, total cholesterol, triglyceride, smoking status, presence of CVD, hypertension, and dyslipidemia. All continuous variables are presented as the mean ± SD or absolute number. A P value < 0.05 was considered statistically significant. The area under each receiver operating curve and 95% confidence intervals (CI) were estimated to compare the relative ability of the SD of SBP and DBP to identify risk of peripheral arterial disease in diabetic patients. The optimal cut-point BP was calculated based on the Youden Index [Means and frequencies of potential confounding variables were calculated. The relationships between variability in SBP and DBP, as well as other variables, and PAD were examined by Pearson's correlation analyses. To examine the effects of various factors on the occurrence of PAD, the following factors were considered simultaneously as independent variables for Cox multiple regression analysis: age at DM diagnosis, sex, BMI, average SBP and DBP, SD of SBP and DBP, maximum of SBP and DBP, delta SBP, delta DBP, hemoglobin Aen Index , which wen Index . Multicoen Index , 33. Theen Index , 33.Nine hundred and thirty-six patients were first diagnosed with DM at Chang Gung Memorial Hospital from 2000 to 2002. Sixty-nine patients who died or were lost to follow-up were excluded. Twenty-three patients without final ABI data and 19 patients who had PAD or CVD before their DM diagnosis were also excluded. The characteristics of the 825 patients enrolled in this study are shown in P = 0.037; P < 0.001, HR = 1.064, 95% CI = 1.043–1.084). In addition, the occurrence of PAD was associated with mean creatinine level (P = 0.012) and current smoking status (P = 0.009). However, mean or SD of hemoglobin A1c, BMI, total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride were not independently correlated with the occurrence of PAD  were placed in the high-risk group, and all the other patients (n = 626) were in the low-risk group. The multicollinearity was assessed between VVV grouping and mean, SD, maximum, and delta of SBP and DBP. The VIFs of all these factors were less than 2 .We next categorized the patients into high- or low-risk groups on the basis of their SD of SBP or DBP. Cut-off points for the SD of SBP and DBP, where the sensitivity approximates specificity for the occurrence of PAD, are 16.3 and 7.6 mmHg, respectively. Patients with SD of SBP and DBP higher than the cut-off values .In the 10 years following their DM diagnosis, 50 patients (25.1%) in the high-risk group had PAD versus 64 patients (10.2%) in the low-risk group . Current smoking status and elevation of mean creatinine level was also associated with increased risk of PAD  than those with sustained hypertension participants [Office BP as the measurement of variability of BP may be limited due to white coat hypertension although this issue is controversial. A meta-analysis that included 7961 untreated participants reported that the cardiovascular risk was not significantly different between white coat hypertension and normotension . Anothericipants . Thus, wThe retrospective nature of the present study and its sample size are two of the limitations of the present study. The possibility of type 2 error exists. Another limitation is the medication record through the 10-year follow-up period. Antihypertensive drug use in each patient was not consistent throughout the 10-year follow-up period. Thus, it is very difficult to clarify the effect of BP visit-to-visit variability amelioration by each category of antihypertensive drug, such as calcium channel blockers, which had a controversial effect on blunting the amplitude of BP visit-to-visit variability . The othDespite the aforementioned limitations, this study has several strengths, including the long follow-up period to assess the occurrence of PAD and the available information on demographic, clinical, and long-term BP data. In addition, the use of an electronic medical record database provided real-world evidence on the status of hypertension control in the first decade following a diabetes diagnosis and minimizes selection bias related to self-selection into the study. Prospective studies are in need in verifying the high variability of SBP visit-to-visit as early biomarker for detection of PAD in the first decade following the diagnosis of T2DM. More research is needed to fully understand the association between BP visit-to-visit variability and risk of vascular events in diabetic patients, and large-scale pooled analyses of multiple cohorts will be required .The present study showed that, in diabetic patients with initially normal ABI values, high BP visit-to-visit variability was a significant early biomarker for detection of PAD in the first decade following the diagnosis of T2DM.


Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care.This study was a parallel randomised controlled trial done in 142 general practices in the UK, and included hypertensive patients older than 35 years, with blood pressure higher than 140/90 mm Hg, who were willing to self-monitor their blood pressure. Patients were randomly assigned (1:1:1) to self-monitoring blood pressure (self-montoring group), to self-monitoring blood pressure with telemonitoring (telemonitoring group), or to usual care . Randomisation was by a secure web-based system. Neither participants nor investigators were masked to group assignment. The primary outcome was clinic measured systolic blood pressure at 12 months from randomisation. Primary analysis was of available cases. The trial is registered with ISRCTN, number ISRCTN 83571366.vs usual care, 140·4 [16·5]; adjusted mean differences vs usual care: self-monitoring alone, −3·5 mm Hg [95% CI −5·8 to −1·2]; telemonitoring, −4·7 mm Hg [–7·0 to −2·4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference −1·2 mm Hg [95% CI −3·5 to 1·2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups.1182 participants were randomly assigned to the self-monitoring group (n=395), the telemonitoring group (n=393), or the usual care group (n=394), of whom 1003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care , Professorship to RJM (NIHR-RP-R2-12-015), Oxford Collaboration for Leadership in Applied Health Research and Care, and Omron Healthcare UK. Hypertension is a leading risk factor for cardiovascular disease, the greatest cause of morbidity and mortality internationally.7vs clinic 140/90 mm Hg) but only followed up patients for 6 months.Self-monitoring as part of a self-management strategy is an effective way to improve blood pressure control, but is only applicable to those willing to self-titrate.Evidence before this studyWe updated our systematic reviews from inception to Jan 2, 2018, in MEDLINE, Embase, and the Cochrane Library with search terms designed to capture all trials using self-monitoring of blood pressure, with or without telemonitoring, to guide the titration of antihypertensive treatment without other co-interventions. Search terms included ambulatory blood pressure monitoring, home or self monitoring, telemedicine, and randomised controlled trials, and we had no language restrictions. We found three trials that fulfilled these criteria, one of which used telemonitoring. Two trials  found that when clinicians used home readings to titrate treatment, this led to worse blood pressure control and less treatment after 1 year as compared with using clinic readings. Identical treatment targets were used for both home and clinic blood pressures. A third trial  used a telemonitoring-based service to capture home readings and guide treatment compared with usual care, both using guideline recommended targets which were lower for home readings. The telemonitoring, home titration group had lower blood pressure than clinic-based care after 6 months.Added value of this studyTo the best of our knowledge, this is the first trial in primary care of antihypertensive titration using self-monitored blood pressure, with or without telemonitoring, to show a benefit in terms of blood pressure after 12 months. Differences in blood pressure recorded at 6 months were amplified by 1 year suggesting that the intervention increased in efficacy in the second 6 months. This was achieved without increased workload and using internationally recommended targets for home and clinic blood pressure, the former lower by 5/5 mm Hg. Additional benefit from telemonitoring was seen in terms of lower blood pressure after 6 months suggesting more efficient titration.Implications of all the available evidenceThis study provides good evidence that self-monitoring can be used, with or without telemonitoring, to guide antihypertensive titration in a primary-care setting for people with poorly controlled blood pressure, provided that lower targets are used for home measurements. The decision to use telemonitoring will depend on whether the additional benefits in terms of speed of titration and ease of use are considered worthwhile. The reductions in blood pressure observed would be expected to reduce stroke risk by around 20% and coronary heart disease risk by about 10%. Self-monitoring can be recommended for the ongoing management of hypertension in primary care in all patients who wish to use it, and general practitioners should incorporate self-monitored readings into their titration of blood pressure medications.Current UK hypertension guidelines reflect the uncertainty in the literature by recommending self-monitoring of blood pressure as one option for the diagnosis of hypertension, but only for longer term management in the context of white coat hypertension.This was an unmasked randomised controlled trial with automated ascertainment of the end point. Detailed methods have been published previously.Potentially eligible participants were identified using automated searches of electronic primary care patient records in practices in England, UK. The searches identified individuals potentially eligible in terms of age, hypertension diagnosis, current medication, and last recorded systolic blood pressure above 145 mm Hg. Inclusion criteria were age older than 35 years, with a diagnosis of hypertension, taking no more than three antihypertensive agents, but with clinic blood pressure not controlled below 140/90 mm Hg. They had to be on stable antihypertensive medication for at least 4 weeks before randomisation and free from orthostatic hypotension, atrial fibrillation, dementia, or chronic kidney disease of grade 4 or worse, or chronic kidney disease with proteinuria.A trial steering group and data monitoring committee supervised the trial. Ethical approval was gained from Oxford NHS Research Ethics Committee B (14/SC/0218). All patients gave written informed consent.Potentially eligible patients were invited to research clinics held in their own general practices between Nov 13, 2014, and Feb 3, 2016 where they were screened for eligibility, informed consent taken, baseline measurements taken, and questionnaires administered. Eligible and willing participants were randomly assigned (1:1:1), using a secure web-based system, to GP antihypertensive titration using clinic readings , using self-monitoring alone (self-monitoring group), or using self-monitoring with telemonitoring (telemonitoring group), with stratification by practice and minimisation on baseline blood pressure, sex, and blood pressure target.Neither participants nor investigators were masked to group assignment in this open trial. Outcome measurement was not masked but used the automatic mode of the sphygmomanometer to measure blood pressure without the need for intervention by the investigator other than to place the cuff and switch the device on.Following randomisation, all participants were asked to attend their own GP for a medication review. Participants randomly assigned to usual care were thereafter managed with titration of antihypertensive treatment based on clinic blood pressure measurements at the discretion of their attending health-care professional.Participants randomly assigned to self-monitoring were taught to use a validated automated electronic sphygmomanometer .18For those self-monitoring alone, a simple colour chart was used to train participants to attend their practice for blood pressure checks in the light of very high or very low readings. At the end of each monitoring week they were asked to record their readings on paper and send them for review to their practice in a reply-paid envelope. Participants in the telemonitoring group were trained to send readings via a simple free SMS text-based telemonitoring service with web-based data entry back-up. The telemonitoring system incorporated an algorithm that alerted participants to contact their surgery in the light of very high or very low readings, reminded them if insufficient readings were transmitted, prompted them to make contact with their practice if their average blood pressure was above target, and presented readings to attending clinicians via a web interface . This seAttending clinicians were asked to review both self-monitoring and telemonitoring groups' readings on a monthly basis and usual care patients as often as they wished. Blood pressure targets were based on current National Guidelines adjusted for self-monitoring: lower than 140/90 mm Hg (<135/85 mm Hg at home) for those younger than 80 years, lower than 150/90 mm Hg (<145/85 mm Hg at home) for those 80 years or older, and lower than 140/80 mm Hg (<135/75 mm Hg at home) for those with diabetes.The primary outcome was clinic measured systolic blood pressure, adjusted for baseline covariates at 12 months. Blood pressure was measured by a research nurse using a validated monitor, six times at baseline and each follow-up appointment in a standardised fashion, using the same arm and cuff size each time, in a seated position after at least 5 min rest.Other outcomes included other measures of blood pressure at 6 and 12 months , adverse events ,It was estimated that 1110 patients  would be required to detect a 5 mm Hg systolic blood pressure difference between the groups with 90% power and an adjusted alpha of 0·017 (two-sided) to account for all three pairwise comparisons. This calculation was based on an assumption of a common SD of 17 mm Hg and a three-way pairwise comparison.Analysis was done following database lock on an intention-to-treat basis fitting a linear mixed-effects model, which modelled outcome data collected at 6 and 12 months from randomisation, adjusting for baseline blood pressure measure. Practices and measurements from the same participant were accounted for by means of random intercepts. Time  and randomised group were fitted as fixed effects, with minimisation variables (sex and blood pressure target), and history of cardiovascular disease fitted as covariates. An interaction term between time and randomisation group was included so that the treatment effect could be assessed at each timepoint. The self-monitoring and telemonitoring groups were first compared with usual care and then with each other since both were found more effective than usual care.The continuous secondary outcomes were analysed by means of a linear mixed-effects model using the same strategy as for the primary outcome. Binary outcomes for symptoms were analysed by means of a logistic mixed-effects model and group differences presented as adjusted odds ratios (ORs) with 95% CIs. Random effects were used to account for repeated measurements and practice. Smoking was analysed using a log-binomial model and group differences presented as adjusted relative risks (RRs), accounting for baseline smoking, with 95% CIs.Sensitivity analyses examined the robustness of the results using different approaches to obtaining mean blood pressure, replacing missing values with other available blood pressure measures, or through multiple imputation.Two amendments to the protocol were approved during the trial: first to clarify the safety reporting requirements and second to clarify that National Institute for Health and Care Excellence (NICE) guidance for self-monitoring of blood pressure, which had been operationalised from the start of the trial, was being followed in both intervention groups. Analysis was done using STATA version 14.2. The trial is registered with ISRCTN, number ISRCTN 83571366.The funders and sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication. The corresponding author (RJM) together with LMY, AN, and SM had full access to all the data in the study. RJM had final responsibility for the decision to submit for publication.Of 2383 individuals assessed for eligibility in 142 practices, 1201 (50%) were excluded: 1196 (50%) did not meet the inclusion criteria and five (<1%) withheld their consent . The maiThe groups were well matched : mean agvs 348 [88%] in the usual care group, p=0·1119 for comparison; Primary outcome data were available from 1003 (85%) participants and retention was not significantly lower in the intervention groups  were excluded, and where multiple imputation was used to replace missing values .After 6 months, mean systolic blood pressure in the group titrated using telemonitoring (139·0 [SD 16·8] mm Hg) but not the self-monitoring group (140·4 [15·7] mm Hg) was significantly lower than usual care (142·5 mm Hg [15·4]): telemonitoring, AMD −3·7 mm Hg (95% CI −5·9 to −1·5), p=0·0012; and self-monitoring, −2·1 mm Hg (−4·3 to 0·1), p=0·0584 . There wThere was no evidence of an effect of prespecified subgroups on the difference between treatment groups. Some of the comparisons had wide CIs reflecting relatively few individuals in some of the groups .Figure 2After 12 months, individuals for whom self-monitoring and telemonitoring was used to titrate their antihypertensives were prescribed additional medications compared with usual care : an AMD of 0·11 (95% CI 0·02 to 0·19) more medications in the self-monitoring group (p=0·0129) and 0·13 (0·04 to 0·21) more medications in the telemonitoring group (p=0·0038), both compared with usual care . Definedvs usual care, AMD −0·05 [95% CI −0·27 to 0·17], p=0·6619; telemonitoring vs usual care, AMD 0·02 [–0·20 to 0·25], p=0·8334).No difference in self-reported adherence was recorded at 12 months between the three groups. MARS questionnaire scores were 23·8 (SD 1·9) in the self-monitoring group, 24·0 (1·5) in the telemonitoring group, and 23·9 (1·9) in the usual care group , perhaps reflecting increased withdrawal due to the self-monitoring intervention. Despite this, recruitment was slightly higher than planned and the numbers in all three study groups comfortably exceeded the 315 participants per group required in the prespecified power calculation.Overall, the trial followed-up 85% of those randomised but there were, albeit non-significantly, fewer seen at final follow-up in both intervention groups compared with control , but given that clinicians were asked to review intervention groups' blood pressure on a monthly basis, might have failed to capture additional workload associated with self-monitoring.We have recently published an individual patient data meta-analysis of self-monitoring in the control of blood pressure, and to our knowledge, this is the first study to directly compare GPs titrating antihypertensives using self-monitoring with or without telemonitoring, with usual care in hypertensive patients, using appropriately lower home targets and followed-up for 12 months.This work extends the evidence from McKinstry and colleaguesNo trial of self-monitoring to date has been powered for clinical events but blood pressure reduction is extremely well correlated with reduced morbidity and mortality.Telemonitoring reminded participants if they had not monitored sufficiently and prompted contact with their GP for out-of-range readings. Health-care professionals were provided with mean blood pressure  along with a graphical presentation of trends in blood pressure. This provision might be expected to be advantageous in situations where doctors feel overwhelmed by the quantities of data they are required to deal with on a daily basis. Whether such advantages over self-monitoring alone are clinically worthwhile will be informed by the economic analysis. The text-based telemonitoring system was simple and could be implemented in other health systems as it was not dependent on a particular mobile phone provider or clinical system. The feedback system could be adapted into a smartphone application and could be incorporated into clinical patient record systems. Furthermore, it might be expected to offer particular advantages to the working age population where telemonitoring might facilitate management and remote access to a physician.By contrast, self-monitoring alone is simple, can be accomplished with a cheap validated monitor, and produced similar results to telemonitoring, albeit with less effect at 6 months. However, although the evidence supports use, the logistical problems of sending back results by post, and manual data processing and recording of results, suggests that comprehensive implementation outside a research study might be challenging.Blood pressure self-monitoring is now commonplace in the UK and elsewhere and practised by at least 30% of people with hypertension.Titration of antihypertensive medication in primary care using self-monitoring, with or without telemonitoring, results in significantly lower blood pressure after 1 year and using telemonitoring leads to lower blood pressure after 6 months. Self-monitoring can be recommended for the ongoing management of hypertension in primary care in all patients who wish to use it, and will require provision of validated blood pressure monitors for home use, ideally with integrated telemonitoring systems. GPs should incorporate self-monitored readings into their titration of blood pressure medications.


To analyze the frequency of blood pressure documentation performed by nursing professionals in an emergency department. This is a cross-sectional, observational, descriptive, and analytical study, which included medical records of adult patients admitted to the observation ward of an emergency department, between March and May 2014. Data were obtained through a collection instrument divided into three parts: patient identification, triage data, and blood pressure documentation. For statistical analysis, Pearson’s correlation coefficient was used, with a significance level of α<0.05. One hundred fifty-seven records and 430 blood pressure measurements were analyzed with an average of three measurements per patient. Of these measures, 46.5% were abnormal. The mean time from admission to documentation of the first blood pressure measurement was 2.5 minutes, with 42 minutes between subsequent measures. There is no correlation between the systolic blood pressure values and the mean time interval between blood pressure documentations: 0.173 (p=0.031). The present study found no correlation between frequency of blood pressure documentation and blood pressure values. The frequency of blood pressure documentation increased according to the severity of the patient and decreased during the length of stay in the emergency department. Furthermore, the assessment of vital signs is frequently made by professionals who may not always understand the importance of this task, or have many different educational background or work experience.So far, the literature has no protocol available that determines the frequency of checking vital signs at the ED. Since 2007, the National Institute for Health and Clinical Excellence has published hospital clinical protocols for severely ill patients, and considers that monitoring of physiological parameters and early warning systems help healthcare professionals identify patients at risk of clinical deterioration.1These protocols also take into account that vital signs  should be recorded at the initial assessment and, at least, every 12 hours, and that the frequency of monitoring should increase if changes in any physiological parameter are detected.7 The ESI has been used in different countries and has shown a significant association between the categories of risk classification and the outcome of the patient at the ED.9 The identification of physiological changes during the ESI classification may predict the risk of clinical deterioration and the presence of severe illness.10The Emergency Severity Index (ESI) is an important triage tool, which provides patient’s risk classification according to their clinical condition and hospital resource.12Although the BP measurement is one of the most frequently performed procedures in the clinical practice, the documentation and interpretation of its values as a decision-making tool is still not enough to ensure patient’s safety.This study aimed to analyze the frequency of blood pressure documentation performed by nursing professionals in an emergency department.This is a cross-sectional, observational, descriptive and analytical study, conducted at the ED of a private hospital, located in the city of São Paulo, Brazil. In 2015, it was estimated that 130 thousand visits were made to this ED and 40 thousand patients were hospitalized by the specialties of Cardiology, Internal Medicine, Orthopedics, General Surgery, and Gynecology.® .The ED observation wards were equipped with calibrated oscillometric BP devices, Infinity model, Delta series, manufactured by DrägerThe study included patient records of both sexes, aged over 18 years, who were admitted to the ED between March 5 and May 5, 2014. They were assessed by a nurse in triage and directed to an adult observation ward after evaluation by the clinician or Cardiologist. The sample calculation was not necessary, since all charts of patients admitted to the ED during the data collection were analyzed.The charts of psychiatric patients, patients with emotional disorders or psychomotor agitation were excluded, which could interfere in BP measurement and documentation. A total of 162 patient charts were analyzed and five were excluded due to lack of required information.Hospital Israelita Albert Einstein, under protocol number 1.105.180/2015, CAAE: 31962014.1.0000.0071.This study followed the national and international standards of ethics in research involving human subjects and the requirements of Resolution No. 466/2012. It was approved by the Research Ethics Committee of - Patient identification: the variables age, sex, time of admission, medical diagnosis/complaints, and medical resources used were analyzed.7- Triage data: ESI is a standardized risk classification based on the clinical conditions and on the need of hospital resources; it is made by a trained nurse, who assesses how long a patient can safely wait to be seen by a physician and treated. The ESI is a tool widely used in the United States and was validated by the Emergency Nurses Association and by the American College of Emergency Physicians. The physiological parameters were recorded by the nurse upon admission , and used as basis to classify the patient into one of five possible levels: level 1 indicates the most urgent category, who require immediate care; level 2 classify patients in a high-risk situation; level 3 takes into account possible changes in physiological parameters of the patient and the need to use two or more resources in the ED to define the diagnosis; level 4 and 5 classify patients as not or as those who require only one or no additional resources in the ED.To facilitate data organization and interpretation, it was assumed that patients classified as levels 1 and 2 were in a high risk situation; patients classified in level 3 were in a stable condition; and patients classified in levels 4 and 5 were not urgent.- Blood pressure documentation: it was defined as the number of BP measurements made by nursing staff during the patient’s stay at the ED. The BP measurements documented in the risk classification (triage) and during the length of stay of the patient in the observation wards were included.Patients were considered as in unstable hemodynamic conditions if the systolic blood pressure was ≤90mmHg or ≥180mmHg.®. To examine the relation between BP values and the frequency of BP measurements, Pearson’s correlation coefficient was used, with a significance level of α<0.05.Descriptive statistics were used to examine the study variables and were expressed as means and standard deviation (SD). Data were entered twice into an Excel worksheet and exported to the Statistical Package for the Social Sciences (SPSS), version 20.0A total of 157 patients were included in the study; in that, 83 (52.9) were female and 74 (47.1%) male. The mean age was 63 years (SD±20.8), range of 18 to 97 years. Most patients (96.2%) were assessed by a clinician, and 3.8% by a Cardiologist. The charts were classified according to the patient severity and the number of hospital resources used to define diagnosis; thus, 92 (58.6%) patients were in a high risk situation, 54 (34.4%) in a stable clinical condition, 2 (1.3%) in a less acute situation, and 9 (6%) charts did not have the triage level documented.A total of 156 (99.4%) patients had their BP within normal parameters, however, when analyzing these values separately, 26 (16.6%) patients were hemodynamically unstable and 47 (29.9%) had a BP ≥140/90mmHg. In other words, 46.5% of patients had abnormal BP values.The mean time from admission to first documentation of BP was 2.5 minutes, ranging from zero to 120 minutes.A total of 430 BP measurements were performed, with a mean of three measurements per patient, ranging from one to eight in a period of 23 hours. All 157 patients had their BP measured upon admission and the number of BP measurements decreased according to length of stay.During stay at the ED, an average of 2.9 BP measurements was performed in patients classified as at high risk, and 2.3 BP measurements in patients classified as being in a stable condition.The BP was measured at an average of every 42 minutes, ranging from 15 minutes to 15 hours. The number of BP measurements for each patient varied from one to eight, and the longest interval occurred between the fourth and fifth measurements.To examine the relation between BP values and the mean time interval between the BP measurements, a correlation analysis was performed. However, no correlation was found between systolic blood pressure and diastolic blood pressure values, considering the mean time interval between the BP measurements: r=0.173 (p=0.031), and r=0.116 (p=0.148), respectively.In the analysis of the BP documentation done by nursing professionals at the ED, there was no correlation between the systolic blood pressure/diastolic blood pressure values and the mean time interval between BP documentations.13 showed that most patients admitted to the ED were classified as in a less acute situation, a recent study conducted in Brazil14 reported 63.5% of patients evaluated in the ED were classified as urgent or very urgent.In this study, most patients admitted to the observation ward were classified as in a high risk situation or stable condition, which meant that a large percentage of patients were at risk of quick clinical deterioration, and required a strict control of vital signs. While international studies5 in the same way, few studies have been done to identify patients at risk of clinical deterioration, and how vital signs can be used to develop protocols to support nursing professionals in their clinical practice.16 The results of this study may contribute to recognizing nursing knowledge gaps on BP documentation and ensure safety of patient admitted to the ED.So far, there is a small number of studies on BP documentation at ED;5Unlike results reported in this article, a study carried out in the United States, in 2011, demonstrated there is a significant difference in the frequency of documenting BP measurements and the risk classification of the ESI. Patients classified as in a stable condition had the longest interval between BP measurements (167.5 minutes), if compared to those in a less acute situation (89.2 minutes).Moreover, the patients classified at high risk had their BP measured at intervals of 1 hour and 32 minutes, in average; while patients classified as in stable conditions and less acute situations had it measure at every, in average, 2 hours and 32 minutes, and 2 hours and 41 minutes, respectively. This fact can be associated with the patient risk of clinical deterioration, nursing judgment, and BP management in the ED.The differences between the frequencies of BP measurement at the ED suggest the need to implement standardized protocols to ensure knowledge of nursing professionals about the interpretation of vital signs. The reasons for this difference were beyond the scope of this project and deserve further investigation on the topic.2In this study, the mean BP values were within the normalcy parameters during the risk classification, but presented changes during the length of stay on the observation wards. Other studies conducted at an ED had similar results, and related these values to a wide variety of complaints, diagnoses, health conditions, and hospital management processes upon admission.19Recognizing changes in BP values, as well as the frequent BP measurement, are essential care activities for severe patients to assess treatment effects, detect procedural complications, and prevent severe adverse events, such as cardiopulmonary arrest, unplanned admission to intensive care unit and increased early mortality.20Although vital sign monitoring is one of the most commonly performed tasks at an ED, there is limited information regarding the optimal frequency to BP measurement. In general, BP measurement depends on hospital policy, nursing clinical judgment, physician’s orders, presumptive diagnosis and symptoms of the patient.21The literature shows that lack of accuracy in BP measurement, recording, and interpretation can be justified by excessive workload, difficulty in interpreting and recognizing changes in vital signs, and difficulties to make decisions about severe patients care.th Brazilian Hypertension Guidelines.22Some limitations of this study should be considered: inclusion of a small number of charts without randomized control, which limited the range of results; the study site did not allow comparison with other hospitals, since it is a private institution, with specific infrastructure and technological management system, which are superior to those of other healthcare organizations in Brazil; the investigator could not maintain neutral relation for being a nursing staff, and directly involved with medical records assessed; the indirect BP measurement was not evaluated regarding the stages validated by the 6The present study found no correlation between the systolic blood pressure or diastolic blood pressure values and the mean time interval between blood pressure documentations. Besides the frequency of blood pressure documentation increased according to patient severity and decreased during the patient’s length of stay at emergency departments. Considering the large number of patients with abnormal blood pressure values and the shortage of decision-making tools for nurses to manage these vital signs, it is suggested the development of blood pressure monitoring guidelines that can ensure the safety of patients admitted to emergency departments.


To characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF).We prospectively observed 1802 patients with CHF and left ventricular ejection fraction (LVEF) ≤45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode-specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year).A 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality , and non-cardiovascular mortality , but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations .Socioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non-cardiovascular events. The prevalence of chronic heart failure (CHF) continues to rise, due to both improving survival from its antecedents, such as ischaemic heart disease, and reducing mortality in patients with established CHF.We conducted a prospective cohort study, aiming to examine factors associated with outcome in 1802 unselected patients with CHF treated with ‘state of the art’ therapies, carried out in cardiology outpatient clinics of four UK hospitals between June 2006 and July 2014. All patients provided written informed consent to participate; the investigation complies with the principles of the Declaration of Helsinki. Patients were eligible for inclusion if they were ambulant outpatients with stable clinical signs and symptoms of CHF for 3 months, with an LV ejection fraction of ≤45% defined by transthoracic echocardiography. This LV ejection fraction cut-off was predefined, based on risk of adverse outcomes demonstrating a threshold effect at this level.All patients underwent resting 12-lead ECGs, and blood testing for measurement of full blood count, electrolytes and serum creatinine. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease method.Individual patient postal codes were used to define allocation to 1 of 32 482 geographical regions, each accounting for approximately 1500 people, for which the Index of Multiple Deprivation (IMD) defines local socioeconomic deprivation.Non-elective hospitalisation was assessed within 1 year after enrolment using recruiting hospital clinical event (Patient Administration System) databases detailing the nature and duration of admissions. Each hospitalisation was subclassified independently by two cardiologists as cardiovascular if the principal presenting complaint was related to cardiac, cerebrovascular or peripheral vascular disease; consensus was sought in all initial cases of disagreement. Heart failure (HF)-related admissions were further subclassified if the patient presented with symptoms and signs of HF and evidence of fluid overload requiring intravenous diuretic therapy for at least 24 hours. All patients were registered with the UK Office of Population Censuses and Surveys to provide details of death until the censoring date of 8 May 2016. Mode of death was subclassified, according to our published methods,2 tests. Zero-inflated Poisson regression analyses applying an offset of total days in study period were used to model the relationship between IMD score and the total number of days a patient was hospitalised, or the total number of hospitalisations, since the distribution of these outcome measures contained a large proportion of zeros. Calibration plots for these models, along with the rationale for their use, are presented in the online Data are presented as mean (SE of the mean) or percentage (number) for continuous and categorical variables, respectively. Continuous data are compared across IMD quintiles using analysis of variance for normal data, or Kruskal-Wallis tests where indicated as non-normal. Categorical data are compared across IMD quintiles using χ10.1136/heartjnl-2017-312539.supp1Within the cohort of 1802 patients, 13.8% were in IMD quintile 1 (least deprived), 20.7% in quintile 2, 16.2% in quintile 3, 19.3% in quintile 4 and 30% in quintile 5. Descriptive data comparing the demographics, comorbidity, severity and management of HF in these groups are outlined in No statistically significant differences were apparent in the proportion of each quintile hospitalised due to cardiovascular or HF-specific causes during the first year of follow-up . HoweverDuring a mean 4 years of follow-up, 737 deaths occurred, of which 399 were cardiovascular, 314 were non-cardiovascular and 24 were unclassifiable. Crude all-cause mortality was significantly different between IMD quintiles , with quUsing observations from a subcohort planned to undergo follow-up assessment approximately 1 year later , it is aOur study provides the most comprehensive available assessment of the association between socioeconomic deprivation and adverse outcomes in people with CHF, accompanied by important insights regarding potential underlying factors. While HF symptoms, short-term cardiac remodelling and provision of evidence-based medical therapy were comparable across quintiles of IMD, deprivation was associated with increased all-cause mortality and hospitalisation. Importantly, this risk was explained by increased non-cardiovascular mortality and hospitalisation, suggesting that adverse outcomes associated with deprivation are related to non-cardiovascular factors. Moreover, the increased cumulative duration of hospitalisations in the most deprived patients with CHF has important health economic implications. Overall, our observations provide circumstantial support for a causal link between deprivation and the burden of non-cardiovascular mortality and morbidity in people with CHF, raising the question of whether outcomes can be improved by non-cardiovascular and social interventions.et al have linked deprivation, measured by the Carstairs index (a census-based larger geographic area score than IMD), to the crude and adjusted risk of cardiac readmission in 478 patients with CHF recruited in the UK between 1993 and 1994.et al showed that living in a low-income area was associated with crude and adjusted all-cause rehospitalisation and mortality, in a large cohort recruited between 1987 and 2004 in the USA.Previous studies have broadly supported the link between socioeconomic deprivation, defined using a diverse range of indices, and rehospitalisation of patients with CHF.A recent large UK-based community CHF cohort study consistently showed no link between IMD quintile and risk of death in the years 2000–2007.In agreement with an earlier large community CHF study in the UK,Although we have not conducted formal health-economic analyses, our data suggest that deprivation is likely to be associated with substantial variation in the costs of caring for people with HF, which accounts for almost 2% of UK healthcare costs.It is important to acknowledge the inability of observational studies to define cause-effect relationships, although this design remains the most appropriate for studies of deprivation. While we are able to offer many insights into the wider health and treatment of our cohort, future studies would benefit from assessment of the community health and social support available to patients, along with defining whether delays in access to these might have impacted upon duration or frequency of hospitalisation. Unfortunately, we were only able to describe hospitalisation within the recruiting centres as no robust nationwide reporting system was available when this study began in 2006. This may underestimate hospitalisation across our cohort (or within specific groups), although most patients are admitted to their local (recruiting) hospital. Finally, the use of area-based indices of deprivation, such as IMD, cannot guarantee accurate designation of individual patient deprivation. However, alternative individual patient indices, such as income, may be less useful markers of deprivation in the older patient group we have followed.Our study has a number of key strengths, including the provision of much more detailed descriptive and outcome data than any prior publication addressing this issue. By defining the frequency and duration of hospitalisations, we provide the first quantification of the personal  burden of hospitalisation in patients with CHF according to their socioeconomic status. Moreover, we also provide the first assessment of how deprivation is linked with mode-specific mortality in patients with CHF. Furthermore, our assessment of changes in disease status, cardiac remodelling and treatment during follow-up allows us to support our suggestion that non-cardiovascular factors may underpin the adverse outcomes linked to deprivation. Finally, our study of unselected outpatients with stable CHF , receiving contemporary therapy, makes our findings of broader relevance to patients attending hospital cardiology clinics.We show that individual patient indices of socioeconomic deprivation are associated with all-cause mortality and the cumulative duration of all-cause hospitalisation in patients with CHF receiving contemporary therapy. However, this adverse risk profile is explained by an excess of non-cardiovascular mortality and hospitalisation, and was not associated with inequitable provision of evidence-based CHF treatment. Our data should prompt the design of clinical trials of non-cardiovascular and socioeconomic interventions in order to reduce the personal and economic burden of disease in patients with CHF and low socioeconomic status. It will also be important to define whether our findings are pertinent to patients with other chronic diseases.Socioeconomic deprivation is an important cause of healthcare-related inequalities, although conflicting data exist regarding its association with adverse outcomes in people with chronic heart failure.In spite of comparable provision of evidence-based heart failure therapy, socioeconomic deprivation was associated with an increased risk of all-cause mortality and hospitalisation. However, these were explained by an excess of non-cardiovascular events.Additional cardiovascular therapies are unlikely to address the adverse outcomes associated with socioeconomic deprivation in people with chronic heart failure; trials of socioeconomic and non-cardiovascular interventions are warranted.


Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.  •First prospective feasibility and safety clinical trial on unilateral CB resection for the treatment of high blood pressure.•In drug-resistant patients with hypertension, unilateral CB resection was feasible and safe.•Unilateral CB resection lowered blood pressure by 26 mm Hg in 57% of patients with drug-resistant hypertension associated with a reduction in muscle sympathetic nerve activity and its baroreceptor reflex control.•Whole drug equivalents were reduced in the responding patients.•Responding patients had characteristics distinct to those that did not respond; these should allow patient selection for future CB modulation trials. Found bilaterally at the bifurcation of the common carotid artery, the carotid bodies (CBs) are strategically located to ensure that adequate oxygen is supplied to the brain. With the highest blood flow per tissue weight of any organ In patients with hypertension, the CBs exhibit both hyper-reflexia and aberrant discharge; in sleep apnea, the activation of the CBs is, in part, responsible for the excessive sympathetic activity and hypertension associated with this condition ClinicalTrials.gov (NCT01745172 and NCT01729988). Informed consent was obtained from all patients.We present pooled results from 2 independent centers in which the primary endpoints were safety and feasibility of uCB excision in patients with drug-resistant hypertension. Secondary endpoints were to assess the proportion of patients showing reductions in ambulatory blood pressure (ABP) and MSNA. Inclusion criteria were: age between 18 to 75 years; taking ≥3 antihypertensive medications, including a diuretic agent, at maximal tolerated dose; no evidence of causes of secondary hypertension following thorough biochemical, clinical, and imaging assessment  and at 1, 3, 6, and 12 months post-CB resection. Following this clinical review, a blood sample (including a full blood count)  and 2 wa1.Adverse event reporting. Adverse events were reported as per local sponsor guidelines, in line with ICH Good Clinical Practice recommendations, and were collated by the independent Clinical Research Organisation monitoring the studies and reviewed by the Clinical Events Committee formed by Cibiem.2.HVR. The HVR was measured before and after uCB to assess any effect on chemoreflex sensitivity. Using an established poikilocapnic hypoxic protocol 2 for up to 10 to 30 s. The procedure was repeated 5 to 10 times to achieve a range of SpO2 from 100% to 75% while measuring respiratory frequency and tidal volume using spirometry . The HVR was calculated by assessing the largest 3 subsequent breaths during/following inhalation of 100% N2. Minute ventilation was plotted against the SpO2, and the slope of the regression reflects the HVR.3.Sleep studies. Sleep data were acquired using Embla Sleep Systems  and analyzed using REMlogic software (Embla Systems Inc.). Post-uCB resection, sleep studies were performed at 1 and 3 months for 11 patients and at 1 month only for the remaining patients. The sleep studies were scored by an independent single scoring specialist center using international guidelines from the American Academy of Sleep Medicine 4.Medications. Patients’ antihypertensive medicines were maintained at baseline values to minimize the effect of medication changes on BP after uCB unless there were strong clinical grounds for the management of symptomatic hypotension or other adverse events.am to 5:59 am; day: 6:00 am to 11:59 pm). The HBP (Omron 705IT) was averaged across the last 2 of 3 morning and 3 evening readings daily for 10 to 14 days; a medication diary was kept with HBP readings.OBP was taken in the sitting position using an automatic oscillometric monitor . BP was measured according to protocol-specified guidelines on the basis of the European Society of Hypertension recommendations During each study visit, continuous BP recordings were measured using a Finometer , which was calibrated to the BP measured in the same arm using an automated cuff, and a 3-lead electrocardiograph was used for continuous monitoring of heart rate; these recordings were used to calculate BRS. Multiunit MSNA was recorded by microneurography in the peroneal nerve at the fibular head Offline, MSNA was normalized to the amplitude of the largest burst in the recording and was represented as a percentage of this burst. For each cardiac cycle, the associated diastolic blood pressure (DBP) was determined and collected into 1-mm Hg bins. The peak, beginning, and end of every MSNA burst were marked in data acquisition software . The area of the burst was calculated as the integral of MSNA between the beginning and end of the burst (units of % · s). Each cardiac cycle was associated with the accompanying MSNA burst area (MSNA burst area = 0 AU if no burst occurred in that cycle). The lowest DBP in each cardiac cycle was recorded to the nearest mm Hg, and the MSNA burst area was correlated with the DBP of each cardiac cycle over the entire range of DBPs obtained in each subject. The spontaneous MSNA BRS was calculated using DBP and a similar calculation to that described previously The surgical removal of the CB was performed following the procedure described by Winter Resected tissue was fixed with 10% formalin, embedded in paraffin, sectioned (50- to 100-μm thick), and stained with hematoxylin and eosin. The presence of glomus cells and organ margins were checked and photomicrographs were taken.All analyses were conducted blind with respect to the sequence of visits and whether the patient was a BP responder or nonresponder (see the following text). All measurements of MSNA burst area and BRS were calculated by importing acquired data into MATLAB 8.0 , and statistical tests of these measures were conducted in Prism version 2.0 . Results are presented as mean ± SEM. A 2-sided probability value of p < 0.05 was considered statistically significant. Statistical comparisons of groups were assessed by 1-way analysis of variance (ANOVA) for parametric data or Kruskal-Wallis ANOVA on ranks for data that were not normally distributed. A 2-way ANOVA with Sidak (between groups) and Tukey (within groups) post hoc tests was conducted to compare data across and within groups at different follow-ups. Serial within-group comparisons were subjected to repeated measures ANOVA. All variables analyzed with ANOVA passed the D’Agostino & Pearson normality test and also Bartlett’s test for equal variance. All variables passed normality except for day ambulatory systolic blood pressure (ASBP), which was analyzed with Kruskal-Wallis test and expressed as median . Medications were calculated as a percentage of the maximal recommended dose for hypertension. For each patient, the whole drug equivalents  were calculated on the basis of doses quoted in the British National Formulary.There were 2 serious adverse events consisting of prolonged hospitalization of patients with BP that was difficult to control. One of the events occurred shortly after the CB removal procedure, and this event was judged by the Clinical Events Committee (CEC) to be “possibly related” to the unilateral removal of the CB. In the other patient, multiple hospitalizations occurred for BP control before and after uCB removal, and the hospitalizations bore no consistent temporal relationship to the CB removal. These hospitalizations were, therefore, judged by the CEC to be “unrelated” or “unlikely to be related” to the uCB.In 1 patient with pre-existing moderate obstructive sleep apnea (OSA), sleep-disordered breathing (SDB) worsened after uCB. This was not noted as an adverse event by the study site. The CEC felt, however, that given that SDB was a pre-existing disease in this patient and the apnea-hypopnea index increased from 20 events/h at baseline to 74 events/h 3 months post-carotid body removal, worsening SDB should be noted as an adverse event. The patient was treated with continuous positive airway pressure, and the apnea-hypopnea index decreased substantially. The adverse events and polysomnography are shown in 2) (Patients maintained their ventilatory response to hypoxia as the average baseline HVR (−0.4 ± 0.1 l/min/% SpO2)  was not 2) , and alt2) .On the basis of its visualization on computed tomography scans , a CB waThere was no significant change in either ASBP or OSBP at any time following uCB resection compared with the corresponding values at screening and baseline , Table 1We defined a responder as a participant with evidence of glomus cells in the resected tissue  and a ≥10-mm Hg drop in ABP at the 3-month follow-up visit to allow time for patient recovery and the resolution of adverse events. A nonresponder was defined as having evidence of glomus cells in the resected tissue, but did not show a ≥10-mm Hg fall in ambulatory BP at 3-month follow-up. On the basis of these definitions, there were 8 responders  who showed significant reductions in ASBP at 3 months and 6 nonresponders ; glomus Among responders, across all study time points, there was a significant difference in whole-dose equivalents (WDE) . There was also a trend toward reductions in both the number of medications (p = 0.06) and medication classes (p = 0.06). The were no changes in WDE (0.98), the number of medications (p = 0.15), or medication classes (p = 0.15), among nonresponders.Neither baseline MSNA burst frequency nor incidence differed between responders and nonresponders . FurtherIn responders, BRS improved as revealed by a decrease at 6-month , but not at 12-month follow-up  compared with baseline . There wBefore surgery and compared with nonresponders, responders had a higher hypoxic ventilatory response (p < 0.027) and faster ventilatory frequency (p < 0.025)  at baselThe present first-in-man, proof-of-principle study was concerned with investigating the safety and feasibility of unilateral surgical resection of CB as a therapy in patients with drug-resistant hypertension. We found that this procedure was safe as evidenced by an absence of persistent serious adverse events, maintenance of a ventilatory response to hypoxia, and with 1 exception, no major alteration in SDB. With the finding of glomus cells in resected tissue from 14 of 15 patients in our study, the feasibility of the surgical approach has been demonstrated.As recently reviewed, CB resection  has been performed historically for the treatment of dyspnea in patients with asthma and chronic obstructive pulmonary disease Across all patients, there were no changes in ABP or OBP after uCB resection. This was not surprising given that hypertension has a heterogeneous etiology and chemoreflex hyper-reflexia was reported in only a subset of patients with cardiovascular disease In the responders (but not the nonresponders), MSNA total activity was reduced over a similar time course to the ABP, indicating reduced vasomotor tone; this is consistent with data from hypertensive rats The elevated HVR and higher respiratory frequency in the responders versus nonresponders is supportive of aberrant hyper-reflexia and high CB drive, respectively. The elevated HVR is consistent with peripheral chemoreceptor hyper-reflexia in hypertension, as reported in animals As a first-in-man, safety and feasibility study, we did not include a control group. However, in the 1 patient in whom we found no evidence of glomus cells in the resected tissue, we failed to see a fall in BP. Notwithstanding the recruitment difficulties associated with a surgical intervention, we acknowledge that the absence of a control arm and the low number of patients are limitations of the present study. A percutaneous catheter-based approach to ablate the CB selectively may be better tolerated, for example.Although patients were fully assessed in specialist hypertension clinics before study entry, drug non-adherence cannot be ruled out. Notably, we fully adhered to the established drug adherence procedures at the time the study was initiated (see the Methods sections). There were no statistical differences between screening and baseline OSBP, which may partly overcome concerns regarding a Hawthorne effect and regression to the mean. Comparing total MSNA from the same patient at different times can be problematic, but we controlled for this by referencing to the largest burst in the neurogram.2S and CO The issue of why the CB develops hypersensitivity is unclear, but may include hypoperfusion as suggested in heart failure Turning to the nonresponders, there are several explanations for lack of BP improvement. Anatomical variations in the distribution of the CB may result in insufficient glomus tissue being resected. We acknowledge the heterogeneous etiology of hypertension and would not expect a BP response in individuals with nondysfunctional CBs or mechanisms unrelated to CB dysfunction. Even in patients with CB dysfunction, it may be that the contralateral CB predominates in driving up BP. We do not rule out stiffened arteries that are unable to regain compliance even with a reduction in sympathetic tone.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: CB modulation therapy could become a novel therapeutic strategy for treating hypertension in some individuals. It remains unclear whether there is a dominant  CB for BP control, but this could be established in future trials. Given the response rate indicated herein (8 of 15 patients), future studies need to devise protocols, which might include the HVR, to select those patients with aberrant CB activity, as these are predicted to respond to treatment.TRANSLATIONAL OUTLOOK 1: Although surgical resection was feasible, less invasive procedures need to be devised such as percutaneous ablation catheter technology; such an approach is ongoing, where an ablation catheter is advanced into the jugular vein and, using intravascular ultrasound, positioned precisely at the level of the bifurcation of the common carotid artery to ablate the CB.TRANSLATIONAL OUTLOOK 2: Reverse translation is needed to identify the molecular mechanisms that cause both the hyper-reflexia and tonicity of the CB in conditions of human hypertension; this would reveal further opportunities for CB modulation therapy.This is the first study that places CB hyper-reflexia in context of a disease state in humans and demonstrates the potential benefit of modifying that activity.


The diagnostic model was further constructed based on the metabolites to diagnose other CHF patients with satisfying sensitivity and specificity , validating the robustness of plasma metabolic profiling to diagnostic strategy. By comparison of the metabolic profiles, 9 biomarkers, 2-arachidonoylglycerophosphocholine, LysoPE 16:0, PS 21:0, LysoPE 20:4, LysoPE 18:0, linoleic acid, LysoPE 18:2, 4-hydroxybenzenesulfonic acid, and LysoPE 22:6, may be especially for the effect of CHM granules. A predicting model was attempted to construct and predict patient based on the related symptoms of CHF and the potential biomarkers regulated by CHM were explored.Chronic heart failure (CHF) is a major public health problem in huge population worldwide. The detailed understanding of CHF mechanism is still limited. Zheng (syndrome) is the criterion of diagnosis and therapeutic in Traditional Chinese Medicine (TCM). Syndrome prediction may be a better approach for understanding of CHF mechanism basis and its treatment. The authors studied disturbed metabolic biomarkers to construct a predicting mode to assess the diagnostic value of different syndrome of CHF and explore the Chinese herbal medicine (CHM) efficacy on CHF patients. A cohort of 110 patients from 11 independent centers was studied and all patients were divided into 3 groups according to TCM syndrome differentiation: group of Qi deficiency syndrome, group of Qi deficiency and Blood stasis syndrome, and group of Qi deficiency and Blood stasis and Water retention syndrome. Plasma metabolomic profiles were determined by UPLC-TOF/MS and analyzed by multivariate statistics. About 6 representative metabolites were highly possible to be associated with CHF, 4, 7, and 5 metabolites with Qi deficiency syndrome, Qi deficiency and Blood stasis syndrome, and Qi deficiency and Blood stasis and Water retention syndrome .This trial was registered with NCT01939236 ( Chronic heart failure (CHF), as a complex clinical syndrome, results from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood  in China between May 2010 and December 2014. During the same period, 54 normal healthy participants of matched age were included from medical center of Dongzhimen Hospital as controls.Diagnostic criteria of CHF: 2007 China Guideline for the Diagnosis and Treatment of CHF , which could be diagnosed by coronary computed tomography, coronary angiography, limb-salvage Q wave for electrocardiogram (ECG), history of acute myocardial infarction, ECG test, radionuclide examination support, etc. The included patients also had no history of taking antihypertensive drugs and exhibited a blood pressure under 160/100 mmHg or of hypertension. Following symptoms and signs were observed with a history of CHD: fatigue, difficulty breathing, fluid retention (edema), left ventricular enlargement, NYHA functional classification II or III, and end systolic volume of left ventricular increase and left ventricular ejection fraction (LVEF) < 40. All subjects between 40 and 75 years old; If there was a “No” answer for any issue, the subject could not enter into this research.Patients with one of the following diseases were excluded: (1) serious valvular heart disease; (2) cardiomyopathy; (3) pericardial disease; (4) congenital heart disease; (5) cardiac shock; (6) acute myocardial infarction (AMI) within 4 weeks; (7) acute myocarditis or serious arrhythmia with variation in hemodynamics. Patients who suffer from pulmonary artery hypertension caused by cor pulmonale, pulmonary embolism, or stroke within a half year were also excluded. Patients who suffer from serious hepatic or renal deficiency. Patients who suffer from diseases of blood system or malignant tumor. Patients who suffer from diabetes mellitus with serious complications, hyperthyrea, or hypothyrea. Patients who suffer from infection. Pregnant women or women in lactation. Patients with mental disorders. Patients with infectious disease or who join in other trials within 2 months of the present study.All qualified participants had signed informed consent prior to the enrollment. This study was conducted according to the principles of the Declaration of Helsinki and the principles of Good Clinical Practice.All patients formed the chronic heart failure group, and were further divided into 3 groups according to TCM syndrome differentiation, including group of Qi deficiency syndrome (QD), group of Qi deficiency and Blood stasis syndrome (QB), and group of Qi deficiency and Blood stasis and Water retention syndrome (QBW). The normal healthy participants composed the NH group.Besides, according to previous research  and echocardiography were also detected at the same time. Both the observer of the 6 MWT and the echo technician were blind to the allocation of the patients.After several preliminary experiments by different mixtures of methanol, acetonitrile, and methanol/acetonitrile (1:1), finally the extraction solvent was acetonitrile. By mixing equal amounts of plasma (30 μL) from all samples, pooled quality control samples were prepared to ensure data quality for metabolic profiling. Detailed sample methods were shown in the This research was approved by the Institutional Committee on Human Research of Beijing University of Chinese Medicine (No. 200807007), and this trial is registered with NCT01939236  using an ACQUITY Ultra Performance LC , whereas mass spectrometry was performed on a SYNAPT G2 Quadrupole-Time of Flight system . With a random-number generator in Excel , 3 sequences for samples in discovery phase, validation phase and placebo group were assigned by the study administrator. During analyses of the sample sequence, after each 20 injections, then 1 quality control sample was run to check the stability of system. The acquired mass spectrometry data were exported to data format (.centroid) files by Masslynx Software . Data pre-treatment procedures, such as nonlinear retention time alignment, peak discrimination, filtering, alignment, matching, and identification, were performed in Progenesis QI , and retention time and the mass-to ratio data pairs as the parameters for each ion. The UPLC-QTOF-MS characteristic chromatogram of CHM granules (6 herbs) was identified, and detailed method was shown in the Supplementary Material. Disturbed metabolites and metabolic pathways were identified by open database sources, including Human Metabolome Database (http://www.hmdb.ca/), METLIN (https://metlin.scripps.edu/), KEGG (http://www.genome.jp/kegg/pathway.html), and MetaboAnalyst .The liquid chromatographic separation of processed plasma was conducted on a 100P-values, from the Student's t-test or Welch's t-test, depended on whether the variances of two populations are assumed to be equal by Levene test. The significant metabolic changes after treatments of Chinese Herb Medicine or Placebo were identified by Partial Least Squares Discriminant Analysis (PLS-DA) and OPLS-DA, and P values were from paired samples t-test. R2Y (cum) was used to estimate the “goodness of fit” of the model, and Q2(cum) to estimate the ability of prediction. All P values for each metabolite in 6 comparisons were corrected by Bonferroni correction and the false discovery rate (FDR) method for multiple testing across all metabolites within each comparison. Matplotlib version 2.0.2 and SciPy version 0.19.1 were used to conducted the heat maps and hierarchical cluster analyses. A standard linear Support Vector Machine (SVM) Classification , the orthogonal projection to latent structure-discriminant analysis (OPLS-DA) model was applied to compare the differences in metabolic profiles between CHF, QD, QB, QBW, and NH group, and https://www.python.org/) with scikit-learn version 0.18.2 (http://scikit-learn.org). An adjusted p < 0.05 was considered statistically significant.And detailed method was shown in the A total of 110 patients with chronic heart failure from 11 hospitals and 54 normal healthy controls in China were enrolled in this research  chromatograms of 4 samples with NH, QD, QB, and QBW, and 5 samples with NH, Prior & Post-CHM group, and Prior & Post-Placebo group obtained are shown in Supplementary Figures Presently clinical diagnosis of different TCM syndromes of CHF depends on personal experience of clinical doctors   of Support Vector Machine (SVM) which trained by each biomarker panel from the discovery phase, appear in Figure ) Figure ; 0.876, With highest prediction specificity and sensitivity of the ROC, the optimal cut-off values were 0.1684 for CHF vs. NH, 0.2934 for QD vs. NH, 0.3403 for QB vs. NH, and 0.4763 for QBW vs. NH in the discovery phase. Different stages of CHF in the verification phase were predicted by the trained classifier and cut-off values. Predictive value was 85.0% for CHF vs. NH in the verification phase Figure ; 95.1% fThere was no significant difference of 6 MWT and ejection fraction between Prior-CHM group and Prior-Placebo group, and 4 weeks later, both changed significantly between Post-CHM group and Post-Placebo group, as shown in Figure The UPLC-QTOF-MS characteristic chromatogram of CHM granules (6 herbs) was shown in Figure p-values <0.05 for 2 OPLS-DA comparisons appear in Table There were significant curative effects of CHM on different diseases, but usually with indistinct metabolic mechanisms  of Support Vector Machine (SVM) which trained by on the basis of the logistic regression of each biomarker panel, appear in Figure n = 62; Figure n = 66; Figure Then five-fold Cross Validation was conducted to verify the specificity and sensitivity of the classifier OPLS-DA results with Python packages “sklearn,” the result showed the optimal cut-off value was 0.3631, and true positive rate (TPR), false positive rate (FPR) were 96.7 ± 4.2, 19.2 ± 2.1% for Post-CHM vs. Prior-CHM (n = 7) and CHM efficacy in QB patients (n = 11), evaluated by Chi-squared test with P = 0.0557.At the same time, there existed a certain correlation between specific metabolites determined in CHF patients with QB Zheng  could distinguish patients from normal healthy participants and provide fingerprints of metabolic changes that characterized the disease and its syndrome differentiation, and highlighted the potential biomarkers in the evaluation of a disease condition. About 6 metabolic biomarkers  were highly possible to be associated with CHF, and 4  with Qi deficiency syndrome, 7  with Qi deficiency and Blood stasis syndrome and 5  with Qi deficiency and Blood stasis and Water retention syndrome. The validated model using ROC curves was further constructed based on the metabolites of CHF patients and patients with 3 different syndromes and NH to diagnose other CHF patients with satisfying sensitivity of 97.1% (CHF), 97.1% (QD), 97.1% (QB), 97.1% (QBW), and specificity of 80.6% (CHF), 80.0% (QD), 79.5% (QB), 88.9% (QBW).As the most common clinical CHF syndrome, patients with Qi deficiency and Blood stasis syndrome were enrolled for the evaluation of Chinese medicine herbs (CHM granules). In placebo group, there were 3 special metabolic biomarkers  with the standardized western medicine treatment; in CHM group, there were 11 special metabolic biomarkers  with the treatment of CHM granules and standardized western medicine. By comparison of the metabolic profiles, 9 biomarkers  may be especially for the effect of CHM granules.In placebo and CHM groups, the levels of arachidonic acid both increased, while arachidonic acid is the potential biomarkers of Qi deficiency and Blood stasis and Water retention syndrome. As one of the pivotal signaling molecules, arachidonic acid is associated with inflammation, pain and self-balance function. Li et al. summarized the advances of giving insights into the arachidonic acid pathways in cardiovascular disease with metabolomic profiling  are known to play multiple roles to maintain membrane phospholipid homeostasis and produce a variety of lipid mediators (Sun et al., In this paper, a predicting model was attempted to construct and predict patient based on the related symptoms. The Syndrome prediction process was implemented by the objective biomarkers in blood forecasting performance. It generated a better performance than 3 classifiers with ROC curve analyses. We concluded that the method in the study may be applied to predict the syndromes of CHF. The potential biomarkers regulated by CHM were explored and it may be essential for the further study of CHM additional efficacy.KG, HZ, and JG: Designed the research, conducted performed the majority of the experiment, and revised the manuscript; BW, CJ, ZW, FZ, JiW, HX, and JuW: Assisted on supported several experimental performances and deal with the statistical data; JC and WW: Supervised the research and revised the manuscript.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.