No other parameters showed significant change from baseline values. Subsequent increases in esmolol showed changes in all parameters except SVV, SVR and PA mean. Correlation between dP/dt and LVSWI was 0.85 , between LVEF and dP/dt 0.39 , and between LSWI and LVEF 0.41 . In this model haemodynamic instability induced by negative inotropy was detected by the HPI algorithm prior to any clinically significant change in commonly measured variables. In addition, the peripheral measure of left ventricular contractility dP/dt correlates well with more established measurements of LV systolic function.To investigate if the Hypotension Prediction Index was an early indicator of haemodynamic instability in a negative inotropy porcine model, and to assess the correlation of commonly measured indicators of left ventricular systolic function. Eight anaesthetised pigs were volume resuscitated and then underwent an incremental infusion of esmolol hydrochloride (0-3000 mg/hr), following which it was then reduced in a stepwise manner. Full haemodynamic measurements were taken at each stage and measurements of left ventricular systolic function including left ventricular stroke work index, ejection fraction and peripheral dP/dT were obtained. At an infusion rate of 500 mg/hr of esmolol there were no significant changes in any measured variables. At 1000 mg/hr MAP was on average 11 mmHg lower (95% CI 1 to 11 mmHg,  Major surgery and critical illness are associated with varying degrees of haemodynamic instability that may lead to hypotension and cardiac dysfunction, which are associated with adverse patient outcomes including mortality, acute kidney injury and myocardial injury –5. Treatmax (hereinafter dP/dt) has been shown to correlate with end systolic elastance, a load independent index of left ventricular function [max and can be measured continuously from an arterial signal, however it has not been validated against echocardiograph derived ejection fraction or LVSWI. Since HPI is a potential measure of physiological instability we hypothesised that esmolol induced negative inotropy would be represented by changes in HPI prior to clinically significant changes in other measured haemodynamic parameters. In addition, we aimed to determine the correlation of peripheral dP/dt with LVEF and LVSWI.One potential cause of instability in the operative setting are the negative inotropic effects of anaesthetic agents, both intravenous –12 and ifunction , 16, andThe study was approved by the Institutional Animal Care and Use Committee (IACUC) at the Edwards Research Center, and all experimentation was performed in accordance with the USDA Animal Welfare Act regulations (AWArs), and the Guide for the Care and Use of Laboratory Animals . The Test Facility is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, International (AAALACi) and registered with the United States Department of Agriculture to conduct research with laboratory animals. Relevant aspects of the ARRIVE  guidelines were followed.−1), ketamine (2.2 mg.kg−1) and xylazine (1.1 mg.kg−1). An endotracheal tube was then placed in the trachea, and anaesthesia maintained by 1–2% isoflurane in an oxygen and nitrous oxide mix (FiO2 0.5). An intravenous catheter was placed in the auricular vein, and ECG and pulse oximetry established. Animals were ventilated on a volume-controlled mode with the respiratory rate set at 15 breaths per minute, and an initial tidal volume of 10 ml.kg−1 adjusted to maintain a PaCO2 of between 4.5 and 6 kPa. Positive end expiratory pressure was set at 5 cm H2O. Rectal temperature was monitored, and the animal temperature maintained between 38 and 40 °C using a heating pad.Eight female adult Yorkshire/ Landrace cross breed pigs with a mean weight of 79.7 (6.2) kg were studied. They were maintained in temperature and humidity-controlled rooms with a typical light–dark cycle and given standard food and tap water ad libitum. Prior to anaesthesia a general physical examination was performed to ensure all animal were in good health. Anaesthesia was induced with premedication using an intramuscular combination of telazol (4.4 mg.kg2). Left ventricular stroke work index [Vascular access was then established under ultrasound guidance as follows; left femoral vein access was established with a 9F introducer sheath for fluid/drug administration, the right femoral vein was cannulated with an 8F sheath through which an intracardiac echo probe was introduced and a short axis view of the left ventricle obtained below the mitral valve. Measurements of left ventricular end diastolic diameter (LEDD) and end systolic diameter (LVESD) were taken and used to calculate left ventricular ejection fraction (LVEF) via the Teicholz formula . The rigrk index  was calc−1. After induction of anaesthesia animals were infused with up to 10 mL.kg−1 of Lactated Ringers solution to achieve a SVV < 12%. Once this had been achieved if the MAP was less than 80 mmHg then an infusion of phenylephrine (100 mcg/mL) was commenced at 5 mL per hour and titrated to achieve a MAP > 80 mmHg. Once the desired targets had been achieved 10 min were allowed to ensure haemodynamic stability. This point was then defined as baseline and all measurements described above were recorded and at every subsequent time point. Following baseline measurements an infusion of esmolol hydrochloride (10 mg/mL) was started at 500 mg/hr and a period of 15 min allowed to achieve a steady state at which point all measurements were repeated (stage Esm 1). The infusion of esmolol hydrochloride was then subsequently increased to 1000 mg/hr, 2000 mg/hr and 3000 mg/hr with a similar period of steady state at each time point . Following measurements at stage Esm 4 the infusion rate was reduced to 2000 mg/hr (stage R1), 1000 mg/hr (stage R2) and then ceased (stage R3) allowing 15 min from dose reduction to measurements.The blood volume of the animals was calculated at 70 mL.kgData are expressed as the mean (SD) or median (interquartile range) as appropriate. The normality of data distribution was checked using quantile–quantile plots. Differences at each experimental stage from baseline values were computed using a mixed effects model with the Geisser-Greenhouse correction and a Dunnet correction for multiple comparisons with individual variances computed for each comparison. Values are reported as a mean difference from baseline value (BA) with 95% confidence intervals. Correlation coefficients were calculated using Pearsons method. A P value of < 0.05 was considered statistically significant and all analysis was performed with GraphPad Prism version 9.3.1 .All animals received lactate ringers with the median dose being 500 mL (IQR 500 to 750), and 2 animals required phenylephrine infusions at a rate of 1500mcg/hr which was continued throughout the experiment.Baseline haemodynamic variables and mean difference in values compared to baseline measurements at increasing doses of esmolol are shown in Table At an infusion rate of 500 mg/hr of esmolol (Esm 1) there were no significant changes in any measured physiological variables.p = 0.027) and a mean of 78 mmHg (SD 11). HPI increased by 33 units  with a mean value of 63 (SD 31). No other parameters showed significant change from baseline values.At an infusion rate of 1000 mg/hr of esmolol (Esm 2) MAP was on average 11 mmHg lower  with a mean of 80 bpm (SD 9), MAP was 21 mmHg lower  with a mean of 67 mmHg (SD 13), stroke volume had decreased by 15 mL  with a mean of 73 mL (SD 11) with an associated decrease in cardiac output of 2.3 L/min . A 20% decrease in SvO2 occurred  and LVSWI decreased by 22 g-m.m−2 . HPI was increased by 50 units compared to baseline  with a mean of 80 (SD 23).At an infusion rate of 2000 mg/hr of esmolol (Esm 3) heart rate was 13 bpm lower  and stroke volume by 16 mL  with a corresponding decrease in cardiac output of 2.8L/min  with a mean value of 5.3 L/min (SD 0.5). Mean arterial pressure had decreased by 33 mmHg  to an average of 57 mmHg (SD 13). All measurements of left ventricular function showed a decrease at this stage with a 32 g-m.m−2 decrease in LVSWI , a 34% decrease in LVEF  and a 171 mmHg.s−1 decrease in dP/dt . HPI increased by 64 units  with a mean of 93 (SD15).After the final increase in infusion rate of esmolol to 3000 mg/hr (Esm 4) significant changes were seen in all parameters except for SVV, SVR and PA mean. Heart rate had decreased by 18 bpm  with a mean of 78 bpm (SD 8), MAP was 15 mmHg lower  with a mean 75 mmHg (SD 10) and SvO2 was 10% lower . Cardiac output was 1.6 L/min lower than baseline  and LVSWI was 28 g-m.m−2 lower . HPI was 42 units higher compared to baseline .Mean difference in values compared to baseline measurements following reduction in esmolol infusion rates to 2000 and 1000 mg/hr respectively (R1 and R2) are shown in Table p < 0.001), and for LVEF and dP/dt the correlation coefficient was 0.39 , whilst for LSWI and LVEF the correlation coefficient was 0.41 .Correlation of LVEF, dP/dt and LVSWI are shown in Fig. p = 0.01). dP/dt decreased by 30% at stage Esm 3  and 37% at stage Esm 4 . Following cessation of the esmolol infusion values at R3 where not significantly different from baseline.Percentage change from baseline values for LVEF, dP/dt and LVSWI are shown in Fig. p = 0.007) and 58% at stage Esm 4 . Following cessation of the esmolol infusion values at R3 LVSWI remained 48% lower than baseline values .LVSWI decreased by 39% at stage Esm 3  the mean HPI increased from 30 to 60 but was not statistically significant and all other physiological parameters measured remained within normal limits. However, the magnitude of change at Esm 2 where HPI had a mean of 63 is similar to that seen at Esm 1. Whilst as mentioned this is not statistically significant, clinically this is likely to be interpreted in similar manner. If HPI is a marker of instability, then the threshold at which instability is deemed significant would need to be defined. At the rate of 1000 mg/hr HPI showed a statistically significant change with a mean value of 63, therefore this could be considered the initial threshold that represents haemodynamic instability, however further work would be needed to be able to define this with certainty. MAP was the only other parameter that showed a statistically significant change at Esm 2, however this remained within a normal range with a mean of 78 mmHg and would not be suggestive of instability in a clinical context.Increasing doses of esmolol resulted in a statistically significant increase in HPI. Whilst other parameters showed significance at increased doses, many remained within normal limits and hypotension defined as a MAP < 65mHg only occurred at the maximal dose. This may suggest that HPI reflects the amount of instability conferred into the model by increasing infusion rates of esmolol, and is not simply a marker of impending hypotension. Whilst HPI is validated as being predictive of future hypotension at values of greater than 85, lower values may be suggestive of haemodynamic instability that may not necessarily lead to a hypotensive event due to activation of compensatory mechanisms. Other work supports the potential use of HPI as marker of instability. In a porcine model of haemorrhage at 5% volume loss HPI was significantly raised and associated with reduced intestinal microcirculation, whilst again no clinically significant changes were seen in other measured parameters .If we can potentially use the algorithm as a marker of instability it would be useful to know whether the underlying cause is due to issue with preload, contractility or afterload. Esmolol is a cardioselective beta 1 adrenergic antagonist, and hence the mechanism of induced instability is through a decrease in contractility, heart rate and conduction . It is rIt correlates with end systolic elastance (Ees) and left ventricular dP/dt, although less accurate in underfilled conditions due to preload dependency . EchocarThere are several limitations to this study, firstly we chose to use esmolol as it is a cardio selective beta blocker, however it still has effects on peripheral vascular tone through nitric oxide mediated vasodilation so instability may be mixed in its aetiology especially at higher doses. This however is unlikely to significantly contribute to the instability seen early in the experiment. Secondly the use of the Teicholz method to calculate LVEF depends on geometric assumptions, and often overestimates LVEF. This method was chosen however as we were interested in showing correlation of LVEF with waveform derived measures of contractility rather than the absolute measurement. In addition, it is a simplistic measurement to calculate. The experiment was also performed on healthy porcine models, in whom it is reasonable to assume had no significant cardiovascular disease, and hence whether these observations will translate to human subjects with cardiovascular pathology where the technology is more likely to be used is unknown. Finally, although we have shown that HPI detects induced haemodynamic stability, the optimal value to define instability that has clinically significant implications has yet to be determined.In this model haemodynamic instability induced by negative inotropy was detected by the HPI algorithm prior to any clinically significant change in commonly measured variables. In addition, the peripheral measure of left ventricular contractility dP/dt correlates well with more established measurements of LV function.


Perfusion index has shown to be helpful in the operative and critical care settings to monitor peripheral tissue perfusion. Randomised controlled trials quantifying different agents’ vasodilatory properties using perfusion index has been limited. Therefore, we undertook this study to compare the vasodilatory effects of isoflurane and sevoflurane using perfusion index.This is a pre-specified sub-analysis of a prospective randomised controlled trial on the effects of inhalational agents at equipotent concentration. We randomly allocated patients scheduled for lumbar spine surgery to either isoflurane or sevoflurane groups. We recorded values of perfusion index at age-corrected 1 Minimum Alveolar Concentration (MAC) concentration at baseline, pre- and post-application of a noxious stimulus. The primary outcome of interest was the measure of vasomotor tone with perfusion index, and the secondary outcomes which were analysed were mean arterial pressure and heart rate.P = .526, repeated-measures analysis of variance).At age-corrected 1.0 MAC, there was no significant difference in the pre-stimulus haemodynamic variables and perfusion index between both groups. During the post-stimulus period, there was a significant increase in heart rate in the isoflurane group compared to the sevoflurane group, with no significant difference in the mean arterial pressure values between both groups. Though the perfusion index decreased during the post-stimulus period in both groups, there was no statistically significant difference between the 2 groups (In a steady state of age-corrected 1.0 MAC, isoflurane and sevoflurane had a similar perfusion index before and after a standardised nociceptive stimulus, which suggests that both of these agents have similar effect on peripheral perfusion and vasomotor tone. Changes in the perfusion index during anaesthesia have been described; however, randomised controlled trials quantifying different agents’ vasodilatory properties using perfusion index has been limited.We compared peripheral perfusion and vasomotor tone at equipotent doses of isoflurane and sevoflurane using perfusion index.In a steady state of age-corrected 1.0 MAC, isoflurane and sevoflurane had a similar perfusion index before and after a standardised nociceptive stimulus. These findings suggest that both of these agents have a similar effect on peripheral perfusion and vasomotor tone.3 With increasing severity and duration of tissue hypoxia, detrimental complications such as organ injury or death could result.1Perioperative tissue hypoperfusion and resultant hypoxia are major contributing factors of poor outcomes in surgical population. Surgical stress response could result in increased oxygen demand and failure to meet this can lead to consequent tissue hypoxia.4 Advanced and continuous monitoring of systemic haemodynamics is invasive and requires dedicated devices and expertise. However, standard perioperative cardiovascular monitoring may fail to detect tissue hypoxia.6 This results in ‘under monitoring’ of patients with an unknown cardiovascular risk, resulting in their increased predisposition to haemodynamic compromise.7 Multiple studies and meta-analyses have shown poor outcomes in surgical patients who had even a short duration of haemodynamic instability.8 This necessitates 2 things: first, comprehending the effects of different anaesthetic agents on homeostasis to optimise its administration ,and second, the need for a feasible, continuous, non-invasive and cost-effective way to monitor tissue perfusion.During the intra-operative period, the pharmacological effects of the anaesthetic agents could affect the homeostasis, which has a significant impact on the outcomes of the patients.9 Changes in the PI during anaesthesia have been described; however, randomised controlled trials quantifying different agents’ vasodilatory properties using the same technique has been limited. Isoflurane and sevoflurane are 2 commonly used volatile anaesthetics agents in spine surgeries. Therefore, we undertook this study to compare the vasodilatory effects of isoflurane and sevoflurane using PI. A quantitative comparison of their effects on the vasomotor tone and peripheral perfusion can help us choose the ideal inhalational anaesthetics in our clinical practice.Perfusion index (PI) has shown to be helpful in the operative and critical care settings to monitor peripheral tissue perfusion.This is a pre-specified sub-analysis of a prospective randomised comparative study on the effects of inhalational agents at equipotent concentration. After obtaining approval from the Institutional Ethics committee, consenting patients between 18 and 60 years scheduled for elective lumbar disc surgery were included in the study. Patients with American Society of Anaesthesiologists (ASA) physical status III and higher, those receiving medications that can affect vasomotor tone such as vasopressors and anti-hypertensive drugs, medications acting on the autonomic nervous system including beta-blockers and vagolytics, presence of systemic or peripheral vascular disease, diabetes mellitus, neurological or psychiatric ailments and history of substance abuse were excluded from the study. Motion artefacts in the plethysmograph wave, entropy values >70 and haemodynamic derangements  were the reason for withdrawal of the subject from the study.Using a web-based response, a random-permuted block randomisation algorithm randomly allocated 20 patients to each group. Allocation concealment was ensured with opaque serially numbered envelopes containing protocol with the name of the agent to be used. Premedication drugs such as anxiolytics and anticholinergics were avoided in the study population.2), were attached. The entropy electrode was applied to the patient's forehead and connected to the monitor. General anaesthesia was induced with IV propofol 2 mg.kg-1, and tracheal intubation was facilitated with IV succinylcholine 2 mg.kg-1. In addition, lignocaine 2 mg.kg-1 was administered to blunt the autonomic responses to intubation. The peripheral nerve stimulator electrodes were placed over the ulnar nerve on the volar aspect of the distal forearm. A train-of-four (TOF) count of 0 was ensured before intubation using a neuromuscular monitor device. After intubation, mechanical ventilation with air: O2 50%: 50% was initiated. End-tidal CO2 monitoring was instituted to ensure normocarbia. Temperature probe was placed in the nasopharynx, and normothermia was ensured throughout the study period. Perfusion index was measured in the index finger using pulse oximetry . The patient was kept supine until the end of the study period, and the hands were placed in a neutral position. We placed the pulse oximeter in the arm opposite to where the non-invasive blood pressure cuff was placed. The room's ambient temperature was constant at approximately 23 to 25°C throughout the study period. An upper body warming blanket was placed after prone positioning, and forced-air warming  was used to maintain the patient’s body at a set temperature of 38 C. I.V. fluid administration was standardised to 5 mL.kg-1.hr-1 of normal saline solution in both groups till the end of the study period.In the operating room, standard pre-induction monitoring, comprising electrocardiography (ECG), non-invasive blood pressure (NIBP) and pulse oximetry . The noxious stimulus was provided after 20 minutes to ensure the steady-state concentration of the volatile agent and to avoid the residual effects of propofol. Next, the noxious stimulus was provided to the subject by tetanic stimulation , and the post-noxious stimulus study parameters were obtained. Opioids were administered after the recording of the post-stimulus values.The study parameters, namely heart rate (HR), mean arterial pressure (MAP), and PI, were recorded at 3 pre-defined time points:Baseline: before anaesthetics inductionPre-noxious stimulus: recorded after induction of anaesthesia, before providing noxious stimulusPost-noxious stimulus: recorded after application of noxious stimuliDuring the study period, if the entropy values were greater than 70, additional sedatives or analgesics would be administered. If any of the patients encountered haemodynamic derangements during the study period, it would be promptly managed.t-test, with a power of 80%, and a significance level of 5%. Statistical analyses were performed using the SPSS 17.0 version . Data are presented as frequency for categorical variables and mean ± SD or median (interquartile range) for continuous variables. The Shapiro–Wilk test was used to test the normalcy of distribution for the variables. The comparison of categorical variables between the 2 groups was made using the Fisher exact test. The Student's t-test or the Mann–Whitney U-test (depending on the distribution) was used for continuous variables. Repeated-measures analysis of variance (RM-ANOVA) was used to compare consecutive measurements of the PI, MAP, and HR values at different time points between the 2 groups. A P-value < .05 was considered to be statistically significant.The primary outcome of interest was the measure of vasomotor tone with PI, and the secondary outcomes which were analysed were MAP and HR. There are no prior studies comparing the perfusion index between isoflurane and sevoflurane. We initially did a pilot study containing 20 patients (10 per group), wherein the pre-stimulation PI values (mean [SD]) were 4.9 (0.8) for the sevoflurane group and 4.1 (1) for the isoflurane group. We estimated the sample size of 20 patients per group for this study using a 2-sided A total of 56 patients presenting for spinal surgery were recruited for the study. A total of 12 patients were ineligible based on the exclusion criterion . One patThe baseline, pre-noxious and post-noxious variables were evaluated for both groups -4 The baP = 0.891]. Though the perfusion index decreased during the post-stimulus period in both groups, there was no statistically significant difference between the 2 groups (P = .167) (P = .63). With RM-ANOVA, there was no statistically significant difference between the 2 groups with regard to both group and time effects (P = .526) , 4.80 (4.2-5.5);  = .167) . The med = .526) .P = .061, MAP P = .172). During the post-stimulus period, there was a significant increase in HR in the isoflurane group compared to the sevoflurane group  (P = .390) (P = .056 and HR P = .422 by RM-ANOVA) when group and time effects were examined  . However = .390) . The MAPexamined and 4.The aim of our study was to compare the effects of age-corrected 1.0 MAC of isoflurane and sevoflurane on vasomotor tone and peripheral perfusion. We have found that isoflurane and sevoflurane had comparable effects on vasomotor tone and peripheral perfusion both before and after noxious stimulus.5 The major caveat is that even though these variables provide a certain level of information on tissue perfusion, it is not precise. Also, in the case of hypotension, vital organ perfusion is maintained at the expense of decreased perfusion of other tissue beds like the gut and skin. The standard monitoring can’t monitor these organs at stake.6 Thus, monitoring the perfusion of these tissues like skin could have potential benefits. First, it would help in the early detection of decreasing tissue perfusion. Second, non-invasive continuous monitoring of peripheral perfusion is easier and feasible and requires lesser expertise.6In conventional clinical practice, global haemodynamic measurements such as blood pressure, HR, markers of fluid responsiveness such as pulse pressure variation and systolic pressure variation, and indicators of organ perfusion such as urine output and serum lactate are considered surrogates of tissue perfusion.9 Any alteration in the peripheral perfusion is accompanied by a concurrent change in the pulsatile component. Since the non-pulsatile component does not change, the ratio changes.5 Sympathetic tone is the primary determinant of PI. Peripheral vasodilation causes an increase in PI, whereas vasoconstriction causes a decrease in the values; thus, PI is a direct indicator of peripheral perfusion. It can be used as a surrogate for quantitative measurement of vasomotor tone produced by drugs, including anaesthetics agents.11 Multiple studies have demonstrated the utility of using this to determine successful sympathectomy in regional anaesthesia.13One way to measure peripheral perfusion is with PI, derived from the photoelectric plethysmographic waveform. Using pulse oximetry, PI is calculated as the ratio between the pulsatile  and non-pulsatile (which reflects the other tissues) signals of absorbed light and is calculated independently of the patient's oxygen saturation.14 As a response to this, the acral arteriovenous shunt dilatation increases around tenfold causing increased peripheral perfusion.15 Second, volatile anaesthetic agents increase peripheral perfusion by causing peripheral vasodilation.17 Ryu et al.10 in their study comparing PI between desflurane and sevoflurane, found an increase in PI at 1 MAC of both the agents. Treschan et al16, in their study, evaluated tissue oxygenation by tonometry in general and epidural anaesthesia and found that both produced an increase in tissue oxygenation compared to baseline values.Volatile anaesthetic agents influence peripheral perfusion predominantly via 2 mechanisms. The temperature at which a particular response is generated is called as threshold temperature. The threshold for vasoconstriction which is normally 36.5°C, is reduced by around 2°-4°C during anaesthesia in a dose-dependent way.18 We demonstrated that the effects of both isoflurane and sevoflurane are similar on the PI and hence on vasomotor tone. In our study, the median baseline PI was identical in both groups. After induction, the PI increased in both the groups; however, there was no significant difference between them. The increase in PI post-induction is a direct indicator of both agents' vasodilatory effect. Post-stimulation, though the values of PI reduced compared to that of pre-stimulus, the difference remained statistically non-significant between the groups.Our study used PI to evaluate the differences in peripheral perfusion produced by isoflurane and sevoflurane. Systemic vascular resistance (SVR) can accurately predict vasodilatory properties. However, it is invasive and expensive and requires high levels of expertise.4 Malan et al19 found that the cardiovascular effects of sevoflurane and isoflurane were similar both quantitatively and qualitatively. However, in their study, systemic vascular resistance (SVR) was maintained at 1 MAC and decreased only at higher concentrations of 1.5 and 2 MAC. Rodig et al18 in their study stated to exclude effects on myocardial contractility, administered sevoflurane and isoflurane during cardiopulmonary bypass and found that both the agents had a similar impact on systemic vascular resistance index (SVRI). They also found that SVRI did not change significantly from baseline at 1 MAC. Moreover, a reduction in SVRI was noted only at 3% sevoflurane and 1.8% isoflurane. However, in our study, we found an increase in PI at 1 MAC. Though it cannot be conclusively deduced from our study, this increase in peripheral perfusion at 1 MAC of isoflurane could be attributed to direct vasodilatory properties of isoflurane and acral arteriovenous dilatation as a part of reduction of thermoregulatory vasoconstriction threshold. This is further purported by a study which found that isoflurane produced a non-linear dose-dependent reduction in vasoconstriction threshold, and at 1 MAC, the threshold was reduced by approximately 4°C.17All volatile anaesthetics induce hypotension with dose and agent-dependent effects on the central and autonomic nervous system by reducing the SVR and depression of myocardial contractility.19 Malan et al19 showed that these agents were comparable in their cardiac effects. However, in their study, HR increased only at 1.5 and 2.0 MAC and not at 1.0 MAC. However, this wouldn’t have much significance in the clinical setting. Our findings are similar to Chen et al.20 who found that though sevoflurane and isoflurane had similar alterations in blood pressure during maintenance, and there was an increased incidence of tachycardia after surgical incision in patients receiving isoflurane. Frink et al21 also found that though both the agents produced similar blood pressure, the HR response to skin incision was greater in patients administered isoflurane. Isoflurane is thought to depress parasympathetic activity more than sympathetic activity and hence, the baroreflex response of tachycardia consequent to hypotension would be predominant.25 Nishiyama22 found that increasing concentration of isoflurane caused hypotension, and tachycardia which was concurrent with increased plasma concentrations of epinephrine and norepinephrine. However, an increase in sevoflurane concentration induced only hypotension and a decrease in plasma epinephrine concentration.Our findings regarding the haemodynamic parameters such as HR and MAP were similar to other studies, showing that sevoflurane's cardiovascular effects were similar to those of isoflurane.10 compared the PI of sevoflurane and desflurane, 2 agents with different effects on SVR. They concluded that desflurane produced a higher PI and substantially lower MAP, which implies more potent vasodilatory properties of desflurane. This study suggests that agents with different effects on MAP would have varied effects on PI. In contrast, Kowalczyk et al26 compared desflurane and propofol and found that though there was a significant difference in MAP between the agents, the PI in both groups was comparable. This would indicate that agents with same effects on MAP and SVR could produce dissimilar PI. While there was a strong correlation between PI and the end-expiratory concentration of desflurane, there was no correlation between PI and the predicted plasma propofol concentration. This finding is interesting because of 2 reasons. First, it shows that changes in PI tracked changes in MAP and CO during general anaesthesia.7 Second, there is a dose-dependent reduction in MAP and SVR with propofol.27 If PI was exclusively dependent on MAP and SVR, there should have been a correlation between PI and propofol concentration. These studies show that PI, though dependent on SVR and MAP, is not exclusively determined by it. The contrasting reports of the aforementioned studies26 including our study warrant research comparing PI of agents with similar and dissimilar effects on haemodynamics to assess whether PI is beyond the influence of systemic haemodynamics.We studied haemodynamic parameters and perfusion index to assess whether agents with similar effects on MAP and SVR would produce comparable effects on the perfusion index. In our study, both sevoflurane and isoflurane produced similar effects on MAP and PI which elucidates that agents with similar effects on SVR would produce similar perfusion index. Ryu et al28 Agerskov et al29 concluded that low intraoperative peripheral PI was associated with severe postoperative complications or death in acute high-risk surgical patients and suggested that PI should be investigated to guide intraoperative haemodynamic management. Genderen et al30 demonstrated that abnormal peripheral perfusion parameters were associated with severe complications following abdominal surgery. Interestingly, in both the above studies, the results were independent of systemic haemodynamics. Perioperative haemodynamic optimisation is usually based on macrocirculatory parameters such as MAP; however, these studies suggest that monitoring of PI is a practical and valuable haemodynamic monitoring modality to reduce post-operative complications. It has also been recommended that the addition of perfusion parameters to goal-directed therapy algorithms could help guide the clinician to the correct intervention rather than relying only on macrocirculatory parameters.31 Differentiating the effects of anaesthetic agents on tissue perfusion and studying their impact on outcomes is essential as microvascular alterations may have a crucial role in post-operative complications. Further studies comparing the effect of anaesthetic agents on peripheral perfusion and microcirculation would throw light on this.There is only limited literature comparing the peripheral perfusion effects of general anaesthetic agents.32 found high inter-individual variability of PI with values ranging from 0.3 to 10%, with a median of 1.4%, thus contributing to a skewed distribution in the normal population. Because of this, PI is more useful in trend monitoring for follow-up rather than being used as a single cross-sectional measure.33Our study results have to be cautiously interpreted in the background of PI as a surrogate quantitative measurement of vasomotor tone and peripheral perfusion. Lima et alWe compared 2 agents commonly used in the perioperative setting in the Southeast Asian subcontinent. Moreover, studies have compared PI for desflurane, sevoflurane, and propofol, the widely used anaesthetic agents. However, isoflurane is not commonly used in an intraoperative setting in developed countries and is slowly being phased out by agents such as sevoflurane and desflurane. Nevertheless, the advanced anaesthetic conserving device (AnaConDa) uses isoflurane and sevoflurane to sedate patients in critical care units. We believe that the study on PI of these 2 agents is beneficial in the background of this revamped interest in a critical care setting to adopt volatile anaesthetics as sedatives. Our sample size was calculated based on a pilot study with 10 patients. Therefore, further studies with a larger sample size are required to corroborate that isoflurane and sevoflurane have the same effects on peripheral perfusion.via vasodilation.14An additional skin temperature monitoring in the peripheries would have been beneficial to preclude effects of this redistribution of heat on perfusion index in the study.We monitored temperature with a nasopharyngeal probe to ensure normothermia and took additional precaution of using forced air warming to a set temperature of 38 degree C. The study period lasted 30 minutes to 1 hour after the induction and during this initial period, the body heat redistributes from the central compartment to the periphery In a steady state of age-corrected 1.0 MAC, isoflurane and sevoflurane had a similar perfusion index before and after a standardised nociceptive stimulus. These findings suggest that both these agents have a similar effect on peripheral perfusion and vasomotor tone. However, further studies to elucidate whether these vasodilatory properties of inhalational anaesthetic agents are beneficial for tissue oxygenation and microcirculation are required.


EPCs, C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 10 (IL-10), and vascular endothelial growth factor (VEGF) were measured. Flow cytometry was used for the quantification of EPCs. Mobilization of EPCs increased and the inflammatory profile improved within each severity group (p < 0.05) after the cardiac rehabilitation program, but there were no statistically significant differences between groups (p > 0.05). A 36-session cardiac rehabilitation program has similar beneficial effects on the mobilization of EPCs and on the inflammatory profile in patients with CHF of different severity.Endothelial dysfunction and inflammation are common pathophysiological characteristics of chronic heart failure (CHF). Endothelial progenitor cells (EPCs) are recognized as useful markers of vascular damage and endothelial repair. The aim of this study was to investigate the effects of a cardiac rehabilitation program on EPCs and inflammatory profile in CHF patients of different severity. Forty-four patients with stable CHF underwent a 36-session cardiac rehabilitation program. They were separated into two different subgroups each time, according to the median peak VO Chronic heart failure (CHF) is a clinical syndrome characterized by increased morbidity and mortality, along with a significant financial and social burden . Common Either a single bout of exercise or a structured exercise training program has been shown to increase the mobilization of EPCs and CECs in patients with HFrEF or heart failure with mildly reduced ejection fraction (HFmrEF) ,8,9. It We hypothesized that exercise training would have similar beneficial effects in patients with CHF of different severity, regardless of their previous functional capacity. The primary aim of the present study was to investigate the effects of a 3-month structured exercise training program on EPCs and CECs in patients with HFrEF and/or HFmrEF of different severity according to functional capacity indices. The secondary aim was to investigate potential differences in inflammatory indices in these patients.This is a post hoc analysis of a previously published randomized controlled trial from our institute   stable CHF for at least 3 months under medication and (ii) a reduced or mildly reduced ejection fraction (EF ≤ 49%). The exclusion criteria were (i) severe valvulopathy, (ii) uncontrolled arterial hypertension, (iii) severe chronic obstructive pulmonary disease, (iv) severe peripheral angiopathy, (v) neuromuscular diseases, and (vi) contraindications for maximum CPET .2, predicted peak VO2, VE/VCO2 slope, and class of EF  on an electromagnetically braked cycle ergometer in order to assess their functional capacity and CHF severity. Blood samples were collected before and after CPET. In the meantime, the patients underwent a 36-session exercise training program and, after the completion of the program, the CHF patients performed a final CPET so as to assess the impact of the exercise training program on their functional capacity. Blood samples were also collected before and after the final CPET.2, VCO2, and VE, as well as more specific variables such as resting VO2, VO2 at peak exercise (peak VO2), predicted VO2 at peak exercise (predicted peak VO2), and VE/VCO2 slope [The ramp symptom-limited maximal CPET on an electromagnetically braked cycle ergometer  had a duration of 8–12 min and was performed according to Hansen et al.’s protocol [O2 slope . The end2–workload plots of the initial CPET [The patients underwent a HIIT protocol as previously described in , which wial CPET . Almost ial CPET . Because6 events. EPCs and CECs were expressed as medians (25th–75th percentiles) in absolute numbers of cells per 106 enucleated cells.Venous blood samples were collected in K3 ethylenediaminetetraacetic acid (K3-EDTA) tubes, while endothelial cellular populations were identified and quantified with the use of four-color flow cytometry within the first hour after the collection, based on Duda’s protocol  and our C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 10 (IL-10), and vascular endothelial growth factor (VEGF) were measured from the upper phase (plasma) of the total venous blood after the centrifugation ,16. Immut-tests were used to analyze differences in dependent parameters with normal distribution, while the Wilcoxon signed-rank test was used to analyze differences in nonparametric data within the total sample and within the severity groups. Independent-samples t-tests or the Mann–Whitney U test were used to analyze differences between independent parameters, based on the distribution of normality as appropriate. Chi-squared tests were employed to check for between-group differences in categorical variables at baseline. Unadjusted differences between severity groups were assessed with factorial analysis of variance (ANOVA) 2 × 2 × 2 (time × intervention × group). Linear regression analysis was performed between the absolute values and the percentages Δθ of each EPC and CEC subgroup after the cardiac rehabilitation program and the baseline values of functional capacity indices including peak VO2, predicted peak VO2, VE/VCO2 slope, EF, and age. Moreover, Spearman’s correlation coefficient was used in order to assess the direction and the magnitude of the association between the absolute and percentage differences of each endothelial cellular population and the values of CPET parameters and inflammatory indices. Due to the existence of a multiple comparison effect, statistical correction with Bonferroni’s test was performed in order to reduce the incidence of false positive findings. All tests were two-tailed, and the level of statistical significance was set at 0.05. Statistical analyses were performed with IBM SPSS 25 Statistics software .Patients were divided according to CHF severity based on CPET assessment, and the results are presented according to the severity groups. Normality of distribution was checked with the Shapiro–Wilk test. Variables are expressed as means ± standard deviations (SD) or medians (25th–75th percentiles). Paired two-sample Student’s The majority of the patients were mainly treated with diuretics, beta-blockers, aldosterone antagonists, or angiotensin-converting enzyme inhibitors. The patients’ compliance with the rehabilitation program was >80% in both groups. The patients did not differ in demographics between the two groups in each comparison, except for the variables for which they were separated .p < 0.05) after the cardiac rehabilitation program, but there were no statistically significant differences between groups (p > 0.05) in each comparison based on peak VO2  and the superiority of HIIT in terms of endothelial function compared to MICT ; p = 0.013).Common pathophysiological features of patients with CHF, as well as the exact mechanisms behind the repair of damaged vessels by EPCs, have already been described in a recent review from our institute . VEGF prThe most significant finding of our study is that the effect of exercise training on the mobilization of EPCs and CECs was beneficial for all CHF patients, irrespective of their severity. So far, there are no data in the literature regarding the effects of a cardiac rehabilitation program on EPCs as far as the comparison between CHF patients of different severity, according to functional capacity indices, is concerned. Only a single clinical study from our institute has examined the same research question, but after acute exercise, and it showed that the mobilization of EPCs and CECs increased after maximal exercise in CHF patients, but this increase was not associated with the syndrome’s severity . This isp = 0.001), IL-6 (SMD −0.158 (95% CI: −0.303 to −0.013); p = 0.032), and sICAM-1 (SMD −0.282 (95% CI: −0.477 to −0.086), p = 0.005). In our study, an exercise training program reduced hsCRP and IL-6 levels and, in some instances, increased levels of IL-10, a major anti-inflammatory cytokine that reduces pathological hypertrophy and promotes cardiac remodeling [As far as systemic inflammation is concerned, patients with CHF usually present elevated levels of inflammatory markers such as CRP  and IL-6modeling ,36. The modeling ,23 in CHFinally, the adherence of CHF patients to an exercise training protocol is another significant parameter of a cardiac rehabilitation program’s success. It is a matter of fact that a smaller number of sessions is usually followed by improved rates of adherence than a longer rehabilitation program for the same effect. A recent review by Collado-Mateo D et al.  investigSmall sample size may be an important limitation of this study for some specific indices, other than EPCs, CECs, and inflammatory markers. Although power analysis was performed and the results are valid for cellular endothelial populations and cytokines, some specific between-group comparisons may have been too underpowered to reach definite conclusions and generate the results for other parameters of interest. Moreover, another possible limitation could be the different number of samples in each comparison for each variable. In the first three comparisons for CPET indices, we separated the total sample according to the median value of each variable for each analysis, so that the severity groups would be almost equal each time. The reason for this was that the functional capacity of our patients was moderate–high, and we had only a few patients with low functional capacity. As a result, we could not separate the sample into three groups of low, moderate, and high functional capacity. For the ejection fraction, the samples were not equal due to the fact that HF categories are well established and we compared HFmrEF and HFrEF. Finally, a multiple comparison effect that could arise from our analyses as a potential bias was corrected with the Bonferroni statistical test.Our study suggests that a 36-session cardiac rehabilitation program has similarly beneficial effects on the mobilization of EPCs and CECs, as well as on inflammatory indices and indices of neovascularization, in patients with CHF of different disease severity, according to functional capacity indices and EF. The potential mechanisms still remain under investigation. More RCTs with greater numbers of CHF patients are required in order to confirm these significant results, reveal the pathophysiology, and further understand the clinical relevance of endothelial cellular populations in CHF.


High blood pressure, anxiety, depression and sleep disorder is very common in patients with hypertension. We aimed to perform a meta-analysis to evaluate the effects of adjuvant music therapy for patients with hypertension, to provide insights to the clinical management of hypertension.Two authors searched PubMed, Embase, Web of Science, the Cochrane Library, Chinese National Knowledge Infrastructure, China Biomedical Literature Database, Wanfang Databases for randomized controlled trials (RCTs) on the role of music therapy in hypertension up to Oct 15, 2022. RevMan 5.3 software was used for meta-analysis.A total of 20 RCTs including 2306 patients were finally included. 1154 patients received music therapy. Meta-analysis showed that music therapy can effectively reduce the systolic blood pressure, diastolic blood pressure, heart rate , self-rating anxiety scale (SAS) score, self-rating depression scale (SDS) score, Hamilton anxiety scale (HAMA), score, PSQI score compared with routine therapy in patients with hypertension. No publication bias in the synthesized outcomes were found .Music therapy can effectively control blood pressure and heart rate, reduce anxiety and depression levels, and improve sleep quality in hypertensive patients. Limited by the quantity and quality of included studies, the above conclusions need to be verified by more high-quality studies.The online version contains supplementary material available at 10.1186/s12906-023-03929-6. Hypertension is the first risk factor for cardiovascular associated diseases. With the change of lifestyle and rhythm, the prevalence of hypertension in countries around the world is increasing year by year . NegativAt present, there are many drugs for the treatment of hypertension in clinic. Although they can control hypertension to a certain extent, long-term use of drug use is easy to produce drug resistance, and it is easy to relapse after drug withdrawal. Nonpharmacological treatments can be effective in lowering blood pressure without other health risks. As one of the non-drug treatment methods, music therapy has been used as an adjuvant therapy in hypertension treatment. Currently, many scholars –11 have We conducted and reported this meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement .Two authors searched PubMed, Embase, Web of Science, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), China Biomedical Literature Database, Wanfang Databases for randomized controlled trials (RCTs) on the role of music therapy in hypertension. The retrieval time is from the establishment of the database to Oct 15, 2022. We used a combination of subject headings and free words to search. The language of searched and included publications were limited to English and Chinese. The search terms were as following: (“music” OR “music therapy” OR “sound therapy”) AND (“hypertension” OR “high blood pressure” OR “cardiovascular”) study type: RCT design; (2) study population was the hypertensive patients, who met the diagnostic criteria for hypertension: Systolic blood pressure ≥ 140mmHg and / or diastolic blood pressure ≥ 90mmHg, 16; (3)The exclusion criteria for this meta-analysis were: (1) studies with unclear diagnosis of hypertension or hypertension complicated with risk factors for other diseases; (2) research population were special populations such as pregnant women and military personnel; (3) Low-quality reports; (4) reviews, cases and those literature reports with data that could not be extracted for analysis.Literature screening and data extraction were conducted independently by two researchers in a blinded manner, and inconsistent literatures were reviewed and discussed. The following data were extracted according to the designed table: author, publication year, country, sample size, details of intervention measures and reported outcome indicators. The primary outcomes included systolic blood pressure, diastolic blood pressure. The secondary outcomes included heart rate, self-rating anxiety scale (SAS), self-rating depression scale (SDS), Hamilton anxiety scale (HAMA), Pittsburgh sleep quality index (PSQI).The quality of the included literature was evaluated according to the risk of bias tool  recommen2 to quantitatively judge the heterogeneity. If there was homogeneity among studies(I2 < 50%), a fixed-effects model was used to calculate the combined statistics; if there was heterogeneity(I2 ≥ 50%), random-effects model was used. Sensitivity analysis was performed by excluding articles one by one and then recombining the calculation. A funnel plot and Egger’s test were used to assess the publication bias of the pooled results. In this meta-analysis, P < 0.05 was considered to be statistically significant between groups.We used Review Manager (RevMan) Version 5.3. software for meta-analysis. Measurement data were expressed as mean difference (MD) and 95% confidence interval (CI). In addition, we performed the heterogeneity test by the Q test, and combined with IA preliminary search obtained 202 relevant literatures. After screening according to the inclusion and exclusion criteria, a total of 20 RCTs –37 that Of the included 20 RCTs –37, a toThe quality of included RCTs is presented in Figs. 2 = 91%), so a random-effects model was used to pool the results. The results of meta-analysis showed that the mean systolic blood pressure drop in the music therapy group was greater than that in the control group, and the difference was statistically significant , so a random-effects model was used to pool the results. The results of meta-analysis showed that the mean diastolic blood pressure drop in the music therapy group was greater than that in the control group, and the difference was statistically significant , so a random-effects model was used to pool the results. The results of meta-analysis showed that the mean heart rate drop in the music therapy group was greater than that in the control group, and the difference was statistically significant , norepinephrine (NE) and other neurotransmitters, and is related to neurological and endocrine dysfunction . Both 5-Several previous systematic reviews have evaluated the role of music therapy on the patients with hypertension. Yang et al. . have anThere are certain limitations in this study that are worth considering. Firstly, most of the included studies lack allocation concealment and double-blind implementation, and there may be selection bias in the time, and type choice of music, which may affect the results of the study. Secondly, some of the included studies did not provide the mean value of the changes before and after intervention, we calculated the coefficient by reporting the complete study, and the results may have a certain bias. Thirdly, some of the included RCTs did not fully report the characteristics of the study population and music type, and the results of some studies were heterogeneous, but there was insufficient data for subgroup analysis, so the results of this study should be treated with caution.In conclusion, music therapy can effectively reduce blood pressure and heart rate in patients with hypertension, reduce anxiety and depression levels, and improve sleep quality of patients, thereby improving blood pressure control and prognosis of patients. Compared with drug therapy, music therapy, as a low-cost, easy-to-operate, non-invasive therapy, can reduce medical expenses while achieving therapeutic effects, and it is an adjuvant therapy that clinicians can provide independently. The music therapy is worthy of discussion and application in clinical practice for hypertension management. Still, it is recommended that future studies be designed strictly in accordance with the RCT requirements, and explore the influence of music therapy on more indicators of hypertensive patients, and evaluate the intervention time, music type, playing time, and listening style, so as to provide support for the clinical application of music therapy intervention for hypertensive patients.Below is the link to the electronic supplementary material.Additional file 1: Supplementary 1. PubMed search strategy table


Background: The genetic factors in assessing therapeutic efficacy and predicting antihypertensive drug response are unclear. Therefore, this study aims to identify the associations between variants and antihypertensive drug response.Methods: A longitudinal study including 1837 hypertensive patients was conducted in Northern China and followed up for a median 2.24 years. The associations of 11 candidate variants with blood pressure changes in response to antihypertensive drugs and with the risk of cardiovascular events during the follow-up were examined. The dual-luciferase assay was carried out to assess the effect of genetic variants on gene transcriptional activity.Results: The variant rs11039149A>G in the promoter of nuclear receptor subfamily 1 group H member 3 (NR1H3) was associated with the change in systolic blood pressure (ΔSBP) in response to calcium channel blockers (CCBs) monotherapy. Patients carrying rs11039149AG genotype showed a significant increase of systolic blood pressure (SBP) at follow-up compared with AA carriers, and the difference of ΔSBP between AG and AA carriers was 5.94 mm Hg . In 1,184 patients with CCBs therapy, SBP levels decreased in AA carriers, but increased in AG carriers, the difference of ΔSBP between AG and AA carriers was 8.04 mm Hg . Further analysis in 359 patients with CCBs monotherapy, the difference of ΔSBP between AG and AA carriers was 15.25 mm Hg . However, there was no significant difference in ΔSBP between AG and AA carriers with CCBs multitherapy. The rs11039149A>G was not associated with the cardiovascular events incidence during the follow-up. Additionally, transcriptional factor forkhead box C1 (FOXC1) bound to the NR1H3 promoter containing rs11039149A and significantly increased the transcriptional activity, while rs11039149 A to G change led to a loss-of-function and disabled FOXC1 binding. For the other 10 variants, associations with blood pressure changes or risk of cardiovascular events were not observed.Conclusion: Hypertensive patients with rs11039149AG genotype in the NR1H3 gene have a significant worse SBP control in response to CCBs monotherapy compared with AA carriers. Our findings suggest that the NR1H3 gene might act as a promising genetic factor to affect individual sensitivity to antihypertensive drugs. Hypertension is a major risk factor leading to cardiovascular diseases . About oCACNA1C) that is found to be associated with antihypertensive response to calcium channel blockers (CCBs) (NEDD4L) that is associated with treatment response with beta-blockers or diuretics (AGT), angiotensin converting enzyme 2 (ACE2) and angiotensin II receptor type 1 (AGTR1), which are found to have effects on antihypertensive response to angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs)  , and NEDiuretics . Some ges (ARBs) . HoweverAGT is found to be associated with blood pressure lowering to beta-blockers in 115 Swedish patients with hypertension and left ventricular hypertrophy (AGTR1 is related to different therapeutic efficacy to CCBs and ACEIs in 311 White Europeans with hypertension (CACNA1C (ACE2 (NEDD4L (ADD1) (MMP3) (NR1H3) (PTPRD)  , matrix ) (MMP3) , nuclear (NR1H3) , and pro (PTPRD)  are alsoAGT, AGTR1, ADD1, ACE2, CACNA1C, NEDD4L, NR1H3, PTPRD, MMP3) are chosen and genotyped in a Chinese prospective cohort study including 1837 patients with hypertension, aiming to explore the association of variants with the changes in blood pressure in response to antihypertensive drugs treatment and the risk of cardiovascular events during the follow-up.The investigations for genetic variants on antihypertensive response in Chinese population are limited. In this study, a total of 11 variants at 9 genes  were enrolled at two time periods according to the same criteria of inclusion and exclusion, of whom 463 patients from January to November in 2009 and 1,490 patients from January 2012 to December 2014. The definition of hypertension was based on the following criteria: SBP≥140 mm Hg and/or diastolic blood pressure (DBP)≥90 mm Hg, and/or receiving antihypertensive drugs, and/or history of hypertension. The enrolled patients were provided with antihypertensive drugs at free of charge, including CCBs, ARBs, ACEIs, thiazide-type diuretics (hydrochlorothiazide), or beta-blockers, unless intolerance was reported. The drug dosages and types were modulated by doctors according to the patients’ blood pressure levels.All patients were followed up face-to-face every 2 years by trained investigators, and the last visit was from May 1 to November 30 in 2016. The main endpoint was the composite of stroke, myocardial infarction, coronary revascularization, hospitalization for unstable angina or acute decompensated heart failure, and deaths from cardiovascular causes. Definitions of the endpoints were described in the Before data assessment, we excluded 98 patients lack of antihypertensive treatment data, 11 patients without genotyping data due to lack of blood samples, and 7 patients who were loss of follow-up due to immigration and lack of follow-up blood pressure. Thus, a total of 1837 patients with complete clinical data and genetic information were included in this study for analyzing the association of variants with blood pressure lowering response and risk of cardiovascular events. The flowchart of study was shown in Baseline demographic characteristics including age, sex, antihypertensive therapy, medical history, and lifestyles  of enrolled patients were collected through interviews, and a standardized questionnaire was utilized for data collection. Height and weight were measured by skilled nurses, and body mass index was computed as weight (kilograms) divided by the square of height (meters). Blood samples were drawn from the antecubital vein after overnight fast and total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, fasting blood glucose and serum creatinine were examined by an automatic analyzer . All measurements were done at Beijing FuWai Clinical Laboratory and certified by the Centers for Disease Control and Prevention.Blood pressure was measured by trained nurses using validated oscillometric monitors with suitable-sized arm cuffs . All patients were requested to avoid smoke, alcohol, tea, coffee, and exercise for at least 30 min before the blood pressure was measured. The sitting blood pressure was measured 3 times at intervals of 1 min after at least 5 min of rest, the average of the second and third readings was recorded as the blood pressure level. The changes in blood pressure were derived from follow-up blood pressure minus baseline blood pressure. ΔSBP and ΔDBP were used for indicating the changes in SBP and DBP, respectively.AGT, AGTR1, ACE2), 2 genes involved in ion channels , 3 genes associated with vascular functions , and ADD1 gene, which encodes adducin-1 and plays important roles in the stabilization of the membrane cortical cytoskeleton, cell-cell adhesions, and cell signal transduction . Genotyping was performed using the Nascent Genotyping system with a custom-by-design 48-Plex SNPscan™ Kit  which was based on double ligation and multiplex fluorescence polymerase chain reaction (PCR) method. For each variant, two special primers  and one common primer were designed . The proThe genotyping method used in this study has been validated by single nucleotide extension with the Multiplex SNaPshot Kit  in previous studies which have reported >99% concordance rates of validation . In our http://jaspar.genereg.net/) was used to explore the potential binding sequence of transcriptional factors in relation to the genetic variants in this study. To verify whether rs11039149A>G influences the transcriptional activity of NR1H3, 200-bp NR1H3 promoter fragments containing rs11039149A or rs11039149G allele were amplified by PCR method using the following primers: forward 5′-GGCGGTACCCCTCAGCAGCTTGCCTCC-3′, reverse 5′- GGCACGCGTAGTGGCTGGG CTGGGATCAGA-3′, then cloned into the pGL3-promoter luciferase vector  at KpnI and MluI restriction sites, and two plasmids were generated: pGL3-rs11039149A and pGL3-rs11039149G. Forkhead box C1 (FOXC1) gene coding sequence was amplified using the following primers: forward 5′-GCGCGATCGCATGCAGGCGCGCTACTCC-3′, reverse 5′- GGCACGCGTCA AAACTTGCTACAGTCGTAG-3′, then cloned into eukaryotic expression vector pENTER  at AsisI and MluI restriction sites to generate the pENTER-FOXC1 plasmid. All plasmids were confirmed by DNA sequencing.Bioinformatic analysis  according to the manufacturer’s protocol. Luciferase vector pGL3-rs11039149A or pGL3-rs11039149G were co-transfected with a transcription factor expression plasmid pENTER-FOXC1 or pENTER empty vector (each vector 20 ng per well). The Renilla luciferase plasmid pRL-TK  were co-transfected as an internal control (1 ng per well) to standardize the transfection efficiency. The transfected cells were harvested after 36 h, and the luciferase activity was measured using the dual-luciferase reporter assay system  by a luminometer .HEK293T cells were seeded at a density of 2.0 × 10Hardy-Weinberg equilibrium for each variant was examined by chi-square test. We used fixed-effect model as the main analysis of genetic association, given that fixed-effect model is more appropriate for exploratory or predictive studies with large sample sizes greater than 500, and it has a smaller median absolute error (4%) of the true marginal effect than random-effect model, as proposed by a simulation study . Univariable general linear model was used to explore the confounding variables that might affect the changes in blood pressure, and baseline characteristics of age, sex, body mass index, serum creatine, blood pressure, smoking status, alcohol intake and antihypertensive drugs were found to be significantly associated with the changes in blood pressure , therefocog-genomics.org) to further explore the effects of interactions of the studied variants on the changes in blood pressure at the follow-up. The P-values for interaction were calculated by multiple linear regression models with adjustment for covariates as mentioned above.In this study, two parallel models were used to give more comprehensive assessments for the genetic association analysis. Generalized linear regression model was used to calculate the means, mean differences and 95% confidence intervals (CIs) of the changes in blood pressure (ΔSBP and ΔDBP) among different genotypes of the variants. Multivariate linear regression model was used to obtain the correlation coefficient of genetic variants with the changes in blood pressure. The effects of antihypertensive treatments and sex on the correlation of variants with the changes in blood pressure were analyzed in further stratification. In addition, we performed epistasis analysis using the PLINK 1.9 , whichever came first.False discovery rate (FDR) derived from the Benjamin & Hochberg method  was calcA total of 1837 patients were included in this study and the baseline characteristics of these patients were shown in p > 0.05). Means, mean differences and 95%CIs of blood pressure changes between genotypes were calculated by generalized linear regression model with adjustment for age, sex, body mass index, serum creatine, blood pressure, smoking status, alcohol intake and antihypertensive drugs. The results showed that NR1H3 gene variant rs11039149A>G was associated with ∆SBP. In this studied population, the minor allele frequency of rs11039149G was 3.0%, and the genotype frequencies of rs11039149 were respectively as AA (94.0%) and AG (6.0%). ∆SBP was 2.95 mm Hg (95%CI: −1.08 to 6.98) for the NR1H3 variant rs11039149AG carriers and −2.99 mm Hg (95%CI: −4.71 to −1.26) for the AA carriers; ∆DBP was −0.56 mm Hg (95%CI: −2.68 to 1.57) for the AG carriers and −2.66 mm Hg (95%CI: −3.57 to −1.57) for the AA carriers. The difference of ∆SBP between AG and AA carriers was 5.94 mm Hg , but no significant difference of ∆DBP was found between the AG and AA carriers after multiple comparison correction by the Benjamin & Hochberg method (FDR = 0.44) (The frequencies of 11 studied variants were shown in  = 0.44) .NR1H3 variant rs11039149A>G, when stratified by sex, the difference of ∆SBP between AG and AA carriers was observed in both men and women  for ∆SBP and 2.08  for ∆DBP, respectively (P for interaction>0.05) (p = 0.01), which was consistent with the fixed-effect model  . Considect model .We compared baseline characteristics of the patients with two genotypes of rs11039149, showing that patients with AG genotype had a lower body mass index and a higher level of serum creatinine than those with AA genotype . In addiNR1H3 variant rs11039149A>G with ∆SBP differed in antihypertensive therapy. In 1,184 patients with CCBs therapy, SBP levels decreased in AA carriers , but increased in AG carriers , the difference of ΔSBP between AG and AA carriers was 8.04 mm Hg  (p = 0.41). As for ARBs, ACEIs, diuretics and beta-blockers, the therapies of these drugs did not significantly affect the association between the NR1H3 variant rs11039149A>G and blood pressure changes  (The association of  = 0.01) . However > 0.05) .p = 0.001). However, in patients with CCBs multitherapy, there was no significant difference in ΔSBP between the patients with two genotypes (p = 0.15). Compared with the patients receiving CCBs multitherapy, the difference in ∆SBP was more significant in patients with CCBs monotherapy (P genotype × CCBs therapy interaction = 0.002)  patients had CCBs monotherapy and 825 (69.7%) patients had multitherapy. Considering the potential effect of multitherapy on the association of the genotypes with CCBs therapy, we further assessed the differences of ΔSBP in patients with or without rs11039149G allele when receiving CCBs monotherapy and multitherapy. In patients with CCBs monotherapy, the difference of ΔSBP between patients with AG and AA genotype was 15.25 mm Hg  .Irregular drug taking  and drug regimen change (defined as the change in types of drugs during the follow-up) may also affect the genetic association. Therefore, after 100 patients with irregular drug taking or 531 patients with drug regimen change were excluded, we further performed the sensitivity analysis. The results showed that the association of rs11039149 with SBP in response to CCBs still remained. .Pgenotype × CCBs therapy interaction = 0.004), which was consistent with the fixed-effect model  showed that the variant rs11039149 A to G change at the NR1H3 promoter region could affect the binding ability with transcriptional factor FOXC1, which changed the transcription activity of NR1H3 gene. Therefore, pENTER-FOXC1 and pGL3-promoter luciferase vectors pGL3-rs11039149A and pGL3-rs11039149G were constructed, and the luciferase activity representative of NR1H3 promoter activity was measured by the dual-luciferase assay carried out in HEK293T. The relative luciferase activity had no significant difference between the pGL3-rs11039149A and pGL3-rs11039149G when without any stimulation of transcriptional factors. As for the wild pGL3-rs11039149A having potential binding sequence with the FOXC1, its relative luciferase activity significantly increased by 2.1-fold comparing the presence of FOXC1 with the absence of FOXC1 (p < 0.001). After co-transfected with the FOXC1 gene, the wild pGL3-rs11039149A had a significantly higher relative luciferase activity by 2-fold than the mutant pGL3-rs11039149G (p < 0.001)  . These rAGT, AGTR1, ADD1, ACE2, CACNA1C, NEDD4L, NR1H3, PTPRD, MMP3) were analyzed in 1837 Chinese patients with hypertension. Our data first provided evidence in Chinese patients with hypertension that NR1H3 promoter variant rs11039149A>G was related to the change in SBP and the SBP response to CCBs monotherapy. However, no significant association was found between NR1H3 variant rs11039149A>G and the risk of cardiovascular events.In this longitudinal study, a total of 11 variants at 9 genes , one of the key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages, and thus takes part in the process of atherosclerosis , thus relax vasoconstriction and reduce blood pressure , all of which are proved to be safe and most widely used antihypertensive drug types in China. Due to possible adverse effects, the study could not exclude some bias with regarding to the association of ntration , and thentration . HoweverNR1H3 gene have a significantly worse SBP control in response to the monotherapy of CCBs, compared with patients with the wild-type rs11039149AA genotype. The underlying biological mechanisms may be related to the disabled binding ability of transcription factor FOXC1 to rs11039149 caused by A to G change. Our findings support that the NR1H3 gene might act as a promising genetic factor to affect individual sensitivity to antihypertensive drugs. Clinical trials in pharmacogenetics will be helpful to investigate genetically determined variations in response to drugs and thus benefit the individual treatment strategies.In conclusion, the key finding of the study is that hypertensive patients with rs11039149AG genotype in the


There are various cross-sectional studies that concluded that vitamin D is associated with blood pressure, but randomized controlled studies have not yielded consistent conclusions. Considering many limitations indeed, our study aimed to examine whether concentrations of 25(OH)D are inversely associated with blood pressure in people without a previous diagnosis of hypertension.We analyzed data from the 2005–2018 National Health and Nutrition Examination Survey. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by applying multivariable logistic regression models. The dose–response relationship was assessed by means of restricted cubic spline regression, and stratification analyses were employed to test the consistency between the subgroups.P for trend = 0.096). Furthermore, as a continuous variable, 25(OH)D concentrations were non-linearly associated with an increased risk of hypertension (P < 0.001). The interaction between the sleeplessness subgroup and higher blood pressure was significant (P = 0.042).Of 17,467 participants aged ≥ 20 years without a previous diagnosis of hypertension, 4,769 had higher blood pressure. Compared with individuals whose 25(OH)D levels were in the bottom quartile (<44.3 nnol/L), adjusting for multiple confounders, the ORs for higher blood pressure were 0.90, 0.85, and 0.86, respectively D were inversely associated with higher blood pressure when it was <84 nmol/L. Approximately 1 billion individuals worldwide suffer from hypertension, making it one of the most common chronic disorders . NeverthAs a fat-soluble steroid hormone, vitamin D is essential for calcium and phosphorus balance and bone health. In addition to dietary intake, subcutaneous endogenous synthesis is an alternative major source of vitamin D. Vitamin D first must be hydroxylated to 25-hydroxyvitamin in the liver and further to 1,25-dihydroxyvitamin in the kidney enabling bioavailability . InteresIn the current study, we attempted to investigate the relationships between serum 25(OH)D and BP, detailing systolic and diastolic blood pressure, in a nationally representative sample of US adults with no previous diagnosis of hypertension.The National Health and Nutrition Examination Survey (NHANES) is a stratified, multistage probability survey, which collected health and nutrition information among the non-institutionalized US population through interviews, physical examination, and laboratory testing. The National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC) conducted NHANES, which was approved by the Institutional Review Board of the National Center for Health Statistics. All participants or their guardians provided signed informed consent.In the current study, we used data from seven consecutive NHANES 2-year cycles . Individuals (aged ≥ 20 years) with no previous diagnosis of hypertension were included in the analysis. We excluded participants with missing blood pressure (BP) or serum 25(OH)D measurements, with measurements of BP <3 times, and with missing serological values >20%. Outliers (through the “scatter” command in Stata) of serum 25(OH)D were further excluded. Hypertension was defined as a self-reported doctor diagnosis of hypertension and use of antihypertensive drugs. We finally had 17,467 eligible participants enrolled for analyses .https://wwwn.cdc.gov/nchs/nhanes/vitamind/analyticalnote.aspx.In the NHANES 2005–2006, serum 25(OH)D was measured by the DiaSorin assay kit . Beginning from the 2007–2008 cycle, serum 25(OH)D concentrations were tested by a standardized liquid chromatography-tandem mass spectrometry (LC-MS/MS). The regression approach was used to convert serum 25(OH)D data from the NHANES 2005–2006 to equivalent 25(OH)D measurements using the LC-MS/MS method. We used LC-MS/MS-equivalent data for all analyses as recommended by the CDC. Detailed information is available at Three successive blood pressure readings were taken after 5 min of calmly resting in a sitting position and establishing the maximum inflation level (MIL). A fourth try would be performed if the measurement of BP was interrupted or incomplete. All measurements of BP were taken in the mobile examination center (MEC). The absolute BP was obtained by averaging three valid measurements. Participants were categorized as having higher BP if systolic blood pressure (SBP) ≥130 mmHg or diastolic blood pressure (DBP) ≥80 mmHg.Several covariates were evaluated as potential confounding factors. Information on age (years), sex , race , education level , smoking status , heavy alcohol drinking (yes and no) was acquired through household interviews utilizing standardized questionnaires. Current smoking was defined as smoking at least 100 cigarettes in one's life and still smoking, previous smoking as smoking at least 100 cigarettes in one's life but not presently smoking, and non-smoking as smoking fewer than 100 cigarettes in one's life. Alcohol consumption was estimated based on self-reported data on the average number of daily drinks. Heavy alcohol drinking was defined as having more than one drink per day for women and more than two drinks per day for men, on average, over the previous 12 months. Vitamin D supplementation refers to the intake of vitamin D2 + D3 in the previous month. During the mobile examination center visit, physical measurements such as body mass index (BMI) and waist circumference were collected. BMI was computed by dividing weight in kilos by height in meters squared.2). According to the KDOQI , aspartate aminotransferase (AST), creatinine, albumin, triglyceride, cholesterol, total bilirubin, blood urea nitrogen (BUN), uric acid (sUA), and HbA1c were included at the baseline. The Chronic Kidney Disease-Epidemiology Collaboration (CKDEPI)  equationAt the baseline, comorbidities consist of a history  of self-reported physician-diagnosed diabetes, coronary artery disease (CAD), stroke, cancer, and sleeplessness.https://wwwn.cdc.gov/Nchs/Nhanes/AnalyticGuidelines.aspx#print. As mentioned before, we combined seven consecutive 2-year cycles  to estimate with greater precision and smaller sampling error.Given the complex sampling design of the NHANES, all analyses were properly weighted in accordance with the analytical guidelines from the National Health and Nutrition Examination Survey for the years 2005 through 2018, which is accessible at p-value for non-linearity was >0.05, we considered the dose–response relationship to be linear, otherwise non-linear. Stratification analyses were performed to examine whether the correlations differed for subgroups classified comorbidities including diabetes, CAD, stroke, cancer, CKD, and sleeplessness.A complex weighting method was utilized for the data description and statistical analysis in this study by using the “Survey” package in R software. The categorical variables were described as frequencies (unweighted) and proportions (weighted), whereas the continuous variables were described as mean standard deviation. The differences were tested using the Wilcoxon rank-sum test for continuous variables and the chi-square test with Rao–Scott second-order correction for categorical variables. To investigate the association between serum 25(OH)D and higher BP, serum 25(OH)D levels were divided into quartiles, and adjusted ORs for increased blood pressure were calculated through weighted logistic regression in three distinct models. Model 1 was unadjusted. Model 2 was adjusted for age, gender, and ethnicity. Model 3 was adjusted for age, gender, ethnicity, education level, smoking status, heavy alcohol drinking, vitamin D supplementation, BMI, waist circumference, diabetes, coronary heart disease, stroke, cancer, sleeplessness, CKD, serum calcium, ALT, AST, Scr, albumin, triglyceride, cholesterol, total bilirubin, BUN, sUA, and HbA1c. The lowest quartile of serum 25(OH)D was used as the reference group. To further examine the dose–response relationship between serum 25(OH)D concentrations and BP, restricted cubic spline regression was performed with four knots, with the multivariate adjustment in Model 3. If the p < 0.05 was used to determine statistical significance. All the data analyses were performed using the software Stata/SE V.15.1  and R software 4.2.2 (http://www.R-project.org).A two-sided p < 0.05) were found in smoking status, heavy alcohol drinking, vitamin D supplementation, BMI, waist circumference, cancer, sleeplessness, CKD, serum calcium, ALT, AST, Scr, albumin, triglyceride, cholesterol, total bilirubin, BUN, sUA, and HbA1c. Participants with higher BP were 4,769, and the weighted percentage reached 25%. Of these, 3,382 patients suffered from higher systolic blood pressure, and 2,739 suffered from higher diastolic blood pressure.As previously stated, we built three logistic models to explore the connection between serum 25(OH)D concentrations and BP .As for higher BP, in Model 1, which was unadjusted for variables, the HRs (95% CI) for the Q2 (44.3–60.5), Q3 (60.5–77.7), and Q4 (≥77.7) were 0.90 , 0.87 , and 0.92 , respectively, compared with the Q1 (<44.3). After adjusting for age, gender, and ethnicity in Model 2, the HRs (95% CI) of higher BP for Q2, Q3, and Q4 were 0.86 , 0.75 , and 0.69 , respectively, compared with the reference (Q1). Meanwhile, in Model 3, compared with Q1, the HRs (95% CI) for Q2, Q3, and Q4 were 0.90 , 0.85 , and 0.86  after adjusted for multiple confounders.p > 0.05).We further evaluated the effect of serum 25(OH)D concentrations on higher systolic and diastolic blood pressure alone. In Model 3, Q2-4 had a significantly lower HR (95% CI) of higher systolic BP than the reference (Q1). However, opposite of Q3 (60.5–77.7) and Q4 (≥77.7), Q2 (44.3–60.5) tended positive correlation with higher diastolic BP in Model 3, but it did not reach statistical significance D concentrations and BP, indicating a U-shaped correlation (p for interaction < 0.05).We adjusted the confounding factors in Model 3 in these subgroups. CKD1 was considered to have no chronic kidney disease (CKD), and CKD2 to CKD5 were regarded as having chronic kidney diseases. As shown in Our analyses, based on a nationally representative population from seven consecutive NHANES cycles (2005–2018), were performed to explore the relationship between serum 25(OH)D concentrations and BP in adults with no previous diagnosis of hypertension in the US. The key findings could be summarized in three points. First, after adjusting multiple variables, serum 25(OH)D was negatively correlated with BP, primarily SBP. Second, the relationships between serum 25(OH)D concentration and BP, including SBP and DBP, were non-linear. Third, the relationship was consistent across the subgroups except for sleeplessness.Early in the 1980s, Sowers et al. . Howevervia activation of angiotensin II type 1 receptor (AT1R). In addition, when vitamin D deficiency induces vascular sclerosis and stretching disturbances, the entire stroke volume flows through the arterial system and peripheral tissues, which results in increased SBP and decreased DBP D is still unknown, and there are several possible core factors. An animal experiment conducted by Li et al.  found a ased DBP . FurtherIncreasing evidence supports the existence of a threshold effect for vitamin D levels . In our via endogenous synthesis D and BP tends to be more pronounced and sustained among participants with sleeplessness. As well, recently, a cross-sectional study showed a more pronounced and stable association between vitamin D status and coronary heart disease in participants with poor sleep patterns . As far ynthesis , 37 and ynthesis . As a reIt is important to note that there are some limitations in our study. First, there is a dearth of data on participants' salt intake and sun exposure, which are important factors in endogenous vitamin D production and hypertension, respectively. Second, we performed a single measurement of plasma 25(OH)D, which had a marked circadian variation. Third, because BP was measured merely in a single appointment, it is possible that some participants were wrongly labeled as having higher blood pressure while they were actually normotensive, and vice versa. Fourth, biases resulting from excluded and unmeasured confounders may still exist, despite our efforts to account for as many confounders as possible. Fifth, relationships between 25(OH)D and BP stratified by sleeplessness deserve to be further verified. Finally, the cross-sectional design also makes it impossible to distinguish between causes and effects.We discovered a non-linear association between serum 25(OH)D concentration and BP in a nationally representative sample of US participants without a previous diagnosis of hypertension. Concentrations of 25(OH)D were inversely associated with blood pressure when it was <84 nmol/L. More specifically, serum 25(OH)D is adversely correlated with systolic blood pressure, and as for diastolic blood pressure, higher serum 25(OH)D concentrations were associated with higher diastolic blood pressure when serum 25(OH)D levels >84 nmol/L.https://www.cdc.gov/nchs/nhanes/index.htm.Publicly available datasets were analyzed in this study. This data can be found here: The studies involving human participants were reviewed and approved by the National Center for Health Statistics Research Ethics Review Board. The patients/participants provided their written informed consent to participate in this study.JC: Writing—original draft, Investigation, Validation. JT: Validation, Writing—original draft. XK: Data curation, Formal analysis, Writing—review and editing. CZ: Data curation, Formal analysis, Writing—review and editing. RZ: Visualization, Writing—review and editing. JS: Visualization, Writing—review and editing. XZ: Visualization, Writing—review and editing. ZL: Conceptualization, Writing—review and editing.


This study hypothesized that elevated glycosylated hemoglobin (HbA1c) levels are associated with abnormal right heart catheterization (RHC) hemodynamic parameters in patients with heart failure with reduced ejection fraction (HFrEF) and no prior diagnosis of diabetes.Retrospective cohort study of adult patients with HFrEF and no prior diagnosis of diabetes who underwent RHC and had HbA1c levels measured 30 days before or after the RHC. This study excluded patients who had received blood transfusions within 90 days prior to HbA1c measurement and patients with known diabetes. Univariate and multivariate regression analyses adjusted for age, sex, and BMI were used to test for an association between RHC hemodynamic parameters and HbA1c levels.2 decrease in expected CI by thermodilution and by the Fick method (P = 0.03 and P < 0.01), respectively. For every one unit increase in HbA1c, there was a 2.39 mmHg increase in expected RAP (P = 0.01).A total of 136 patients were included with a mean age of 55 ± 15 years and mean HbA1c was 5.99 ± 0.64%. Unadjusted univariate models showed that HbA1c is significantly associated with cardiac index (CI) by the Fick method and thermodilution, right atrial pressure (RAP), and mean pulmonary arterial pressure (MPAP). After multivariate analysis, for every one unit increase in HbA1c, there was a 0.19 and 0.26 L/min/mElevated HbA1c levels measured within 30 days before or after the index RHC in patients with a left ventricular ejection fraction <40% were associated with congestive hemodynamic parameters. Diabetes mellitus (DM) and heart failure (HF) are frequently associated with clinical disorders. DM has a prevalence of approximately 25% in stable HF, compared to only 7% in the general population . This reRight heart catheterization (RHC) is an invasive procedure that allows direct right heart pressure measurements and cardiac output (CO) estimation, with the goal of either assess hemodynamic status or diagnose certain cardiopulmonary diseases that are not identified with noninvasive tests. Although an RHC can help determine the patient’s volume status and distinguish HF from other disorders that cause circulatory instability, there is no established role for periodic invasive hemodynamic measurements in HF management .HF may increase the propensity to develop insulin resistance with a subsequent increase in plasma glucose. Furthermore, it has been shown that patients with HF are more insulin resistant than normal controls –6. This Many landmark clinical trials have addressed the relationship between tight glycemic control and cardiovascular endpoints. However, the relationship between hemodynamics and glycemia has not been studied. Glycosylated hemoglobin (HbA1c) is the result of nonenzymatic hemoglobin glycosylation and indicates the average blood glucose concentration over the past 6–8 weeks . TherefoThis study is based on a retrospective cohort of patients managed in the Internal Medicine clinics at Texas Tech University Health Sciences Center and University Medical Center in Lubbock, Texas, under IRB L21-159. It included all adult patients (>20 years) with HFrEF who underwent an RHC between 1 June 2015 and 1 June 2021 and had HbA1c levels measured within 30 days before or after the index catheterization. Included patients had to have a documented left ventricular ejection fraction of <40% by echocardiography 1 month after or up to 6 months before the index RHC was done. Patients were excluded if they had received blood transfusions within 90 days prior to HbA1c measurement or had a prior DM diagnosis, a history of hypoglycemic medication use, end-stage renal disease, and/or chronic corticosteroid use since these factors could affect HbA1c levels.2 were defined as abnormal.Hemodynamics were measured by RHC and dichotomized into normal and abnormal values based on conventional levels of clinical significance. Hemodynamic abnormalities were defined by a right atrial pressure (RAP) > 6 mmHg, right ventricular systolic pressure (RVSP) > 25 mmHg, right ventricular diastolic pressure > 8 mmHg, pulmonary artery systolic pressure (PASP) > 25 mmHg, pulmonary artery diastolic pressure > 15 mmHg, mean pulmonary artery pressure (MPAP) > 19 mmHg, and pulmonary artery wedge pressure > 15 mmHg. Using the Fick formula and thermodilution, CO < 4L/min and a cardiac index (CI) < 2.2 L/min/mHemodynamic measurements were obtained with a Swan-Ganz pulmonary artery catheter , a fluid-filled catheter. This catheter is connected to pressure transducers which have an accuracy, per factory specifications, from −3 mmHg to 50 mmHg. In this pressure range the minimum reading is −1 mmHg or −1%, and the maximum reading is +1 mmHg or +1% of current readings.t-tests. Fisher’s exact test was used instead of the chi-square test when cells had expected frequencies below 5.Numerical variables are reported with means and SD, and categorical variables are reported using counts and frequencies. Descriptive statistics were used to determine differences in patients with normal and abnormal cutoff hemodynamic parameters. Categorical variables (gender and ethnicity) were compared using chi-square tests, and numerical variables (age and BMI) were compared using P-value <0.05 was considered to be statistically significant for all the tests. All statistical analyses were done in SAS 9.4 version for Windows.Univariate linear regression analyses were used to evaluate the relationship between HbA1c as the predictor variable and RHC hemodynamics as the outcome variable. Additional RHC hemodynamic predictors were selected after performing a stepwise selection technique for model analysis. Multivariate regression analyses were performed by adjusting for age, gender, and BMI; regression coefficients and 95% confidence intervals are reported. A http://links.lww.com/CAEN/A41). Compared to patients with low RVSP pressures, patients with high RVSP pressures were more likely self-reported white ethnicity . The mean BMI differed in patients classified by CO measured by thermodilution, RAP, and RVSP. Compared to patients with abnormal parameters, patients with normal parameters had higher mean BMIs .A total of 136 patients were included  or the Fick method (P < 0.01), MPAP (P = 0.04), and RAP (P = 0.01). After conducting multivariate analyses, for every one unit increase in HbA1c, there was a 0.19 and 0.26 L/min/m2 decrease in expected CI by thermodilution and by the Fick method, respectively  and a negative correlation between HbA1c levels and CI by both thermodilution and the Fick method (P = 0.03 and P < 0.01). These results correlate with congestive/abnormal hemodynamics (reduced CI and elevated RAP). Based on the current literature, this is the first study that has evaluated the association between RHC hemodynamics and glucose control in non-diabetic patients. This study agrees with prior results that evaluated the presence of impaired glucose and hyperinsulinemia in non-diabetic patients with HF [In this retrospective cohort of patients with HFrEF, HbA1c levels were associated with RHC hemodynamic parameters. There was a positive correlation between HbA1c levels and RAP  is an independent risk factor for HF after adjustment for age, sex, race, and traditional cardiovascular risk factors [The second hypothesis considers the effect of continuous hyperglycemia (represented by elevated HbA1c) on the vasculature leading to HF, which can be explained by several factors. First, hyperglycemia stimulates sodium retention that activates the autonomic nervous system causing hemodynamic derangements that lead to fluid overload causing HF ,18. Secoischemia . In patiischemia –23. Mats factors . Based oThe demographic information indicated that most patients were middle-aged white males with non-ischemic cardiomyopathies and BMIs in the overweight range. None of the patients included in the study had a BMI within normal limits. There are studies showing that BMI is positively correlated with HbA1c . HoweverThis retrospective study has several limitations. Patients with possible confounders that could affect HbA1c levels in HF patients  were excluded from the study, but other possible confounders that were not excluded  could have influenced the results. This study suggests that abnormal hemodynamics in HFrEF could be associated with glycemic derangements, but this cannot be conclusive since in this study no causal effect experiments were performed. There are no experimental data available in the literature supporting this observation. After conducting multivariate analyses, HbA1c remained the primary predictor of RHC hemodynamics. However, results are limited to a specific model with preselected variables and do not include all the factors that could affect the HbA1c-RHC hemodynamic relationships. Considering these limitations, the findings of the present study should be interpreted as only hypothesis-generating and should not be overstated. More studies are needed to determine if an association between impaired glucose control and abnormal hemodynamics in HF is clinically relevant. If there is significant improvement in HbA1c after HF optimization, this simple test could potentially be used as a prognostic factor for disease severity and as a method to monitor fluid balance status and cardiac function over longer treatment periods, for example, over quarterly clinic visits.HbA1c levels measured within 30 days before or after the index RHC in patients with left ventricular ejection fractions <40% were associated with parameters that correlate with congestive hemodynamics (reduced CI and elevated RAP). A larger study is needed to determine if these associations are consistent in all of the hemodynamic parameters obtained during an RHC and to see if HbA1c levels reflect responses to treatment.There are no conflicts of interest.