To explore the effects of inspiratory muscle training (IMT) on hypertension and provide guidance for its clinical application as an auxiliary approach.Articles published prior to July 2022 were searched in Cochrane Library, Web of Science, PubMed, Embase, CNKI, and Wanfang databases. Included were randomized controlled studies that used IMT to treat individuals with hypertension. The mean difference (MD) was computed using the Revman 5.4 software. In individuals with hypertension, the effects of IMT on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and pulse pressure (PP) were compared and studied.There were found to be eight randomized controlled trials totaling 215 patients. According to a meta-analysis, the IMT reduced the SBP , DBP , HR , and PP  in patients with hypertension. In subgroup analyses, low-intensity IMT showed a better reduction in SBP , DBP .IMT may become an auxiliary means to improve the four hemodynamic indexes  in patients with hypertension. In subgroup analyses, low-intensity IMT was more effective in regulating blood pressure than medium-high-intensity IMT.https://www.crd.york.ac.uk/prospero/, identifier: CRD42022300908. The literature search was carried out without language restrictions or a beginning date until July 2022 using the following terms: “high blood pressure”, “hypertension”, “blood pressure”, “diastolic blood pressure”, “systolic blood pressure”, “systolic blood pressure”, “pulse pressure”, “heart rate”, “breathing exercise”, “inspiratory muscle training”, “inspiratory loaded breathing training”, “high-resistance inspiratory muscle strength training”, “slow load breathing training”, and “IMT.” We contacted the authors via email for additional information in cases of insufficient data, and the available data were used to run analyses if they failed to respond within 14 days.2.3.Relevant literature was searched using the following process: The first step was a preliminary screening using the title and abstract, which was then loaded into Endnote X9 software, where duplicate literature was then removed. The remaining full text of literature was carefully examined in light of the established inclusion and exclusion criteria, and any content that did not meet the standards was eliminated. The whole screening process was independently performed by two reviewers (GL and LC). The third reviewer (YZ) was ready for consultation if there were any discrepancies between the two independent reviewers.2.4.Two researchers (SZ and SYL) independently retrieved the following information: the first author, publication year, sample size, average age, type of hypertension, gender, medication, load intensity, intervention time, training time, training frequency, respiratory rate, training equipment, data  of the intervention group and control group data, time of measurement, equipment of measurement, and position of measurement. When there was insufficient data, we emailed the authors for additional information, and if they didn't reply within a week, we ran analyses using the data that were available instead.2.5.The quality of each study was assessed by two researchers (QZh and SZ) using a modified Jadad quality scale  that inc2.6.I2 statistics, this study quantitatively discussed the heterogeneity of various studies. These relevant data results were analyzed using the Revman5.4 software. The pooled MD and the 95% CI were represented graphically using a forest plot. According to its weight in the meta-analysis, each study was represented in the plot by a square. The threshold for statistical significance was a two-sided P value of 0.05. As the number of included researches was lower than ten pieces of research, we did not use statistical or graphical methods to evaluate publication bias.The Cochrane Handbook for Systematic Reviews of Interventions was used to analyze the data. For continuous variables, the mean difference (MD) and 95% confidence interval (CI) were used to compare net changes . For each study group and important outcome, mean and standard deviations (SD) were gathered in order to calculate the effect size. A negative effect size indicated that IMT effectively reduced SBP, DBP, HR, and PP. Using the heterogeneity chi-square test and 3.3.1.The initial search identified 5,754 pieces of literature, 5,141 of which were left after eliminating duplicate literature using the EndNote x9 software. Only 104 publications, chosen based on titles and abstracts, were used for the rest of the analysis. Eight RCTs , 25–29, 3.2.Eight studies with a total sample size of 215 patients aged between 50 and 70 years were finally analyzed: seven clinical trials were designed as parallel trials –29 and o3.3.Ambulatory BP and PP were measured in two studies , 29 and 3.4.Five , 25–27 i3.5.According to the improved Jadad scale, low quality was defined as 1–3 points and high quality as 4–7 points. Seven studies , 26–29 s3.6.3.6.1.n = 228, MD = −12.55 mmHg, 95%CI , P < 0.01] . Therefore, for the meta-analysis, we used a fixed effects model. The results demonstrated that IMT training was more successful than a control group in decreasing DBP in patients with hypertension  , P < 0.01] (Because Daniel H 2021  study co < 0.01] .3.7.2.2I = 17%) was small; thus, it was decided to use the fixed effect model, and the analysis's findings revealed that IMT could reduce the PP of patients with hypertension  , P < 0.01] , P = 0.31] , P < 0.01] , P = 0.01] , P < 0.01] , P = 0.004]  a small number of RCTs were included in this investigation, and the bulk of them had modest sample sizes; therefore, the total sample size was small; (2) some heterogeneity problems encountered in this study may be due to different equipment, training frequency, training duration, intervention time, and intervention intensity; (3) since the respective number of different types of hypertension was very small in the included studies, this study did not do a subgroup analysis of distinct kinds of hypertension.5.IMT may become an auxiliary means to improve the four hemodynamic indexes  in patients with hypertension. Furthermore, low-intensity IMT was preferred over medium-high-intensity IMT in subgroup analyses for regulating SBP and DBP. Both low and medium-high-intensity IMT could reduce the HR of patients with hypertension. However, the training time, respiratory rate, and training frequency of IMT, as well as the therapeutic effects on different types of hypertension, should be further explored.


Background: Diabetic kidney disease (DKD), a common cause of CKD and kidney failure, is usually diagnosed clinically. However, there is little evidence comparing the performance of a clinical diagnosis to biopsy-proven diagnosis. Purpose of the study: Diagnostic performance of a clinical diagnosis was determined in a group of patients with diabetes and chronic kidney disease who underwent kidney biopsy after an initial clinical diagnosis. Methods: A data analysis of 54 patients who were part of a study cohort for a prospective analysis of cardiovascular and kidney outcomes and who had undergone kidney biopsy after an initial clinical diagnosis of DKD or non-DKD (NDKD) at enrolment was used. We determined the sensitivity, specificity, and positive and negative predictive values of a clinical diagnosis of DKD. Results: A total of 37 of 43 patients clinically diagnosed with DKD also had biopsy-proven DKD, whilst only 1 of 11 patients who had clinically diagnosed NDKD had biopsy-proven DKD. Sensitivity was 97.4%, specificity was 62.5%, positive predictive value 86%, and negative predictive value 90.9%. Comparable values were obtained when analysis was restricted to those with primary rather than secondary diagnosis of DKD or when restricted to those with only DKD found at biopsy. Conclusion: A clinical diagnosis of DKD has high sensitivity and is unlikely to overlook cases but may lead to overdiagnosis. Diabetic kidney disease (DKD) remains a common complication of diabetes mellitus (DM) and is a common cause of both chronic kidney disease (CKD) and kidney failure worldwide. Given the increasing prevalence of DM  worldwide , the preNonetheless, kidney biopsy still has a role in the clinical management of DKD and is certainly still performed in patients with DM and kidney disease. It remains the “gold standard” for the diagnosis of DKD and helps to establish prognosis by determining the severity of disease. Renal pathology society has developed a histopathological classification consensus of diabetic kidney disease applicable to those with DM types 1 and 2 . Given the reliance on a “clinical diagnosis” of DKD, there is little published evidence on its diagnostic performance  compared to the “gold standard” histopathological diagnosis.In a pooled meta-analysis of 48 studies involving 4876 diabetic patients , Fiorentino et al. . In thisMore recently, Tong et al.  performeWe performed a separate literature search across two databases (MEDLINE and EMBASE), dating as far back as 1976, looking for studies where the diagnostic performance of a pre-assigned clinical diagnosis of DKD was compared against a subsequent histopathological diagnosis. This search yielded only the same study mentioned above .It is useful to know whether DKD is present (even if co-existent with another pathology) because this will certainly help guide prognosis. If DKD is present, then even specific therapy for co-existent NDKD will not fully reverse kidney damage as the DKD will still be present. In some cases, specific treatment might even accelerate the progression of DKD, e.g., steroid or calcineurin inhibitor therapy for certain glomerulopathies may worsen DM and BP control, both of which will accelerate the progression of the co-existing DKD.Even when DKD is believed the sole pathology, there is still merit in being certain that this is indeed the case, because once again, the prognosis might also differ significantly from the situation where NDKD is present, e.g., SGLT-2 inhibitor therapy might be less effective if NDKD co-exists. In this study, our purpose was to determine the diagnostic performance of a clinical diagnosis of DKD in a series of patients who underwent kidney biopsy after first being assigned a clinical diagnosis.The patients were all enrolled in the CKD.QLD registry. This is the first formal Australian registry of non-dialysis CKD patients receiving public hospital kidney specialist care ,9 and haAt the time of enrolment, clinicians assigned at least one diagnosis for the underlying CKD, based on the primary renal disease coding system utilized by the Australian and New Zealand dialysis and transplant registry (ANZDATA) . On thisIf more than one clinical diagnosis was assigned, we considered the order as hierarchical, and clinically diagnosed DKD was deemed present if DKD was among the first two listed diagnoses (if more than one was assigned). All other patients were considered to have clinically diagnosed NDKD.All kidney biopsies performed within Queensland Health require written informed consent from the patient. Biopsies are performed by nephrologists  under ultrasound guidance. Tissue cores are sent for analysis via light microscopy, immunofluorescence, and electron microscopy. The reporting of kidney biopsies for the pre-specified study period (2011–2017) was performed by renal pathologists at the state capital’s two tertiary hospitals.DKD was defined as present if there were histopathological changes as per the renal pathology society consensus guidelines , even ifWe calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a clinical diagnosis of DKD against the “gold standard” of a biopsy diagnosis.2 test or Fisher’s exact test. A 95% CI for sensitivity and specificity were calculated using the binomial (“Clopper–Pearson”) method. A 95% CI for positive predictive value, negative predictive value, and diagnostic accuracy was calculated using the method of Mercaldo et al. [Summary statistics were number (%), mean (+/− SD), or median (IQR). Comparisons of proportions were carried out using the chio et al. . The lato et al. , we estiAmong the 2370 patients with DM enrolled in the registry during the specified period, 185 (7.8%) had undergone kidney biopsy although of these, only 54 had undergone kidney biopsy after their initial clinical diagnosis/diagnoses. All 54 biopsies yielded sufficient tissue for a histopathological diagnosis to be assigned. 2 , 85% of patients had proteinuria (urine ACR > 30 mg/mmol or protein:creatinine >50 mg/mmol), and >90% were already on RAAS blocker therapy (The baseline characteristics of these 54 patients and listed indications for biopsy are presented in  therapy . It is o therapy . In 43 pCardiac:Acute coronary syndrome.Coronary revascularization event—elective or emergency (but not including diagnostic angiogram).Heart failure.Cerebrovascular:Cerebrovascular accident (not including transient ischaemic attack).Carotid artery revascularization (elective or emergency).Other vascular:Gangrene requiring limb/digit amputation.Peripheral artery revascularization procedure (elective/emergency) not including diagnostic angiogram.Aortic aneurysm hospitalization for rupture or leak or repair (elective or emergency)—not including incidental discovery during admission or outpatient clinic review.Bowel infarction—confirmed via the histology of resected bowel or relevant history and imaging (if managed conservatively).All 54 biopsy specimens yielded sufficient tissue for histopathological diagnosis. A total of 38 patients (70.3%) had evidence of DKD at biopsy. A total of 14 of these (25.9%) had co-existing pathologies present .Co-existing pathologies in the 14 patients are listed in A total of 16 patients only had evidence ofNDKD on biopsy. Their biopsy diagnoses are listed in The clinical diagnosis and subsequent biopsy findings are compared in Based on the information in Excluding four patients with a second listed clinical diagnosis of DKD (presuming that these were patients in whom there was less confidence in the diagnosis)—the results are summarized in Excluding the 14 patients who had DKD as a shared pathology at biopsy—the results are summarized in We performed two sensitivity analyses:p < 0.05). Furthermore, nephrotic range proteinuria (Category 4) was more common in those with DKD (p = 0.001). The latter remained true even when analysis was restricted to those with only DKD or NDKD at biopsy (p < 0.005).We examined the association between biopsy diagnosis (DKD or only NDKD) and proteinuria level at enrolment. These results are summarized in p = 0.19).We examined the association between biopsy diagnosis (DKD or NDKD only) and microscopic haematuria  and it did not seem to matter whether the clinical diagnosis of DKD was first or second listed . The specificity was lower, suggesting a tendency to “over-diagnose” the condition. However, given the higher prevalence of DKD compared to NDKD in this population, the negative predictive value was also high, i.e., “no likely means no”. The overall accuracy of clinical diagnosis was >80%. The diagnostic performance was similar even when the question being asked was “is DKD the only pathology present?” rather than “is DKD present?”.Multiple studies in patients with type 2 DM have examined the association of various clinical parameters with the presence of DKD or NDKD on histopathology. In the systematic review by Tong et al. , the fivIn six studies published since the that systematic review ,18,19,20However, these studies examined the performance of individual factors rather than that of an overall clinical impression, which considers the impact of multiple factors. Thus, the authors cannot claim to examine the diagnostic performance of a clinical diagnosis. The associations were determined in retrospective fashion  and clinically significant associations were not then explored in a prospective fashion . Furthermore, the associations were weak in two studies ,16, limiOur multi-centre study enrolled patients from 11 different hospitals across the state, which should address the issue of site-specific clinical practice. Whilst the data collected by the CKD.QLD registry did not allow us to assess the impact of diabetic retinopathy or duration of diabetes, it is likely that enrolling clinicians would have considered the presence of these factors when assigning a clinical diagnosis of DKD, given the widespread and long-held acceptance of both as predictors of DKD.Three recent studies ,22,23 haTo our knowledge, only one prior study  has genuAlthough the ADA guidelines  have sugWe also found that microscopic haematuria was more commonly reported in patients with DKD at biopsy, although the difference did not achieve statistical significance.In the DAPA-CKD study, CKD patients without DM (and therefore no DKD) derived similar kidney outcome benefits from SGLT2 inhibitor therapy to patients with DM2 . These fThis is a small patient sample. Furthermore, the small proportion of patients with type 1 DM mean that we cannot comment on the diagnostic performance of a clinical diagnosis in these patients. However, the sample size in not much smaller than some recently published studies.Whilst indication bias is likely to be present, this is no different from most other published studies on kidney biopsy in patients with DM, where the majority had been performed because of suspected NDKD. Our principal intent was determining the accuracy of a prior allocated clinical diagnosis of DKD rather than to determine indications for the biopsy. In any case, ~80% of our patients had already been clinically diagnosed with DKD  prior to biopsy.Biopsy safety was not explored here as it was not part of the study intent. However, no major bleeds were recorded from these 54 biopsies. Although the lack of bleeding complications could be attributed to selection of “lower risk” patients for biopsy, the rate of significant bleeding complications is generally quoted as ~1% , such thWe have shown that clinician-labelled diagnosis of DKD in the kidney specialist care setting has high sensitivity and seems unlikely to miss diagnosing cases. However, there is a tendency towards overdiagnosis (lower specificity). Caution should also be exercised, as non-proteinuric DKD is likely to be more prevalent in the kidney specialist care setting. Thus, we propose a larger pragmatic study to further investigate this. Adult patients with DM, who have any of the standard indications for native kidney biopsy in adults  (i.e., n


No improvement in median Qs/Qt could be detected . A total of 7 patients with improved Qs/Qt had a significant reduction in risk score compared to those without improved Qs/Qt. Conclusion: PEA did not alter Qs/Qt assessed after 1 year in operable CTEPH despite an improvement in hemodynamics and risk score, potentially indicating a persistent microvasculopathy. In patients whose shunt fraction improved with PEA, the reduced shunt was associated with an improvement in risk score.Background: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (CTEPH) with accessible lesions. Breathing pure oxygen (hyperoxia) during right heart catheterization (RHC) allows for the calculation of the right-to-left shunt fraction (Qs/Qt). In the absence of intracardiac shunt, Qs/Qt can be used as a marker of ventilation–perfusion mismatch in patients with CTEPH. This study involved investigating Qs/Qt after PEA and its relation to other disease-specific outcomes. Study design and Methods: This study is a retrospective study that focuses on patients with operable CTEPH who had Qs/Qt assessment during RHC before and 1 year after PEA. Additionally, 6 min walking distance (6MWD), WHO functional class (WHO-FC), and NT-proBNP were assessed to calculate a four-strata risk score. Results: Overall, 16 patients  with a median age of 66 years  were included. After PEA, an improvement in mean pulmonary artery pressure , pulmonary vascular resistance , oxygen saturation , WHO-FC, and risk score was observed (all  Precapillary pulmonary hypertension (PH) is defined as mean pulmonary artery pressure (mPAP) > 20 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 WU (assessed via right heart catheterization) . The inc2 1.0) during RHC allows for the calculation of Qs/Qt [As shown in a recently published study, a high proportion of patients with precapillary PH due to pulmonary vascular disease (PAH/CTEPH) showed an increased fraction of right-to-left shunt (Qs/Qt) (measured by RHC) . Right-tof Qs/Qt . Data onThe purpose of this study was to investigate the change in the right-to-left shunt fraction after PEA (assessed during RHC). In addition, we aimed to compare the improvement in shunt fraction to hemodynamic parameters and other outcomes, such as changes in 6 min walking distance (6MWD), WHO functional class, levels of NT-pro brain natriuretic peptide (NT-proBNP), and, consequently, the possible changes in risk category with respect to the four-strata risk assessment tool.2 0.21) and pure oxygen  for 10 min each were included in the analysis. All patients provided written informed consent. The study protocol was approved by the Cantonal Ethics Committee Zurich (No. 2020-01541).In this retrospective study, we examined Qs/Qt and other hemodynamics assessed during the clinically indicated RHC of patients with CTEPH before and 1 year after PEA. All RHCs were performed at the PH-Center, University Hospital Zurich, Switzerland . This st2 0.21), and additional measurements were taken whilst patients were breathing pure oxygen  via a three-way non-rebreathing valve from a reservoir bag  for >10 min. The hemodynamic parameters, heart rate (HR), systolic, mean and diastolic systemic blood pressure , systolic, mean and diastolic PAP , pulmonary arterial wedge pressure (PAWP), and right atrial pressure were averaged over several respiratory cycles at baseline and whilst breathing hyperoxic gas for >10 min [2, SmvO2), arterial and mixed venous partial pressures of oxygen , and carbon dioxide  [The RHC was performed via jugular venous access using a balloon-tipped, triple-lumen, fluid-filled, 8 French Swan-Ganz CCOmbo V catheter  in supine resting position following a previously described method . Zero le >10 min ,11,13. A, PmvO2) ,11. Card, PmvO2) . The rig, PmvO2) :QsQt=0.02FiO—fraction of inspired oxygen; BP—standard barometric pressure; H2OP—partial pressure of water at body temperature; 2PaCO—arterial partial pressure of carbon dioxide; R—respiratory quotient; 2ScapO—pulmonary capillary oxygen saturation; Hb—hemoglobin; 2SaO—arterial saturation of oxygen; 2PaO—arterial partial pressure of oxygen; 2SmvO—mixed venous saturation of oxygen; 2PmvO—mixed venous partial pressure.6MWD, WHO functional class, and NT-proBNP levels were evaluated shortly before pulmonary endarterectomy and during the 1-year post-surgical follow-up. The collected variables were used to calculate the risk score by using the simplified four-strata risk assessment tool as recommended to determine 1-year mortality in patients with pulmonary arterial hypertension .The main outcomes were the change in Qs/Qt 1 year after PEA and the association between Qs/Qt changes and the changes in the hemodynamic parameters . Other outcomes included changes in WHO functional class, 6MWD, NT-proBNP levels, and change in four-strata risk category (assessed by risk score) compared to the improvement in shunt fraction.p-value <0.05 was considered statistically significant. Missing values were not replaced. The statistical analyses were performed using IBM SPSS Statistics .Categorical data are reported as number (percentage), and continuous data are reported as median (interquartile range). Due to the small sample size of 16 patients nonparametric tests were used. The Wilcoxon signed-rank test was used to compare the parameters measured before and after PEA. After forming two groups by virtue of a decreased shunt fraction, which was considered as an improvement in Qs/Qt of >10% compared to baseline and no improvement, parameters such as hemodynamics, 6MWD, NT-proBNP, risk score and corresponding four-strata risk category, and WHO functional class were compared before and after PEA for each group separately by using the Wilcoxon signed-rank test. The Mann–Whitney U test was used to compare patients with and without improvements in Qs/Qt. Additionally, Fisher’s exact test was used where appropriate to analyze changes in WHO functional class, 6MWD, NT-proBNP levels, and the risk scores or four-strata risk categories related to the shunt groups. For all tests, a We included 16 patients with CTEPH (38% women); the patients had a median age of 66  years, and Qs/Qt measurements were taken before and 1 year after PEA . A flowcHemodynamics, blood oxygenation, and shunt fraction variables were assessed before and 1 year after pulmonary endarterectomy.p-value = 0.679). Fourteen patients (88%) had a shunt fraction >10% after the surgery compared with twelve patients (75%) before PEA (p < 0.001), whereas no significant changes in PAWP and CI were detected. Furthermore, the arterial and mixed venous blood gas samples showed a significant improvement in oxygen saturation , PaO2 , and PaCO2  after the surgical procedure  % compared to before 13.7  %  during RHC at baseline and one year after PEA. Among all patients, the median shunt fraction was unchanged 1 year after PEA, but 7/16 (44%) patients improved their shunt fraction (>10% from baseline). A year after PEA, mPAP, PVR, oxygen saturation, and PaO2 on ambient air were significantly improved, and WHO-FC and four-strata risk score also improved, while 6MWD and NT-proBNP remained unaltered. Half of the patients were free of resting PH 1 year after PEA. Regarding the groups stratified by improvement in shunt fraction, both groups showed the same significant hemodynamic improvements as mentioned. The only significant difference between the groups was the decrease in the four-strata risk score in the group with improved Qs/Qt, whereas the group without any improvements in shunt fraction maintained the same risk score one year after PEA, although the absolute risk scores were very low in both groups.In this retrospective study, we investigated the right-to-left shunt fraction (Qs/Qt) in patients with CTEPH whilst breathing pure oxygen  is a pulmonary vascular disease characterized by recurrent pulmonary embolisms and the fact that it often follows vascular remodeling, leading to an increase in pulmonary pressure (measured via right heart catheterization). CTEPH affects up to 38 individuals per million adults worldwide. Pulmonary endarterectomy (PEA), the surgical removal of thromboembolic material from the pulmonary vessels, is the current treatment of choice to reach normal pulmonary hemodynamics in operable cases. As already shown in previous studies, many patients with CTEPH show an increased fraction of right-to-left shunt (measured by right heart catheterization). Data on the effect of PEA on shunt fractions are rare. The aim of this study was to investigate the change in the right-to-left shunt fraction after PEA and its relation to other disease-specific outcomes. In this study there was no significant improvement in shunt fraction after PEA. However, on an individual patient level, a decrease in shunt fraction was associated with a decrease in simplified four-strata risk score.2 and during exercise, though these would be difficult to assess [This study’s sample size of 16 patients is relatively small but still considerable with respect to the rarity of the disease and the complexity of the measurements taken . This study’s findings need to be interpreted with caution due to the low sample size. In this study, only patients with operable CTEPH were included. Qs/Qt can only be calculated when breathing pure oxygen; it is not yet clear if shunt fractions change under different FiOo assess .We detected no significant improvement in Qs/Qt one year after pulmonary endarterectomy in patients with operable CTEPH, which may be explained by an inaccessible microvasculopathy. A decrease in Qs/Qt was associated with a decrease in simplified four-strata risk score.


The goal of blood pressure (BP) control will be lower when hypertensive patients have comorbidities that can affect the risk of cardiovascular diseases. But, the goal of BP control for hypertensive patients coexistent with obstructive sleep apnea (OSA) is not discussed, which is a special population at high risk of cardiovascular diseases.Using data from a retrospective study(Urumqi Research on Sleep Apnea and Hypertension (UROSAH) study, we enrolled 3267 participants who were diagnosed with hypertension and performed polysomnography during 2011–2013 to explore the association between BP control and long-term major adverse cardiovascular and cerebrovascular event (MACCE). Outcomes of interest was the levels of BP control, MACCE, cardiac event and cerebrovascular event. Then we calculated the cumulative incidence of MACCE and performed Cox proportional hazards with stepwise models.379 of 3267 patients experienced MACCE during a median follow-up of 7.0 years. After full risk adjustment, BP control of 120-139/80-89mmHg was associated with the lowest risk of cerebrovascular event  rather than MACCE and cardiac event in the total cohort. The association did not change much in patients with OSA. When the SBP and DBP were discussed separately, the SBP control of 120-139mmHg or < 120mmHg was associated with the decreased incidence of MACCE and cerebrovascular event. When DBP control < 80 mm Hg, the risk of cerebrovascular event showed 54% decrease  in patients with hypertension and OSA.In this retrospective study, antihypertensive-drug-induced office and home BP control at 120-139/80-89mmHg showed possible beneficial effect on incident MACCE. However, current results need to be verified in future studies. Obstructive sleep apnea (OSA) is a disorder characterized by recurrent episodes of upper airway obstruction during sleep, resulting in chronic intermittent hypoxia and sleep fragmentation. OSA is widely accepted as one of the most important causes of secondary hypertension, even though the hypertension may not necessarily be a consequence of the OSA. About 30–50% of hypertensive patients will have comorbid OSA . MoreoveThe pathophysiological changes caused by OSA, such as the intermittent hypoxia, hypercoagulable state , excessiIt is known that the antihypertensive goals are lower when hypertensive patients have comorbidities that can affect cardiovascular risk and treatment strategies . HoweverAll subjects are from Urumqi Research on Sleep Apnea and Hypertension (UROSAH) study, which is a single-center retrospective cohort study. The inclusion and exclusion criteria have been described in our previous study . At baseHypertension is defined as SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg on 3 different days, or the current usage of any antihypertensive medication. OSA is defined as apnea-hypopnea index (AHI) ≥ 5 based on the in-laboratory polysomnography. Diabetes is defined as fasting glucose ≥ 7.0 mmol/L, the usage of glucose-lowering medication, or self-reported history of diabetes.All participants were followed up through outpatient visits, inpatient medical records review, and telephone interviews by the trained nurses and physicians. The follow-up period ended Jan 2021, or first onset of major adverse cardiovascular and cerebrovascular event (MACCE) after the enrollment, or lost to follow-up.For the participants who come to our hospital for follow-up used electronic sphygmomanometers  to measure upper arm BP in sitting positions in accordance with standard measurement procedures, all the BP measurement was performed by the trained nurses of our center during follow-up. The daytime BP readings at least 3 times on different days during the follow-up period were collected from the electronic medical record system of our hospital for the final analysis. For the patients who did not undergo follow-up visits at our hospital, the follow-up BP readings were obtained by the telephone interview. The readings of home BP monitoring were recorded as accurately as possible (at least 3 BP readings on the different days) or the range of BP monitoring in the recent 6 months were recorded, and confirmed the correct method of BP measurement. Finally, we also obtained BP monitoring information from participants who had regular annual BP measurement in their local hospitals. For patients who suffered MACCE, the level of BP before MACCE was collected via hospitalized medical records. After fully collecting the BP control levels of the participants during the follow-up period, we divided them into the following three groups according to their BP control levels: ≥140/90mmHg, 120–139/80-89mmHg and < 120/80mmHg.As well, the treatment of OSA was asked, especially for the use of CPAP was recorded. Regular use of CPAP was defined as average use ≥ 4 h/night for > 70% of the follow-up period. The others with no or less than regular use were thought as ‘untreated’. For the patients whose BP controls ≥ 140/90mmHg or “untreated OSA” during follow-up were suggested to come to our center or the local hospital for further consultation and adjusted the antihypertensive treatment.The primary endpoints were the first onset MACCE after the enrollment during the follow-up period, including fatal and non-fatal cardiovascular event and cerebrovascular event. All endpoints were defined in accordance with the proposed definitions by the Standardized Data Collection for Cardiovascular Trials Initiative . In the Continuous variables were reported as mean ± standard deviation (SD) if normally distributed and as the median and interquartile range (IQR) if not. Differences between the two groups for normally distributed continuous variables were compared using the independent samples t-test and the Mann Whitney U test were used for non-normally distributed continuous variables. Categorical variables were presented as observed numbers and percentages and compared using the Pearson Chi-square test among groups. The cumulative incidence of primary outcomes was estimated by Kaplan-Meier survival curves, and the log-rank test was used to estimate the difference between the different levels of BP control. Cox proportional hazards models were performed to test the association between CVDs outcomes  and the levels of BP control in the total cohort and patients with OSA. The risk factors such as age, sex, body mass index, baseline systolic BP and diastolic BP, AHI, low-density lipoprotein cholesterol, eGFR, smoking, type 2 diabetes, and the usage of drugs were adjusted. Furthermore, to eliminate the impact of OSA-specific treatment on the association between BP control and MACCE, we conducted the sensitivity analysis in the OSA population by excluding individuals who use CPAP regularly. Data were analyzed using SPSS statistical software . All analyses were two-tailed and a P value of < 0.05 was statistically significant.A total of 3267 patients  was included and divided into 3 groups by the follow-up BP. Table 2 = 3.44, P = 0.064), ≥ 140/90mmHg vs. < 120/80mmHg , and 120–139/80-89mmHg vs. < 120/80mmHg . But no significant difference was observed between BP control and MACCE and cardiac event : 0.71 (0.51–1.98), P = 0.040], OSA patients with DBP < 80mmHg had a decrease in MACCE of about 30% , and a decrease in the risk of stroke of 58%  taking DBP control ≥ 90mmHg as a reference, but no benefit from BP control was found for cardiac event, and BP < 120/80mmHg seemed to increase the risk of cardiac events  global hypertension practice guidelines suggested BP < 140/90mmHg as the essential target of office BP for treated hypertension and < 130/80mmHg as the optimal target for treated hypertensives aged < 65yrs , a lowerWhen the systolic BP and diastolic BP control were considered separately, it was found that when SBP was controlled at 120-139mmHg, the risks of MACCE and cerebrovascular event in OSA patients with hypertension were reduced significantly. With the decrease of DBP, the risk of MACCE and cerebrovascular event significantly decreased, especially when the DBP < 80mmHg, the risk of cerebrovascular event can be reduced by about 50%. Similar to the results of ALLHAT study . As wellWe did not analyze the association between BP control and cardiovascular mortality due to few dead cases. All subjects in our study were prescribed individualized antihypertensive regimens after systemic evaluation of hypertension, and if necessary, lipid-lowering drugs, anti-diabetic drugs and/or anti-platelet drugs were also used, which may attenuate the association between BP control and incident risk of MACCE. Moreover, as Diastolic Chronic Heart Failure Study (DIAST-CHF) explained, OSA did not show a significant adverse effect on cardiovascular morbidity and mortality in patients with cardiovascular risk factors , in whicThere are several limitations. Firstly, as the treatment rate of OSA was far from satisfactory , 19, andIn this retrospective study, antihypertensive-drug-induced BP control at 120–139/80-89mmHg showed possible beneficial effect on incident MACCE. However, current results need to be verified in future studies.


Methods: Mean airway pressure was measured in the nasopharyngeal space. To evaluate breathing volumes, a polysomnographic device was used (16 patients). All subjects received 20, 30, 40, and 50 L/min and—to illustrate the effects—nCPAP and nBiPAP. Capillary blood gas analyses were performed in 25 hypercapnic ILD subjects before and 5 h after the use of NHF. Additionally, comfort and dyspnea during the use of NHF were surveyed. Results: NHF resulted in a small flow-dependent increase in mean airway pressure. Tidal volume was unchanged and breathing rate decreased. The calculated minute volume decreased by 20 and 30 L/min NHF breathing. In spite of this fact, hypercapnia decreased at a flow rate of 24 L/min. Additionally, an improvement in dyspnea was observed. Conclusions: NHF leads to a reduction in paCO2. This is most likely achieved by a washout of the respiratory tract and a reduction in functional dead space. NHF enhances the effectiveness of breathing in ILD patients by the reduction in respiratory rate. In summary, NHF works as an effective ventilatory support device in hypercapnic ILD patients.Introduction: Acute hypercapnic respiratory failure has a poor prognosis in patients with interstitial lung disease (ILD). Recent data demonstrated a positive effect of nasal high-flow (NHF) in patients with acute hypoxemic respiratory failure. Preliminary data also show benefits in several hypercapnic chronic lung diseases. Objectives: The aim of this study was to characterize flow-dependent changes in mean airway pressure, breathing volumes, and breathing frequency and decreases in PCO Interstitial lung disease (ILD) is characterized by a decrease in lung volumes, reduced diffusion capacity and interstitial changes in chest X-rays and CTs. The current classification describes several categories of idiopathic interstitial pneumonias: diffuse parenchymateous lung diseases with a known reason, granulomateous lung diseases, and rare entities such as lymphangioleimyomatosis or pulmonary Langerhans cell histiocytosis. For several years now, there have been drugs available with considerable effects on the fibrosing process ,2.2 retention [One of the most prominent symptoms in ILD patients is breathlessness with hypoxemia or combined hypoxemia and hypercapnia when respiratory muscles are no longer able to keep up compensatory work. The application of long-term oxygen appears to be at least a symptomatic relief of dyspnea. Mechanical ventilation in end-stage disease without the perspective of listing for lung transplant is not advised and is followed by high mortality rates ,4. Some etention ,5. Non-ietention ,4,6,7. Hetention ,9. A retetention . Despite2) in rapid breathing due to sufficient flow (20–60 L/min), thereby reducing most of the ambient air entrainment [2 reduction with greater leak and higher flow rates [2 and the effective provision of large flows, if necessary, result in a decrease in the work of breathing, which is well suited to help patients with ILD and respiratory stress [Nasal high-flow (NHF) is a new device providing warmed and humidified airflow supplemented with oxygen in case of need. Flow rates range up to 60 L/minute. Reduced intubation rates were found in the study by Frat et al. in acute hypoxemic respiratory failure mostly caused by pneumonia . NHF shorainment ,16. NHF rainment ,18,19,20ow rates . Togethey stress ,23. We tIn this study, we used the TNI softflow 50 device . NHF was applied using nasal prongs with different bore outlets  in order to apply the intended elevated flow rates. Small (ID 3.2 mm), medium (3.9 mm), and large (ID 5 mm) sizes of nasal prongs were compared as part of the study. nBiPAP and nCPAP were both applied using a nose mask .A total of 25 ILD subjects in advanced stages of disease with hypercapnia were recruited from the respiratory ward at the university hospital of Leipzig from August 2015 to November 2017. All patients underwent long-term oxygen therapy. Of these subjects, 16 participated in the physiological tests as part of the protocol. The study was approved by the local ethics committee (414-14-06102014) and registered . Subjects provided written informed consent to the trial protocol including the analysis of their data. The main exclusion criterion was an acute respiratory insufficiency.2. Outcome parameters included changes in mean airway pressure, tidal volume (TV), and respiratory rate (RR). The clinical end-point was the change in paCO2 from baseline after 5 h of NHF breathing.The aim of this study was to gain a first impression on the effects of NHF versus conventional NIV in subjects with ILD and to characterize the influence of flow on ventilation and pCO®-cable type standard, B. Braun, Melsungen, Germany) was placed in the nasopharyngeal space and then used as pressure transducer. A pressure sensor  connected to a laptop was used to record the signal. Ten breaths each were recorded during spontaneous, NHF, and nCPAP/nBiPAP breathing. Pressure during spontaneous breathing defined the baseline pressure (zero). Measurements were performed and repeated with different prong sizes. The measurements were carried out in the order shown. Data collection only took place after the baseline was reached again.A water-filled flexible tube  were used to measure tidal volumes. Subjects were measured in a sitting position. Elastic sensor belts were placed 10 cm below the jugular notch and 10 cm below the xiphoid process, and tidal volume measurements were performed. Subsequently, we calibrated the device individually for each subject, starting with “normal” tidal breathing which was recorded with standard lung function equipment . While measuring tidal volumes of 10 breaths and simultaneously registering the sensor signal, we were able to calibrate the sensor belt signal to changes in lung volume. Following calibration, volume measurements during NHF and spontaneous breathing were started. Chest and abdominal excursions were recorded, and the medians in percental changes were used to calculate the volume in ml. Also, the minute volumes (MVs) were calculated. Measurements were performed and repeated with different prong sizes . The measurements were carried out in the order shown. Data collection only took place after the baseline was reached again.Subject impressions were correlated with various prong sizes and the use of nCPAP and nBiPAP. We used simple own dyspnea and comfort scales to evaluate patient satisfaction. We did not try to differentiate effects from flow rates, etc., on these scales. The comfort scale ranged from 1 to 10 and the dyspnea scale from 1 to 5. A smaller number defined more comfortable ventilatory support or less dyspnea.®, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany). Measurements were performed with constant oxygen flow before and after five hours NHF use. The flow rate was chosen for maximal tolerability.Capillary blood gases were taken from the earlobe ten minutes after applying a hyperemia-inducing ointment  was accepted for significance. The results were expressed as mean values ± SD. Changes compared to baseline values were also expressed as percentages because of the variation in the baseline values. Measurements following ventilatory support were compared with baseline values. Significance was defined as a significant change in percentage.Data were analyzed using ANOVA . A probability level for the null hypothesis (no difference) of 5% or below (2 measurements.Demographic data are presented below . The grop = 0.00). When the flow rate was increased to 50 L/min, the mean airway pressure increased to 3.1 ± 1.5 mbar; p = 0.00. nCPAP/nBiPAP led to an increase in mean airway pressure strongly dependent on the set pressure   .TV did not change significantly during NHF breathing, while nCPAP/nBiPAP breathing went along with an increase in tidal volume . HoweverSubjects felt more comfortable during the use of small NHF prongs independent of flow rates and rated dyspnea to be lower with small and medium NHF prongs. NIV breathing was associated with lesser comfort and more dyspnea compared to NHF .2 and pH were not different at the end of the NHF treatment periods in comparison with the baseline values, while paCO2 had decreased significantly , and thus, the full potential of NHF to reduce hypercapnia cannot be recognized from these studies [2 decrease during NHF breathing was more effective, and the extent of pCO2 reduction correlated to baseline PCO2 values [A reduction in pCO2 in various conditions with NHF breathing has been described in several studies ,21,23,26 studies ,14. When2 values ,21,23,262 values . Increased patient comfort and a better tolerance might be suggested by our patient questionnaires. In chronic hypercapnic COPD, for example, NIV intolerance may be as high as 30% . NHF is NIV is not standard therapy in patients with interstitial lung disease but has been used in acute respiratory failure and may be helpful in a subset of patients without increased right ventricular load. However, the outcome of patients with IPF and acute respiratory failure (ARF) is poor, and more so with mechanical ventilation . Our dat2, but not FIO2 and SpO2, were documented during the hypercapnia reduction test. Furthermore, the authors point out that NIV is probably not the gold standard for comparisons in these patients with a risk of high expiratory tidal volume and ventilator-induced lung injury (VILI). Another limitation is the exploratory nature of this pilot study. Subject comfort and dyspnea scales were easy-to-understand school mark scales that were not validated prior to use. Thorax expansion was measured externally and translated into tidal volume. Due to individual compliance and the elastance of the thorax in each ILD subject, changes may have been over- or underestimated. The duration of NHF use varied to some extent, influenced mainly by the clinical schedule of ILD subjects. One of the main limitations of the study is the lack of randomization and the fact that a number of patients did not tolerate the physiological tests. In addition, only paO2, demonstrating increased breathing efficiency. NHF might be a useful non-invasive ventilatory support in severe ILD patients with increased levels of paCO2.In summary, NHF breathing increased the mean airway pressure and changed breathing patterns in subjects with ILD. This led to a decreased respiratory rate but also a decrease in paCO


N-acetylgalactosamine ligand–conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent  Targeting hepatic angiotensinogen as a novel approach to block the renin-angiotensin system.N-acetylgalactosamine–conjugated small interfering RNA therapeutic that specifically targets human hepatic angiotensinogen mRNA. A phase 1 first-in-human study has revealed that zilebesiran is an effective strategy to lower blood pressure in patients with hypertension.Zilebesiran is an investigational This review addresses the mechanism of action of zilebesiran, making use of detailed animal studies comparing this novel drug with classical blockers of the renin-angiotensin system like ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers. It also describes its safety profile.1 Since the renin-angiotensin system (RAS) is central in blood pressure regulation, several approved antihypertensive therapies target this pathway. Despite the availability of effective antihypertensive agents, a large proportion of patients with hypertension still do not achieve guideline-recommended blood pressure levels, and thus hypertension remains an area of high unmet need.2Hypertension is one of the major preventable risk factors for cardiovascular diseases including ischemic heart disease, stroke, myocardial infarction, as well as other complications such as chronic kidney disease.www.ahajournals.org/atvb/atvb-focus for all articles published in this series.Please see 4 This would result in upregulated angiotensin formation, allowing the  return of Ang II (angiotensin II)–induced effects, including its effects on aldosterone release.5 Poor adherence or nonadherence might result in huge costs, given that additional investigations will be needed to assess why there is no response.Possible reasons for inadequate blood pressure management under the current RAS-blocking antihypertensive therapies include poor patient adherence and the so-called RAS escape phenomenon elicited by the compensatory renin elevation upon RAS blockade.11 AGT is the sole substrate for renin cleavage, that is, the first enzymatic step of the RAS cascade, which eventually leads to the production of Ang II in the circulation and peripheral tissues to activate its AT1 (Ang II type 1) receptor. AT1 receptor activation results in a number of downstream physiological events, most notably vasoconstriction and a rise in blood pressure. By depleting AGT production, one could envision that Ang II will also eventually be depleted even in the presence of compensatory upregulation of renin, thus circumventing the RAS escape phenomenon. AGT mRNA and protein are primarily produced by the hepatocytes in the liver, although expression of AGT is also claimed in extrahepatic tissues such as the kidney, brain, heart, and adipose tissue.15 Data on extrahepatic production are often conflicting, for instance, first claiming that adipocyte-specific AGT deletion reduced plasma AGT by 25%,16 and then suggesting that adipose-specific AGT deficiency does not affect plasma AGT levels.17 Yet, preclinical studies support that plasma and tissue Ang II are solely derived from liver AGT protein.18 Hepatic AGT is secreted into the circulation and subsequently enters peripheral tissues, either by diffusion19 or via receptor-mediated cellular uptake.20 Therefore, hepatocyte targeting of AGT depletion becomes an attractive strategy to block the RAS pathway, as it can circumvent the RAS escape phenomenon.Recently, preclinical and clinical evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon.N-acetylgalactosamine  ligand–conjugated small interfering RNA (siRNA) represents an emerging therapeutic modality that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner. The ASGR , also known as the Ashwell-Morell receptor, is expressed on hepatocytes and facilitates uptake and clearance of circulating glycoproteins with exposed terminal galactose and GalNAc glycans via clathrin-mediated endocytosis.21 The architectural design of this trivalent GalNAc ligand,21 when attached to a chemically modified siRNA,22 allows for highly efficient hepatocyte uptake through interaction with the ASGR, followed by cell internalization of both the receptor and ligand with the siRNA cargo . This ASGR-mediated delivery system for GalNAc-siRNA conjugates currently represents one of the state-of-the-art modalities in the therapeutic development of investigational oligonucleotides as clinical candidates.23 Likewise, there are currently 4 Food and Drug Administration–approved GalNAc-siRNA therapeutics: GIVLAARI (givosiran),24 OXLUMO (lumasiran),25 LEQVIO (inclisiran),26 and AMVUTTRA (vutrisiran),27 targeting the hepatocyte-specific expression of 5-aminolevulinic acid synthase 1, glycolate oxidase 1, PCSK9 (proprotein convertase subtilisin kexin type 9), and transthyretin, respectively. Givosiran is used in patients with acute hepatic porphyria, lumasiran in patients with primary hyperoxaluria type 1, inclisiran in patients with hypercholesterolemia, and vutrisiran in patients with polyneuropathy of hereditary transthyretin-mediated amyloidosis.Trivalent 23 Whereas the first generation of GalNAc-siRNA conjugates required relatively high-dose levels and higher dosing frequencies to afford the desired in vivo pharmacological activity,28 advancements of the chemical modification patterns led to the enhanced stabilization chemistry siRNA designs, which significantly improved potency and duration compared with the first generation,22 resulting in effective RNAi-mediated mRNA silencing in hepatocytes with much lower dose levels across species, including humans. Potency improvement in vivo is attributed by the refinement of siRNA chemistry, in particular by optimizing the positions of 2′-deoxy-2′-fluoro and 2′-O-methyl ribosugar modifications, as well as phosphorothioate backbone modifications across both sense and antisense strands of the double-stranded siRNA duplex to enhance stability without compromising its intrinsic RNAi activity.22 Advanced designs with low 2′-deoxy-2′-fluoro content that yield further improved potency and duration in preclinical species, including nonhuman primates,29 have been linked to higher liver drug levels, indicating that the improvement in potency is predominantly due to increased metabolic stability of the siRNA conjugates in vivo.While the GalNAc ligand is the chemistry component that allowed for oligonucleotide delivery to hepatocytes, the evolution of RNA interference (RNAi) therapeutics has been driven by advances in siRNA chemical modification designs.31 Mechanistically, the increased metabolic stability of the chemically modified siRNA molecules in the hepatocyte acidic intracellular compartments  contributes to the prolonged duration and activities in vivo.32 It has been demonstrated that functional siRNAs can be liberated from these compartments over time and loaded into the Argonaute 2 protein in the cytoplasm, a key step to form a functional RNA-induced silencing complex, which ensures hybridization of the siRNA guide strand with the target mRNA and mediates mRNA cleavage and degradation .32 A previous report32 highlighted that due to the chemical modifications mentioned above, the chemically modified siRNAs are able to maintain prolonged stability in these acidic intracellular compartments, thus enabling the continuous generation of functional RNA-induced silencing complexes and continuous RNAi activity over a long period of time (weeks to months), providing evidence that the intracellular acidic compartments serve as a long-term depot for GalNAc-siRNA conjugates.32 In summary, the metabolically stable, chemically modified, enhanced stabilization chemistry GalNAc-siRNAs,22 combined with the durable intracellular depot, are the major contributor to the extended duration of activity observed in vivo. The long-duration pharmacokinetic and pharmacodynamic properties may provide the potential to apply infrequent dosing schedules  and could potentially address therapy nonadherence.Another hallmark of the GalNAc-siRNA conjugates is the long durability of silencing that can persist for several months after a single-dose administration in preclinical species and also humans.33 In this context, a single glycol nucleic acid or a 2′-5′-RNA modification reduces siRNA seed-mediated Watson and Crick base pair hybridization binding to off-target transcripts while maintaining the on-target RNAi activity. In siRNAs with established hepatotoxicity driven by off-target effects, these novel designs with seed-pairing destabilization, termed enhanced stabilization chemistry plus, demonstrated an improved therapeutic window in rats.34 It is also noted that recent clinical data from multiple investigational GalNAc-siRNA therapeutics supported acceptable long-term safety profiles of the GalNAc-siRNA platform, suggesting a potential to utilize this technology more broadly to treat prevalent diseases in the general population.31More recently, a further chemical nucleotide modification has been reported that enhances the clinical safety of GalNAc-siRNA conjugates by reducing the potential for off-target mRNA binding. This strategy utilizes siRNA guide strand seed-pairing destabilization and has demonstrated its benefit both in preclinical species and in clinical development.35 Second-generation ASOs promote degradation of complementary mRNA via the RNase H mechanism .36 Similar to GalNAc-siRNAs, a majority of the target mRNAs for ASOs are predominantly expressed in hepatocytes, which makes the ASGR-GalNAc targeting strategy particularly advantageous.37 There are currently no clinically approved GalNAc-ASOs. However, there are over 10 different ongoing clinical trials.39Another class of therapeutic oligonucleotides, antisense oligonucleotides (ASOs), has also benefited from the introduction of the GalNAc ligand for effective delivery to hepatocytes.10 the deoxycorticosterone acetate (DOCA)-salt–treated SD rat, and the diabetic TGR(mRen2)27 rat.15 The latter rat overexpresses mouse renin and thus represents a model of Ang II–dependent hypertension. It was found that effective blood pressure lowering is achieved when >95% of AGT is knocked down.15We and others have investigated the GalNAc-siRNA strategy as an antihypertensive approach in multiple preclinical hypertension rodent models (Table), including the spontaneously hypertensive rat (SHR), the 5/6th nephrectomy Sprague-Dawley (SD) rat,8 The latter is to be expected, since DOCA acts as a mineralocorticoid receptor agonist. Yet, in this model, upregulated brain RAS activity has also been proposed to underlie the hypertension.40 From this perspective, central RAS blockade would be required for a blood pressure–lowering effect. Although liver-targeted AGT siRNA did not affect brain AGT synthesis, it did lower brain Ang II levels, indicating that brain angiotensin generation in this model, if occurring, depends on hepatic AGT. The disappearance of brain Ang II combined with a lack of a blood pressure–lowering effect after AGT siRNA raises doubt about the concept of selective brain RAS upregulation in the DOCA-salt model  as the cause of hypertension, also because the amount of renin in brain tissue is low and at most represents circulating renin in trapped blood.41 A more simple explanation is that brain Ang II is taken up from blood.42 Interestingly, despite the absence of a blood pressure–lowering effect, AGT siRNA did reduce cardiac hypertrophy in the DOCA-salt rat. Since this was paralleled by a reduction in cardiac Ang II, it most likely represents the fact that AGT siRNA is capable of blocking Ang II formation at cardiac tissue sites. Clearly, such formation also depends on hepatic AGT.44Not surprising, in the DOCA-salt model, where circulating renin is greatly suppressed, no blood pressure–lowering effect of AGT siRNA was observed, while mineralocorticoid receptor blockade with spironolactone did normalize blood pressure.1 receptor blockers), while combining GalNAc-AGT siRNA and an ARB resulted in synergistic and superior blood pressure lowering (≈70 versus ≈20–25 mm Hg for each drug separately).7 This might be the consequence of further renin upregulation during combined RAS blockade, resulting in the virtual disappearance of AGT. The latter resembles the situation in patients with heart failure who are being treated with multiple RAS blockers.46 Their renin levels are so high that they induce AGT depletion. Indeed, when combining GalNAc-AGT siRNA and an ARB, circulating AGT levels in the SHR were reduced by 99.8%  and circulating Ang II virtually disappeared. Greatly diminishing Ang II production plus simultaneously blocking the AT1 receptor  appeared to be a powerful combination that brought RAS activity to almost zero.47 These data strongly support the concept that circulating AGT is liver derived, in full agreement with data in liver AGT knockout animals.48 They also raise the question to what degree AGT production at extrahepatic sites plays a role. Surprisingly, although GalNAc-AGT siRNA did not affect the AGT mRNA levels at extrahepatic sites (including the kidney and adipose tissue),9 it did greatly diminish the AGT protein levels at these sites. Apparently, therefore, despite local AGT expression, the actual AGT protein at these extrahepatic sites is liver derived. Given these findings, which coincide with observations in transgenic animals genetically lacking kidney or adipose tissue AGT,52 currently, mechanisms are being investigated that might explain AGT uptake from blood. Here, an important newly identified candidate is the megalin receptor.56 Indeed, without this receptor, renal angiotensin content was greatly reduced, both under normal and disease conditions.57 Another candidate, at least in the heart, is low-density lipoprotein receptor–related protein 1.58 Taken together, it appears that tissue production of angiotensins depends on liver-derived AGT. This concerns virtually every known site of local angiotensin production, that is, heart, vascular wall, adipose tissue, kidney, and brain. Future studies should reevaluate whether local AGT expression outside the liver truly has any role. Importantly, in the SHR AGT, siRNA did lower cardiac Ang II and cardiac hypertrophy.7 However, the main determinant of the latter appeared to be the reduction in blood pressure, rather than the disappearance of cardiac Ang II.In the SHR, the degree of blood pressure lowering by AGT siRNA was similar to that of classical RAS blockers including ACE (angiotensin-converting enzyme) inhibitors and ARBs , and this involved the suppression of renal Ang II independently of any blood pressure–lowering effect.In the 5/6th nephrectomy SD rat, blood pressure slowly rises over time. GalNAc-AGT siRNA, when given after 5 weeks, prevented a further rise, yet did not normalize blood pressure. This effect was similar to that of combined ACE inhibitor plus ARB treatment.Similarly, GalNAc-AGT siRNA offered renoprotection in the diabetic TGR(mRen2)27 rat. Streptozotocin-induced diabetes in this rat model resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in the glomerular filtration rate. RAS blockade with either the ACE inhibitor captopril, the ARB valsartan, or GalNAc-AGT siRNA lowered blood pressure identically, and modestly larger drops in blood pressure were observed when combining GalNAc-AGT siRNA and valsartan or captopril and valsartan. This differs from the synergistic antihypertensive effects of dual RAS blockade observed in the SHR and suggests that the high blood pressure in this model is largely the consequence of mouse renin overexpression and not related to diabetes per se. In other words, as soon as blood pressure is back to normal (by blocking the effects of mouse renin overexpression), more RAS blockade does not yield substantial further blood pressure lowering. All treatments lowered cardiac hypertrophy. Given the strong correlation between cardiac hypertrophy and blood pressure, the main underlying mechanism for this effect appeared to be the decrease in blood pressure. Although AGT siRNA did not affect renal AGT mRNA expression, confirming its liver specificity, it did lower renal AGT levels. Furthermore, only AGT siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal Ang II, and the reduction was the largest (>95%) in the AGT siRNA+valsartan group . All treatments identically lowered albuminuria. Yet, only AGT siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. These data, therefore, suggest that the renoprotective effects of AGT siRNA reflect interference with renal Ang II generation, in a blood pressure–independent manner.7 Interestingly, non–GalNAc-conjugated ASOs additionally suppressed extrahepatic AGT expression, for example, in kidney and adipose tissue, while GalNAc conjugation, as expected, exclusively resulted in hepatic AGT suppression.6 Yet, non–GalNAc-conjugated and GalNAc-conjugated AGT identically lowered blood pressure, and the degree of blood pressure lowering correlated with the degree of circulating AGT reduction. The maximum hypotensive effect persisted until day 10, in agreement with the fact that the ASO liver half-life is 2 to 4 weeks. AGT ASO suppression has also been evaluated in 8% salt-fed SHR (a low-renin model),6 and here, its antihypertensive effect was comparable to the combined effect of captopril and losartan, while captopril alone was ineffective. Only AGT ASO lowered aldosterone in the 8% salt-fed SHR, and this aldosterone reduction may have contributed to its blood pressure–lowering effect. When exposing salt-depleted SD rats (a high-renin model) to either non–GalNAc-conjugated ASOs or GalNAc-conjugated ASOs, it was observed that only the non–GalNAc-conjugated ASOs resulted in histological alterations in the kidney, like tubular degeneration and thickening of the glomerular basement membrane.6 Such alterations were also observed with the ARB losartan, and when treating the 5/6th nephrectomy SD rat with a non–GalNAc-conjugated ASO, a GalNAc-conjugated ASO, or the ACE inhibitor captopril, it was again observed that only the non–GalNAc-conjugated ASO and the classical RAS blocker captopril induced histological alterations.6 These alterations have been suggested to rely on the multiclonal expansion and transformation of renin cells from a classical endocrine phenotype to a matrix-secretory phenotype.59 Based on these observations, it was argued that non–GalNAc-conjugated ASOs and classical RAS blockers result in excessive RAS suppression in the kidney (which massively upregulates renin), thereby eventually inducing renal damage, while GalNAc-conjugated ASOs would not do this since they leave renal AGT intact. Here, it is important to realize that full suppression of the RAS, particularly at the level of the kidney, is not desirable, given that normal renal function is RAS dependent.5 Hence, too much RAS blockade might result in renal damage due to the absence of renal Ang II. Unfortunately, the authors did not report renal Ang II levels after ASO exposure, and thus, to what degree GalNAc-conjugated ASOs truly left renal Ang II in the normal range  is unknown. They did observe reduced renal AGT levels after exposure to GalNAc-conjugated ASOs, suggesting that also in their hands, at least part of renal AGT was liver derived. Moreover, rises in plasma renin were higher with the non–GalNAc-conjugated ASOs than with the GalNAc-conjugated ASOs. This latter finding supports that the RAS blockade with the non–GalNAc-conjugated ASOs was more potent, and thus an alternative explanation of the data is that the hepatic effects of the non–GalNAc-conjugated ASOs were stronger than those of the GalNAc-conjugated ASOs. This explanation does not require the concept of ongoing renal Ang II generation from locally synthesized AGT. Indeed, near-complete suppression of hepatic AGT synthesis with liver-targeted AGT siRNA has already been reported to abolish renal Ang II.60The ASO approach targeting AGT was capable of lowering circulating AGT in SHR to a similar degree as AGT siRNA.15 It is thought that lowering of tissue  Ang II levels by GalNAc-AGT siRNA is a key contributor to the overall therapeutic benefits seen in animal models in addition to its effect in systemic blood pressure lowering. Observations with GalNAc-AGT ASO were largely similar to those with the siRNA approach.In summary, in a variety of animal models, GalNAc-AGT siRNA alone or in combination with an ARB resulted in renal and cardiac protective benefits accompanied by consistent lowering of local tissue Ang II levels in both blood pressure–dependent and blood pressure–independent manners.https://www.clinicaltrials.gov; NCT03934307) of zilebesiran was conducted in patients with hypertension.30 Patients received single ascending subcutaneous doses of zilebesiran (10–800 mg) or placebo. Compared with placebo, zilebesiran was associated with dose-dependent reductions (up to >95% in high-dose levels) in serum AGT. Moreover, single doses of zilebesiran (≥200 mg) resulted in reductions in systolic (>10 mm Hg) and diastolic (>5 mm Hg) blood pressure by week 8 post-treatment, and the zilebesiran-mediated blood pressure reductions were consistent throughout the 24-hour diurnal cycle and sustained to 24 weeks. The effects of zilebesiran 800 mg on blood pressure were also assessed under low/high-sodium diet conditions and with irbesartan coadministration. Blood pressure reductions upon zilebesiran treatment were attenuated by high-salt diet and augmented with irbesartan coadministration. The phase 1 results provide strong support that hepatic AGT targeting using an RNAi approach may be an effective strategy to lower blood pressure in humans. Importantly, single doses of zilebesiran up to 800 mg were well tolerated in patients, with no observation of hypotension, hyperkalemia, or worsening renal function requiring medical intervention up to 24 weeks after dosing. Consistent with the levels of hepatic protein lowering observed in other therapies that utilize the GalNAc-siRNA platform,61 zilebesiran demonstrated prolonged pharmacodynamic profile of serum AGT lowering and sustained reduction of blood pressure up to 24 weeks. Two follow-on phase 2 studies for zilebesiran are also underway: KARDIA-1  is a randomized double-blind dose-ranging study evaluating the efficacy and safety of zilebesiran in patients with mild-to-moderate hypertension, and in KARDIA-2 , the efficacy and safety of zilebesiran on blood pressure will be investigated in combination with 3 different classes of conventional antihypertensives with distinct mechanisms of action.Zilebesiran is an investigational GalNAc-siRNA therapeutic that specifically targets human hepatic AGT mRNA and eventually inhibits the production of AGT protein. A multipart phase 1 first-in-human study ,63 RAS blockers are contraindicated in pregnancy. This likely also applies to AGT siRNA. Nevertheless, future studies should address to what degree it passes the placenta and whether it might be used for the treatment of preeclampsia.64AGT levels rise during pregnancy (up to 2-fold to 3-fold).31 Indeed, with a number of approved clinical products, and with a substantial body of preclinical investigative work,65 it is now well established that liver-targeting GalNAc-siRNA conjugates have favorable preclinical safety profiles and wide therapeutic windows. Furthermore, liver enzyme data in diabetic TGR(mRen2)27 rats did not show any liver deterioration after AGT siRNA treatment, either alone or in combination with valsartan.15Given the liver accumulation of the siRNA, one might speculate about liver toxicity or inflammatory and immunologic side effects. Yet, no such observations were made for liver-targeted PCSK9 siRNA (inclisiran) over a 6-month period.15The GalNAc-siRNA therapeutic is a novel approach to lower hepatic AGT. In the abovementioned animal studies, hepatic AGT-lowering approaches were associated with blood pressure–lowering effects at least comparable to those of classical RAS blockers like ACE inhibitors and ARBs, and when combined with such blockers, synergy may occur. The first data in humans thus far align with this view. Additionally, preclinical evidence suggests that this approach may result in both renoprotection and cardioprotection. AGT siRNA predominantly acts at the tissue level, illustrating the fact that tissue angiotensin production relies on hepatic AGT. Theoretically, it allows the full disappearance of circulating AGT, but the desired degree of RAS suppression is unlikely to be 100%, since the RAS is needed for normal kidney function and the maintenance of blood pressure, for example, during shock. Using a GalNAc-siRNA approach for the treatment of hypertension may yield a future therapeutic regimen that is administered 1 to 2× per year, thereby potentially improving medication adherence. Nevertheless, this also poses a threat in situations where the RAS is acutely needed, and thus preclinical and clinical programs are now carefully investigating its efficacy and safety profile. Finally, to what degree the beneficial effects of AGT suppression also involve long-term suppression of aldosterone still needs to be investigated. Short-term studies in animals support that its effects on aldosterone are comparable to those of classical RAS blockers.The authors thank Petya Zlateva for the graphical artwork on the Figure.None.E.O. Cruz-López was supported by the Mexican National Council of Science and Technology (grant No. 739513). I. Zlatev and H.-C. Tu are employees and stockholders of Alnylam Pharmaceuticals. A.H.J. Danser received a grant from Alnylam Pharmaceuticals, which has partially supported the work described in this review. The other author reports no conflicts.


Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the renin–angiotensin–aldosterone (RAA) system is enormously activated in this disease, there are few reports that attempt to characterize the effect of early use of RAA inhibitors (RASi) on the temporal course of kidney function.This retrospective cohort study was conducted to clarify whether the early use of RASi during hospitalization offered more favorable benefits on short-term renal function and long-term renal outcomes in patients with hypertensive emergencies. We enrolled a total of 49 patients who visited our medical center with acute severe hypertension and multiple organ dysfunction between April 2012 and August 2020. Upon admission, the patients were treated with intravenous followed by oral antihypertensive drugs, including RASi and Ca channel blockers (CCB). Kidney function as well as other laboratory and clinical parameters were compared between RASi-treated and CCB- treated group over 2 years.2 at 1 year. The renal effect of antihypertensive drugs was particularly conspicuous when RASi was started in combination with other conventional antihypertensive drugs at the early period of hospitalization (2nd day [IQR: 1–5.5]) and even in patients with moderately to severely diminished eGFR (< 30 mL/min/1.73 m2) on admission. In contrast, CCB modestly restored eGFR during the observation period. Furthermore, renal survival probabilities were progressively deteriorated in patients who had manifested reduced eGFR (< 15 mL/min/1.73 m2) or massive proteinuria (urine protein/creatinine ≥ 3.5 g/gCr) on admission. Early use of RASi was associated with a favorable 2-year renal survival probability (0.90 [95%CI: 0.77–1.0] vs. 0.63 [95%CI: 0.34–0.92] for RASi ( +) and RASi (-), respectively, p = 0.036) whereas no apparent difference in renal survival was noted for CCB.Antihypertensive treatment effectively reduced blood pressure from 222 ± 28/142 ± 21 to 141 ± 18/87 ± 14 mmHg at 2 weeks and eGFR was gradually restored from 33.2 ± 23.3 to 40.4 ± 22.5 mL/min/1.73mEarly use of RASi contributes to the renal functional recovery from acute reduction in eGFR among patients with hypertensive emergencies. Furthermore, RASi offers more favorable effect on 2-year renal survival, compared with CCB.The online version contains supplementary material available at 10.1186/s12882-023-03117-1. Hypertensive emergency is an acute progressive disorder caused by severe hypertension and requires prompt recognition and timely intervention which could prevent the occurrence of catastrophic events, including cerebral hemorrhage, heart failure, and acute kidney impairment. This disorder is arbitrarily defined in many guidelines as acutely elevated blood pressure (BP), mostly more than 180/120 mmHg , with baGreat progress has been made regarding the development of antihypertensive drugs, and various drugs with different mechanisms are available and have been in clinical use solely or in combination with other types of antihypertensive agents. In malignant hypertension, long-term control of BP is reported to offer favorable renal outcomes . BecauseIn the present study, we conducted a 24-month follow-up evaluation of renal function as well as renal survival to clarify whether the early use of RASi during hospitalization effectively ameliorated the short- and long-term renal outcomes in patients with hypertensive emergencies.This study is a retrospective cohort analysis to investigate the effect of RASi, compared to calcium channel blockers (CCB’s), on the temporal course of renal function and 2-year renal outcomes in patients with hypertensive emergencies. The study was approved by the Ethics Committee of Tokyo Bay Urayasu-Ichikawa Medical Center with waiver of the requirement for obtaining informed consent  and was registered at UMIN . The study was conducted in accordance with the Declaration of Helsinki. Information from medical records was anonymized and deidentified prior to final analysis.During the period between April 2012 and August 2020, the patients who visited the emergency department of our hospital with severe hypertension (systolic BP ≥ 180 mmHg or diastolic BP ≥ 120 mmHg) were screened for possible possession of hypertension-induced organ damage, including renal impairment, heart failure, stroke, retinopathy and thrombotic microangiopathy. A total of 77 patients met the inclusion criteria based on various clinical and laboratory examination. Among them, 28 patients were excluded; 5 patients died upon the hospitalization, 18 patients were transferred to other hospitals from our emergency room without admission, and 5 patients required maintenance dialysis therapy upon hospitalization. Ultimately, 49 patients were deemed eligible for further analysis.2) and cardiovascular complications such as heart failure, myocardial infarction, cerebral infarction, and thrombotic microangiopathy (TMA) was also evaluated. TMA was determined by the presence of microangiopathic hemolytic anemia and thrombocytopenia (platelet count less than 15 × 104/mm3) . Data were compared with the Student’s t-test or the Mann–Whitney U test. Serial changes in eGFR over 2 years were assessed with linear regression analysis. Multiple regression analyses were applied to evaluate independent predictors for the changes in eGFR. The serial  changes in the regression coefficients were evaluated as a function of the following independent parameters; systolic BP, initial eGFR, Ald levels on admission, and antihypertensive drugs used. The chi-square or Fisher’s exact test was used to compare categorical variables, including the number of patients. Kaplan–Meier analysis was used to generate renal survival curves. Comparison between two survival curves was made using the log-rank test. Statistical analyses were performed using IBM SPSS Statistics (version 25). P values less than 0.05 were considered statistically significant.The prevalence of hypertensive emergencies showed that males predominated (75.5%) and BP was markedly elevated, exceeding 200/130 mmHg , and ESKD ensued in 6 patients during the 2-year observational period . Among 38 patients who received fundoscopic evaluation on admission, 30 subjects  had severer retinal damage (≥ H3) and manifested higher Ald levels (301 [IQR: 173–450] pg/mL) than those with less retinal damage .TMA developed in 5 cases Table , who hadp < 0.001) and were maintained constant thereafter , and remained elevated throughout the study period. Urine-P/Cr was decreased, which paralleled the changes in BP. Kaplan–Meier analysis showed a modest reduction in renal survival probability during the 24-month observational period (0.82 [95%CI: 0.68–0.95]).Both systolic and diastolic BP were strikingly decreased within 2 weeks of hospitalization . Because RASi and CCB strikingly affected renal hemodynamic function, the impact of these drugs on eGFR was serially assessed over 2 years.At the time of hospital discharge, the patients received 3 [IQR: 2.0–3.0] different types of antihypertensive drugs . Obviously, the RASi therapy progressively elevated eGFR during the first 6 months of admission and then maintained eGFR constant until the end of the observational period  did not modify the temporal course of eGFR over 24 months. Finally, the interactive effects of RASi and CCB indicated that the RASi therapy, whether or not in combination with CCB, elicited a recovery of eGFR from the kidney impairment induced by hypertensive emergencies. Similarly, early decreases in urine-P/Cr was observed in patients treated with RASi, which did not depend on whether CCB was co-treated or not , and this difference was maintained throughout the subsequent period . The changes in hematocrit nearly paralleled those in eGFR  and greater urine-P/Cr (≥ 3.5 g/gCr) seen on admission were associated with reduced renal survival probabilities whereas plasma Ald had no effect on the subsequent renal survival , with an odds ratio for renal survival of 8.75 [95%CI: 1.36–56.38] .When evaluated based on the antihypertensive drugs used, the renal survival probability was well preserved in patients who received RASi  or on day 6 or later during hospitalization . Furthermore, among the RASi(-) group (n = 12), 5 patients actually started RASi after hospital discharge . The BP was reduced in a similar manner among the 3 groups (data not shown). In contrast, Thus, there was observed a greater upward tendency of the change in eGFR in patients receiving RASi very early (regression coefficient = 0.34), compared with those who were given RASi early  or late . When compared based on the day of RASi initiation , the trend in the increases in eGFR over 24 months was greater when RASi was given very early after admission  and heavy proteinuria (urine-P/Cr ≥ 3.5 g/gCr) seen on admission are associated with the downward progression toward ESKD (Supplementary Fig. SThe hypertensive emergency causes acute renal impairment, which, in some cases, deteriorates into ESKD requiring renal replacement therapy , 24. Ourp = 0.194, Supplementary Fig. SRegarding BP control, Amraoui et al.  reportedConsistent with the changes in eGFR, the early treatment with RASi is associated with more favorable renal outcomes than that without RASi, irrespective of simultaneous use of CCB Fig. . It is rThe results of the present study are obtained at a single medical facility in the urban area. The patients’ characteristics may therefore affect the medication adherence as well as the chance for regular medical checkups, which might influence the incidence of hypertensive emergencies. Although regular medical checkup systems are widely distributed in Japan and, indeed, 79.6% of the patients were aware of having hypertension, most patients are reluctant to receive antihypertensive therapy Table . Second,Despite tremendous progress in the management of BP, the incidence of the hypertensive emergency does not decrease. Early initiation of RASi may play an important role in the renal recovery and, consequently, the long-term renal prognosis in patients with hypertensive emergencies. Large-scale and more long-term studies are required to dissipate the concern that early initiation of RASi may increase the risk of further rapid renal impairment in patients with hypertensive emergencies.Additional file 1: Supplementary Table S1. Multiple regression analysis for evaluation of the impact of antihypertensive drugs on the changes in eGFR from baseline.Additional file 2: Supplementary Fig. S1. Temporal changes in blood pressure over 24 months. SBP; systolic blood pressure, DBP; diastolic blood pressure, RASi; renin-angiotensin system inhibitor, CCB; Ca channel blocker.Additional file 3: Supplementary Fig. S2. Renal survival probabilities during 24-month follow-up. Urine-P/Cr; urinary protein/creatinine ratio, Ald; aldosterone, SBP; systolic blood pressure.


The goal of this study was to assess the effectiveness of machine learning models and create an interpretable machine learning model that adequately explained 3-year all-cause mortality in patients with chronic heart failure.The data in this paper were selected from patients with chronic heart failure who were hospitalized at the First Affiliated Hospital of Kunming Medical University, from 2017 to 2019 with cardiac function class III-IV. The dataset was explored using six different machine learning models, including logistic regression, naive Bayes, random forest classifier, extreme gradient boost, K-nearest neighbor, and decision tree. Finally, interpretable methods based on machine learning, such as SHAP value, permutation importance, and partial dependence plots, were used to estimate the 3-year all-cause mortality risk and produce individual interpretations of the model's conclusions.In this paper, random forest was identified as the optimal aools lgorithm for this dataset. We also incorporated relevant machine learning interpretable tand techniques to improve disease prognosis, including permutation importance, PDP plots and SHAP values for analysis. From this study, we can see that the number of hospitalizations, age, glomerular filtration rate, BNP, NYHA cardiac function classification, lymphocyte absolute value, serum albumin, hemoglobin, total cholesterol, pulmonary artery systolic pressure and so on were important for providing an optimal risk assessment and were important predictive factors of chronic heart failure.The machine learning-based cardiovascular risk models could be used to accurately assess and stratify the 3-year risk of all-cause mortality among CHF patients. Machine learning in combination with permutation importance, PDP plots, and the SHAP value could offer a clear explanation of individual risk prediction and give doctors an intuitive knowledge of the functions of important model components. Chronic heart failure (CHF), which is characterized by cardiac systolic or diastolic dysfunction , is the Several researchers have developed risk score models to stratify HF patients, such as the Seattle Heart Failure Model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) –12. The In recent years, with the rapid development of artificial intelligence, machine learning technology has been used to build cardiovascular disease prediction models more and more widely. To more accurately predict mortality in HF patients, artificial intelligence,specifically machine learning (ML) , 14, mayTo solve these disadvantages, we introduce six machine learning methods for training, including logistic regression (LR), naive bayes(NB), random forest classifier, extreme gradient boost(XGBoost), k-nearest neighbors (KNN), and decision tree , 16. MeaThe goal of this retrospective study is to forecast the 3-year risk of all-cause mortality in patients with CHF. The data in this paper were selected from patients with CHF (NYHA class III or IV) who were hospitalized at the First Affiliated Hospital of Kunming Medical University, Yunnan Province, from 2017 to 2019. Patients were screened through the electronic medical record system according to the inclusion and exclusion criteria.Patient data were gathered in accordance with the Chronic heart failure case report form, which was created by this study group based on the case records and CHF guidelines .The repoA total of 104 indicators were collected per patient.According to previous studies , 23. RelThere were 27 groups of selected data with a small amount of missing data see Fig. . For num2.Since the survival rate and mortality rate are basically the same, the problem of data imbalance is not addressed.3.Data normalization: We normalized the data to ensure that the data variance per dimension was 1 and that the mean was 0. This treatment ensures that the results will not be dominated by excessively large eigenvalues of some dimensions.To predict 3-year all-cause mortality, we created six ML models utilizing follow-up data. They are logistic regression, K-nearest neighbor, random forest, naive Bayes, decision tree, and extreme gradient boost. Logistic Regression(LR): The logistic regression algorithm is a probabilistic nonlinear regression, which is a multivariate analysis method that examines the relationship between two or more categorical outcome variables and influencing factors –33. K-NeFrom the six ML models, the optimal algorithm for this dataset was identified as random forest. At the same time, because the interpretability of machine learning is generally poor, it is not conducive to the formulation of diagnostic strategies for doctors and the understanding and cooperation of patients. We used ML interpretable tools and techniques, permutation importance, PDP plots and SHAP values for analysis.In this paper, we located 626 patients who had been followed up for more than three years or had passed away; 332 patients were alive, and 294 had died. The average age of the enrolled patients was 66.27 ± 12.25 years, of whom 402 were men and 224 were women  or categorical variables (as frequencies and percentages) Table. To idenThe hyperparameters of the ML models were optimized using a grid search method with five-fold cross-validation (CV) , and red represents a positive effect on the forecast . The baseline  was 0.53; that is, the mean survival rate for all study patients was 0.53. The first patient was 0.55 and was higher than the baseline. The number of hospitalizations was a more important factor Fig. . The reaML technology does not require assumptions about input variables and their relationship with output. The advantage of this completely data-driven learning without relying on rule-based programming makes ML a reasonable and feasible approach. An increasing number of studies are applying ML to predict cardiovascular disease. In recent studies, it has also been used to predict adverse outcomes in patients with HF by integrating clinical and other data , 45, 46.To identify the optimal prediction model for prediction, this paper employs six machine learning algorithms, including logistic regression, naive Bayes, random forest classifier, extreme gradient boost, K-nearest neighbor, and decision tree. During a 3-year follow-up period, we created and evaluated an interpretable machine learning-based risk forecasting tool to predict all-cause death in CHF patients. The machine learning risk score was produced using the random forest model because it performed the best out of the six models. This model risk score greatly exceeded the other risk scores currently available, with an average AUC of 0.82.Moreover, because the interpretability of machine learning is generally poor, it is not conducive to the formulation of diagnostic strategies by doctors and the understanding and cooperation of patients. We used ML interpretable tools and techniques, including permutation importance, PDP plots and SHAP values, for analysis. The permutation importance showed that the number of hospitalizations, age, glomerular filtration rate, BNP, and NYHA cardiac function classification were the top five important factors.We selected seven variables, namely, number of hospitalizations, age, glomerular filtration rate, BNP, NYHA cardiac function classification, absolute neutrophil value and RBC volume distribution width, to draw its PDP, which allowed us to intuitively see the impact of the change trend of each feature on survival prognosis. Finally, it is clear from SHAP values and SHAP plots that the number of hospitalizations, followed by age, glomerular filtration rate, and BNP, has the greatest significance. We demonstrated how machine learning can be applied to create a high-accuracy mortality prediction model in CHF patients and predicted the crucial features. The graphical description may help physicians understand the key components intuitively.The significant factors that predict all-cause mortality in patients with HF were further identified in this investigation. According to the significance of the features, it was clear that a good risk assessment required consideration of clinical traits, demographic traits, and treatment status. Age, BNP concentration, NYHA classification,glomerular filtration rate, and other factors are still significant in predicting death for CHF patients, in line with prior research and clinical practice , 27.To create a survival prediction model for patients with CHF, this study uses a more recent survival analysis algorithm. Based on the confusion matrix analysis of each algorithm model, the optimal random forest model was selected as the prediction model. The model was investigated based on ML interpretable tools and techniques. The importance of variables based on permutation importance, partial dependence plot and SHAP value showed that number of hospitalizations, age, glomerular filtration rate, BNP, diastolic blood pressure, systolic blood pressure, and NYHA cardiac function classification were the most important factors in predicting survival after 3 years of follow-up in heart failure patients.