To evaluate the correlation between the TIMI frame count, IMR, and CFR in coronary microvascular disease (slow flow phenomenon).  TFC and IMR were recorded in the nitroglycerin and ATP administration states, and the relationship between TFC, IMR, and CFR in specific states was analyzed. r = 0.775, P=0.008), TFC and IMR after nitroglycerin , and the minimal TFC and IMR that could be obtained with nitroglycerin or ATP administration . There was also a significant correlation between the proportional improvement in TFC and CFR before and after nitroglycerin injection . In addition, we observed a lower IMR measured after nitroglycerin than after ATP in three patients, suggesting that CMD may be dominated by NO-sensitive vascular such as prearterioles and that an extensive analysis of the target site of CMD may be achieved by stepwise drug administration.  A total of 41 patients with baseline TFC >25 frames on coronary angiography were enrolled, and nitroglycerin reduced TFC by 50% from baseline in 24 (58.54%) patients; 16 of the remaining 17 patients were able to achieve a 50% reduction in TFC by further intracoronary ATP injection. 10 patients were further tested for IMR, and the results showed significant correlations between baseline TFC and IMR ( Induction of TFC in different states by a stepwise drug approach may serve as a potential primary screening method for coronary microcirculatory dysfunction, thereby reducing the need for further IMR or CFR testing. Coronary microvascular dysfunction (CMD) is a clinical phenomenon that causes myocardial ischemia due to functional or structural abnormalities of the microvascular and is considered one of the causes of nonobstructive coronary heart disease . The invPatients with coronary angiography showing slow flow were enrolled consequently. CSF was defined as the TIMI frame count >25 frames at 15 frames per second (fps). The clinical diagnosis in all patients favored microvascular angina, i.e., coronary angiography showed no >50% stenosis or significant thrombotic, dissection lesions in the large epicardial vessels; also, there was no evidence of typical variant angina-epicardial large vessel spasm.Base) will be recorded without any intracoronary medication; in the second step, TIMI frame (TFCNIT) will be recorded after intracoronary injection of 200 μg of nitroglycerin; if the decrease in TFCNIT compared to TFCBase is less than 50%, then the third step is followed—inject 100 μg of adenosine triphosphate intracoronarily and record the TFC once again (TFCATP). It is important to note that there should be at least a 2-minute interval between the nitroglycerin and ATP injections and to confirm that the TFC returns to baseline levels to ensure complete elution of the nitroglycerin effect.Coronary angiography was performed using a 5 F TIG catheter through the radial artery. The contrast medium was injected manually by the same operator, and it was required to ensure satisfactory filling of the intravascular contrast medium and clear display of the vessel contour. The image acquisition frequency was standard 15 frames per second (fps), with a blank phase, and the image acquisition was maintained until the last branch of the distal coronary artery was visualized [IMR, CFR, and fractional flow reserve (FFR) were evaluated in all patients who signed an informed consent form using a C12008 pressure wire  following a standard procedure. Blood was flushed out of the system with saline prior to testing, and the pressure of the catheter system was equalized to the atmospheric pressure and the pressure of the catheter system before the pressure guide wire entered the catheter. The test was performed using a 6 F guide catheter, and the pressure guide wire was equalized to the system pressure when it reached the ostium of the LCA. The pressure guide wire was advanced as far as possible into the distal segment of the LAD while avoiding wall attachment or significant tension on the tip of the pressure guide wire.mn), and mean distal pressure (Pd) was recorded simultaneously [mn were acquired in 3 specific states: baseline state (without any vasoactive drug), after intracoronary injection with 200 ug nitroglycerin, and during continuous intravenous pumping of adenosine triphosphate (160 ug/kg ∗ min). After each specific state is tested, the next state is waited for the TIMI frame count to return to baseline levels.After confirming that the guiding catheter and LCA ostium were well engaged, intracoronary bullet injections of 5 ml of room temperature saline were performed to obtain the mean transit time .P value <0.05 was considered statistically significant.Statistical analyses were performed using SPSS 26.0 software . For continuous variables, the Kolmogorov–Smirnov test was used to determine whether the data are normally distributed. Continuous variables were presented as mean ± standard deviation or median (quartile), whereas gender, past medical history, etc., were presented as percentages. Spearman's correlation analysis was used to analyze the correlation between parameters. A two-tailed 2 in males and 24.92 ± 3.24 kg/m2 in females, both meeting the criteria for overweight. Mean systolic blood pressure was 125.39 ± 16.89 mmHg, diastolic blood pressure was 75.95 ± 10.83 mmHg, and heart rate was 72.05 ± 11.39 bpm. Ancillary examinations showed that mean HbA1c was 6.80 ± 1.50%, NT-proBNP was 77  pg/ml, and mean LVEF was 63.95 ± 6.47%. Detailed examination results are shown in A total of 41 patients were enrolled, including 28 males and 13 females, with a mean age of 59.02 ± 12.01. All patients were admitted with chest pain/discomfort, but not exertional. 24 had a history of hypertension, 17 had type 2 diabetes mellitus, 21 patients (51.22%) were current smokers, and the proportion of other comorbid diseases was low. The mean BMI was 25.01 ± 3.72 kg/mBase for all 41 patients was 38.12 ± 10.12 frames, and mean TFCNit was 19.34 ± 8.39 frames, with a mean reduction in TFCNit over TFCBase of 49.40 ± 15.91%. The proportion of patients with >50% reduction was 58.54% (24/41), and their baseline median frames were 37  frames, which decreased to 14  frames with nitroglycerin, with a median reduction of 60.49% ; the proportion of patients with ≦50% reduction was 41.46% (16/41), and their baseline median frames were 36  frames, which decreased to 25  frames with nitroglycerin, with a median decrease of 36.11% . There was no statistically significant difference between the two groups of effective/ineffective nitroglycerin in TFCBase (P=0.519) (Mean TFCP=0.519) .Base induced by nitroglycerin, TFCATP was assayed after nitroglycerin elution, and the results were 11  frames with a median reduction of 69.44%  compared to TFCBase. All patients could obtain more than 50% reduction in the TFC from baseline by nitroglycerin or ATP injection, except for 1 patient who had a reduction of less than 50% from baseline.For the 17 patients with <50% reduction in TFCBase of 32  frames and TFCNIT of 15  frames, and the minimum TFC induced by nitroglycerin or ATP (TFCMin) was 12  frames. IMRBase was 115.58 , IMRNIT was 48.33 , IMRATP was 23.10 , and the minimum IMR induced by nitroglycerin or ATP (IMRMin) was 16.33 . Three patients had IMRNit <25, six patients had IMRATP <25, and there was no correlation between IMRNit and IMRATP . Six of them had >50% reduction in the TFC induced by nitroglycerin, three had >50% reduction in the TFC induced by ATP, and one could not achieve >50% reduction in the TFC by both nitroglycerin and ATP. The results showed that the included patients had TFCd IMRATP .Min decreased to below 25 in 8 patients. The other 2 patients had IMRMin of 40.50 and 43.55, respectively, and their corresponding TFCMin was 16 and 15 frames, respectively. Spearman's correlation analysis showed that TFCBase was significantly correlated with IMRBase , but not with IMRNIT, IMRATP, or IMRMin. TFCNit was significantly correlated with IMRNit , and TFCMin was significantly correlated with IMRMin   .Nit compared to TFCBase was not significantly correlated with the value of the decrease in IMRNit compared to IMRBase    , while t< 0.001) .Base/Nit) and CFR (CFRBase/Nit) for the coronary nitroglycerin-injected state compared with the baseline state and the maximum ratio of TFC (TFCBase/Min) and CFR (CFRBase/Min) that could be obtained for the nitroglycerin-injected or ATP state compared with the baseline state. The results showed median TFCBase/Nit of 2.17  and median CFRBase/Nit of 2.43 , showing a significant correlation  , and median CFRBase/Min was 7.09 , and there was a significant correlation between them   . Median P=0.011) .CMD includes both functional and structural types, and some patients have both of these types, which are called mixed types. The incidence of structural abnormality is relatively low and is commonly caused by various causes of myocardial hypertrophy and atherosclerosis; functional CMD is relatively common and mainly results from vasospasm caused by various abnormalities in vasodilation and contraction regulation, which can usually be reversed using vasodilator drugs. Although there are differences in the technical principles of TFC, IMR, and CFR, what is more important is the difference in patient status at the time of testing. TFC is the state of CMD at baseline without medication and may contain both functional and structural factors, IMR is the state of maximal hyperemia induced by medication and retains only structural factors, whereas CFR evaluates the effect of medication and corresponds to the weighting of functional factors. Therefore, it is not reasonable to directly compare the three parameters and obtain results without correlation in previous studies. A more reasonable approach would be to compare the clinical values of the three parameters in the same hyperemic state.In the present study, TFC and IMR were recorded separately for baseline and drug-induced maximum hyperemic states. Under the same state, TFC and IMR showed a good correlation, and there was also a significant correlation between improvement in TFC and CFR. Since TFC is a simpler method than CFR and IMR, the above results suggest a possible initial screening of coronary microcirculatory function by the results of TFC in different states to exclude the majority of patients with functional CMD. Only patients with insufficient drug effect require further IMR. To achieve this, there are still some issues that need further work to be addressed.To further ensure the consistency of TFC and IMR in terms of measurement status, the choice of the target artery to be measured may have to be changed. The LAD was used in this study, which may not be a good choice. Since TFC is usually measured using an angiographic catheter, while IMR requires a guiding catheter, and the morphology of the LCA ostium and the diameter of the LM are highly variable, there are differences in the engagement of the LCA ostium between the two catheters, further affecting the coaxiality and filling speed of the contrast in the LAD. RCA, on the contrary, has relatively few problems in this regard and may be a more appropriate choice. Of course, this choice can only be made if it is not a significant left dominant, and RCA also shows a significant slow flow. The use of an extension catheter for the LAD with larger internal diameters may also be an option. This problem mainly affects the stability and reproducibility of the assay and is also present in the IMR measurement process.In-depth consideration is also needed in the selection of vasodilator drugs to achieve maximum hyperemia. The coronary microvasculature is a complex network that includes three components: prearterioles (200–400 um), arterioles (20–200 um), and capillaries. Both prearterioles and arterioles are the main regulatory vessels and can be classified as nitric oxide-dependent and nondependent, with differences in response to drugs. Adenosine/ATP acts mainly in 20–200 um vessels , whereasNIT than IMRATP observed in some patients further suggests variability in the site of spasticity, the exact mechanism and clinical implications of which need to be further investigated. Thus, the stepwise administration strategy of nitroglycerin and ATP can be used to identify endothelium-dependent or nonendothelium-dependent, while a combination strategy of nitroglycerin and ATP/adenosine or the use of drugs such as nicorandil/fasudil that have a dilating effect covering the entire microvascular network may be relevant in determining the presence of structural dysfunction [In this study, we used a stepwise administration strategy: (1) nitroglycerin was used instead of acetylcholine in patients with CSF to determine the presence of endothelium-dependent dysfunction; (2) nitroglycerin was first given to observe the effect of nitroglycerin on CSF, and ATP was given to patients who responded poorly to nitroglycerin. We observed a “biphasic” improvement in TFC, with nitroglycerin, which could reduce TFC by more than 50% in 58.54% of patients, suggesting that the CSF in this group of patients was mainly from the spasm of the prearterioles; and the phenomenon that ATP was effective suggests that the site of their coronary spasm may be located in the arterioles. The phenomenon of lower IMRfunction , 14. WheThis study is only a preliminary exploratory study with a small sample size, which does not provide sufficient evidence for the generalizability of the results and is insufficient to analyze the factors associated with different phenotypes, and larger clinical studies are currently underway. In the follow-up study, the study process needs to be further improved, and it is proposed to perform TFC testing in both nitroglycerin and ATP states in all patients to further determine the proportion of different sites of microcirculatory abnormalities in the population and to analyze the associated factors. The clinical significance of the variability in response to drugs needs to be further explored.CMD is a highly prevalent phenomenon, and the current diagnostic criteria for TFC, CFR, and IMR have significant overlap in terms of underlying theory. The preliminary results of the present study give a first insight into the association between the three parameters. Further clarification of this relationship through a larger study would be valuable to optimize the overall process of coronary microcirculation assessment and the diagnosis of CMD.


Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological entity characterized by variable neurological manifestations, primarily caused by pathophysiological changes related to cerebral autoregulation that result in radiologically evident vasogenic edema. It is usually associated with hypertensive states, but it is not exclusively related to those. A healthy 18-year-old primigravid woman with no proteinuria or hypertension on admission presented with normotensive PRES. She had an intense diffuse headache that preceded a generalized tonic-clonic seizure. Her neurological status deteriorated, and hypertension was detected afterward. Brain imaging revealed bilateral vasogenic edema in the occipital region. Magnesium sulfate and antihypertensive medications were administered. A cesarean section was performed, and her neurological symptoms subsequently improved, leading to discharge with no complications. This case highlights the importance of suspecting PRES in pregnant patients even in the absence of preeclampsia. The hypertensive disorders of pregnancy (HDP) - chronic hypertension, gestational hypertension, and preeclampsia/eclampsia - remain one of the major causes of maternal mortality and morbidity worldwide, including in Latin America and the Caribbean. HDP is associated with an increased risk of cardiovascular and renal diseases even long after delivery. A higher risk of HDP has been described in primiparous women compared to multiparous women .Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological condition characterized by neurological manifestations associated with posterior cerebral edema, usually transient. Its incidence in the general population is unknown, and its signs and symptoms can vary according to the severity. However, some patients may present with headaches, visual disturbances, altered consciousness, and generalized tonic-clonic seizures ,3.PRES is usually associated with hypertension, preeclampsia, and eclampsia but can also occur in the setting of infection/sepsis/shock, autoimmune diseases, chemotherapy, and transplantation. It is more common in females and middle-aged adults, but it may be underdiagnosed in other population groups. Radiologically, bilateral symmetric vasogenic edema has been described in the territories of the posterior cerebral circulation ,4.In this report, we present a case of a young female patient diagnosed with PRES in the absence of preeclampsia, prompting clinicians to suspect it in atypical scenarios.A healthy 18-year-old G1P0, 28 weeks' gestational age by first-trimester ultrasound with no previous prenatal care, was admitted to the obstetric intensive care unit of a hospital in Barranquilla (Colombia). She was evaluated for a two-day history of intense diffuse headache and grade II lower limb edema, preceding a generalized tonic-clonic seizure that lasted approximately three minutes without any other associated sign or symptom. Physical examination performed on admission revealed eye-opening in response to verbal command, incomprehensible speech, withdrawal to pain, and mildly reactive isochoric pupils [Glasgow Coma Scale (GCS) score: 9/15]. Vital signs were within normal limits (blood pressure was 118/72 mmHg).Eclampsia or previously uncontrolled epilepsy were among our differentials. At the time, magnesium sulfate was initiated for neuroprotection. Later, our patient’s neurological status deteriorated (GCS score: 8/15), requiring endotracheal intubation. Furthermore, she developed new-onset elevated blood pressure (168/112 mmHg), which required intravenous antihypertensive management . Toxicological panels, immunologic workup, lumbar puncture, hematologic profile, urinary protein determination, and obstetric Doppler ultrasound were requested, which yielded normal results. Measurement of angiogenic and antiangiogenic factors was performed with results above the normal limits  to ensure perfusion and meet metabolic demands. This autoregulation is determined by the partial pressure of carbon dioxide and mean arterial blood pressure and, to a lesser extent, by the partial pressure of oxygen, adenosine, pH, etc. . When thOur patient had a normotensive generalized tonic-clonic seizure followed by a hypertensive crisis and neurological deterioration that resolved after pregnancy termination and blood pressure management. Since she had no previous history of arterial hypertension, it was hypothesized that her cerebral autoregulation mechanisms were overwhelmed by mild to moderate fluctuations or elevation above baseline blood pressure (explaining normotensive presentation) and later by high blood pressure levels  .Hefzy et al. analyzed 151 patients and described some risk factors for PRES, including arterial hypertension, immunosuppression, sepsis, and preeclampsia . BartynsAccording to some publications, the location and distribution of edema may determine the severity. Based on fluid-attenuated inversion recovery (FLAIR) MRI, McKinney et al. defined mild cases as those in which the edema affects the cortical and subcortical white matter, moderate cases as those in which there is confluent edema extending from the cortex to the deep white matter, and severe cases as those in which there is confluent edema extending from the cortex to the ventricle, hemorrhage, midline shift, herniation, mass effect, involvement of the cerebellum, brain stem, or basal nuclei (DBRE) -16. TherHefzy et al. reported that despite its usual favorable outcome, this syndrome is associated with a mortality of 5-15% and that hemorrhagic transformation  increases mortality to 29%; based on this data, a high index of suspicion and timely diagnosis of PRES are essential for good clinical outcomes -19.We reported a case of a healthy 18-year-old G1P0 with an elevated risk for eclampsia presenting with PRES. Proteinuria and hypertension were absent on admission, but clinical syndrome and neuroimaging findings were indicative of a positive diagnosis. Autoregulation mechanisms of cerebral blood flow in patients with pregnancy-associated hypertensive disorders are very vulnerable since they can get overwhelmed due to a lack of adaptation. The relevance of the case report lies in the positive impact resulting from the timely identification of PRES associated with pregnancy even though it did not meet all the established criteria for HDP during its initial presentation. Early recognition and management of the condition can help prevent further damage.


P = 0.005). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP was − 5.27 mmHg . Changes in office BP were consistent with ABPM. Empagliflozin was well tolerated. Empagliflozin was associated with significant and clinically meaningful reductions in BP versus placebo in Chinese elderly patients with type 2 diabetes and hypertension. The underlying mechanisms possiblely at least in part were the improvements of endothelial function and arterial stiffness associated with empagliflozin.The current study evaluated the effect of SGLT-2 inhibitor, empagliflozin, on blood pressure reduction in Chinese elderly hypertension patients with type 2 diabetes and investigated its possible mechanisms. 124 patients were randomized to receive 25 mg empagliflozin QD, or placebo double blind for 12 weeks. Patients underwent 24-h ABPM. Endothelial function and arterial stiffness were also measured prior to randomization and at week 12. At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP was − 8.14 mmHg (95% CI − 10.32, − 3.96, Registration number: ChiCTR2100054678, Registration date: December 23, 2021. Prevalence of hypertension in patients with diabetes is 2 times that of non-diabetic people. Meanwhile, prevalence of simultaneous diabetes and hypertension in elderly people is 1.5 times that of young people3. Both hypertension and diabetes are cardiovascular disease risk factors. The cardiovascular disease risk is 3 times in patients with type 2 diabetes compared with non-diabetic subjects4. In addition, 1.7 fold and 1.5 fold increased risk for all-cause mortality and cardiovascular events, respectively, are shown in diabetic individuals with hypertension compared with those with normal blood pressure5. Tight blood pressure control could decrease risk of macrovascular and microvascular complications in type 2 diabetes by 20–40 percent3. Studies have indicated that the adverse effects of hypertension and diabetes may be addictive7, making the treatments targeted both glycemic and blood pressure control are crucial options for physicians.Type 2 diabetes and hypertension are the most common non-communicable diseases in elderly people8. Beta-blockers increase the incidence of diabetes by 28 percent, impairing blood supply and insulin sensitivity in tissue9. Although ACEI/ARB could improve insulin resistance, high prevalence of persistent cough and angioneurotic edema induced by them urges us to find a new efficient and safe antihypertension drug in patients with diabetes.Traditional antihypertension drugs, such as diuretics and β-adrenoceptor blockers, the effects of which on glycaemic control are negative. Thiazide diuretics inhibits insulin function by acting on ionic channel in cell membranes, decreasing intracellular magnesium and potassium contents, reducing glucose transporter protein expression10. Multiple mechanisms involve BP reduction by SGLT-2 inhibitors, including osmotic diuresis, mild natriuresis, body weight loss, local inhibition of the RAAS11, and nitric oxide release12. Whether there are other relevant mechanisms related to the BP-lowering effect of SGLT-2 inhibitors is still elusive.Some hypoglycemic drugs, such as GLP-1 receptor agonists, DPP-4 inhibitors and thiazolidinediones, have a slight antihypertensive action. SGLT-2 inhibitors is a new antidiabetic drug class which lower blood glucose by promoting the renal excretion of glucose. Some studies have indicated that they also have hypotensive effectThe current study evaluated the effect of SGLT-2 inhibitor, empagliflozin, on blood pressure reduction in elderly hypertension patients with type 2 diabetes and investigated its possible mechanisms.2 and HbA1c 7.0–10.0% at screening were eligible for inclusion. Previous antidiabetes and antihypertension therapies had remained unchanged after enrollment. Key exclusion criteria included uncontrolled hyperglycemia (fast plasma glucose ≥ 13.3 mmol/L), mean seated SBP ≥ 180 mmHg and/or mean seated DBP ≥ 110 mmHg, known/suspected secondary hypertension, malignant hypertension, history/evidence of hypertensive retinopathy or hypertensive encephalopathy, renal impairment , or indication of liver disease , history of acute coronary syndrome, stroke, or transient ischemic attack.Patients with type 2 diabetes and hypertension (mean seated office SBP 140–179 mmHg or DBP 90–109 mmHg) aged 65–80 years with a BMI ≤ 30 kg/mPatients were randomized (1:1) to receive 25 mg empagliflozin QD, or placebo double blind for 12 weeks. Randomization was undertaken using a computer-generated numbers and sealed envelopes were used for allocation concealment. Patients continued their antihypertensive and antidiabetes background therapy throughout the trial at an unchanged dose and regimen. Office BP was measured using Omron M digital BP monitor by three physicians. Three measurements after resting in a quiet and temperature-controlled room were performed and average was recorded. ABPM was performed by ABPM lab in the hospital using Spacelabs Ultralite 90217 devices in accordance with manufacturer recommendations and in agreement with current ESC/ESH Guidelines. The ABPM devices were programmed to measure BP and pulse every 30 min. Patients underwent 24-h ABPM ≤ 7 days prior to randomization and at week 12. At both times, patients’ daytime and nighttime activities during the 24 h were to be similar. Blood sample was collected and sent to assay in the clinical lab of the hospital for fasting plasma glucose, serum insulin and HbA1c. HOMA-IR score was calculated using the HOMA-IR formula (HOMA-IR = fasting insulin (mIU/l) × fasting glucose (mmol/l)/22.5. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease Study equation.Patients underwent 24-h ABPM, endothelial function assessment [brachial artery flow-mediated dilation (FMD)], arterial stiffness assessment [carotid artery pulse wave velocity (cPWV)] prior to randomization and at week 12. Endothelial function was assessed in accordance with current guidelines through brachial artery FMD. Patients laid supine with their right arm extended and fixed on the examination table with rubber foam. Blood pressure was recorded using the other arm. An additional blood pressure cuff was used on the right forearm. The brachial artery was recorded by ultrasound and its diameter was obtained by using the machine’s continuous tracking software. Baseline diameter was obtained for 1 min, and after that, the blood pressure cuff was inflated to 50 mmHg above the systolic blood pressure for 4 min, resulting in the occlusion of the forearm arteries. After that time, the blood pressure cuff was rapidly deflated, inducing reactive hyperaemia. Te brachial artery diameter was then continuously recorded for another 3 min. At the end of examination, the ultrasound machine automatically generated the values of baseline and maximal brachial artery diameter and FMD. cPWV measurement was performed on the right common carotid artery. Patients laid in a supine position, their head additionally elevated by 45° and tilted to the side by 30°. Using the device’s software, stiffness was measured through analysis of the pulse waves obtained. The tracker pair was fixed at the anterior and posterior wall of the common carotid artery. The machine obtained the pressure wave forms from the changing arterial diameters that were calibrated based on systolic and diastolic blood pressure. Then cPWV was calculated automatically as a mean of 12 beats.The protocol was approved by the ethics committee of Jiangxi Provincial People’s Hospital. The study was conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent before enrollment into the study.A sample size of 60 patients per treatment group would provide a power of 90% to detect a treatment difference of 8 mmHg (SD 13) in 24-h SBP at a significance level of 5% (two-sided), and a 5% dropout rate. This sample size would have 97% power to detect a 5 mmHg difference in mean 24-h DBP assuming an SD of 7 mmHg.t test for continuous variables and the χ2 test for categorical variables. For the clinical endpoints (change in various indices from baseline to week 12), the analysis of covariance was used; the results were expressed as adjusted mean (standard error). Analysis of covariance included the baseline value of each analyzed variable as covariates. SPSS22.0 statistical software was used. P < 0.05 was statistically significant.Baseline characteristics are expressed as the number of observations and percentage for categorical variables or the median ± SEM for continuous variables. Differences between groups were assessed with the independent-samples Between September 2020 and March 2021, 124 elderly patients with type 2 diabetes and hypertension were randomized and received study medication. Patient baseline characteristics are shown in Table Hourly mean SBP and DBP at week 12 are shown in Figs. P = 0.005). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP was − 5.27 mmHg . Similarly, at week 12, adjusted mean difference versus placebo in change from baseline in office SBP was − 6.27 mmHg . Adjusted mean difference versus placebo in change from baseline in office DBP was − 4.47 mmHg . Data are shown in Table At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP was -8.14 mmHg . At week 12, adjusted mean difference versus placebo in change from baseline in nighttime mean 24-h SBP was − 7.63 mmHg . At week 12, adjusted mean difference versus placebo in change from baseline in daytime mean 24-h DBP was -6.10 mmHg . Adjusted mean difference versus placebo in change from baseline in nighttime mean 24-h DBP was − 4.46 mmHg . Patients with achieving target of 130/80 mmHg (ABPM) at week 12 accounted for the whole study population by 56.5% (35 cases) and 83.9% (52 cases) in placebo group and empagliflozin group, respectively. Data are shown in Table At week 12, adjusted mean difference versus placebo in change from baseline in daytime mean 24-h SBP was − 10.01 mmHg  reporting treatment effects of SGLT-2 inhibitors on ambulatory BP. Compared with these seven trials, our study has not investigated the different effects between the high-dose and low-dose empagliflozin groups. Furthermore, we also have not taken hydrochlorothiazide as active comparator. These were the insufficiency of our study. However, the merit of our study was that we presented two of possible mechanisms in BP-lowering effect of empagliflozin which were the improvements of arterial stiffness and endothelial function making a case for the further studies.Georgianos et al.Empagliflozin was associated with significant and clinically meaningful reduction in BP versus placebo in Chinese elderly patients with type 2 diabetes and hypertension. The underlying mechanisms possibly at least in part were improvements of endothelial function and arterial stiffness associated with empagliflozin.


Established prediction models of Diabetic kidney disease (DKD) are limited to the analysis of clinical research data or general population data and do not consider hospital visits. Construct a 3-year diabetic kidney disease risk prediction model in patients with type 2 diabetes mellitus (T2DM) using machine learning, based on electronic medical records (EMR).Data from 816 patients  with T2DM and 3 years of follow-up at the PLA General Hospital. 46 medical characteristics that are readily available from EMR were used to develop prediction models based on seven machine learning algorithms . Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). Shapley additive explanation (SHAP) was used to interpret the results of the best performing model.The LightGBM model had the highest AUC . Recursive feature elimination with random forest and SHAP plot based on LightGBM showed that older patients with T2DM with high homocysteine (Hcy), poor glycemic control, low serum albumin (ALB), low estimated glomerular filtration rate (eGFR), and high bicarbonate had an increased risk of developing DKD over the next 3 years.This study constructed a 3-year DKD risk prediction model in patients with T2DM and normo-albuminuria using machine learning and EMR. The LightGBM model is a tool with potential to facilitate population management strategies for T2DM care in the EMR era. Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD), cardiovascular (CV) disease, and all-cause morbidity and mortality in patients with diabetes . NotablyPredictors of DKD risk include albumin excretion rate (AER), blood pressure, blood glucose, glomerular filtration rate (GFR), diabetic retinopathy, and plasma lipid levels. In the real-world setting, collecting longitudinal data from the large population of patients with diabetes is challenging . In clinMachine-learning of big medical data derived from electronic medical records (EMR) in the real-world setting is supporting physicians in their clinical diagnoses and management of asthma and life-style related diseases such as diabetes , 6. ModeA recent study revealed that the predictive power of a real-world data (RWD)–based model for diabetes-related CKD outperformed published algorithms based on data from clinical trials . The objData for this study were retrospectively derived from the EMR database at the People’s Liberation Army (PLA) General Hospital, the largest hospital in North China. The EMR database contains patient information and medical records from all hospital departments. The data set was de-identified and spanned from October 2008 to December 2019. This study was approved by the PLA General Hospital ethics committee (S2017-133-01) and conducted according to the guidelines of the Declaration of Helsinki.Patients diagnosed with T2DM, according to International Classification of Diseases (ICD)-10 codes, with 3 years of follow-up were eligible for this study. Exclusion criteria were: (1) aged < 18 years; (2) undergoing an invasive procedure; (3) presence of an acute infection; (4) presence of a malignancy; (5) or pregnancy.2, calculated using the Chronic Kidney Disease Epidemiology Collaboration  > 30 mg/g, protein excretion rate > 150 mg/24 h, or urine dipstick test ≥ 1 + , or eGFR(CKD-EPI ) equatioAt the 3-year follow-up, included patients (n = 2809) were stratified according to the presence (n = 408) or absence n = 2401) of DKD; under-sampling was used to balance the number of patients with or without DKD to 408 each . Patient of DKD; Patients’ demographic and clinical characteristics at baseline and the 3-year follow-up were recorded. Laboratory variables were derived from universally implemented tests. Comorbidities , including hypertension, cardiovascular disease, peripheral neuropathy, diabetic retinopathy and cerebrovascular disease, were diagnosed according to ICD-10 codes.The risk prediction model was trained using 46 variables selected from medical reports and published literature, including sex, age, body weight and height, BMI, urine specific gravity (SG), urine red blood cell count (RBC), hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), white blood cell count (WBC), percent neutrophil granulocytes (N%), percent lymphocytes (L%), neutrophil to lymphocyte ratio (NLR), platelet count (PLT), mean platelet volume (MPV), activated partial thromboplastin time (APTT), plasma fibrinogen (FIB), random blood glucose (RBG), HbA1c, blood urea nitrogen (BUN), serum creatinine (SCR), serum uric acid (SUA), eGFR, total bilirubin (T-BiL), direct bilirubin (D-BiL), ALB, γ-glutamine transferase (GGT), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), LDL, serum potassium (K), serum sodium (Na), calcium (Ca), phosphate (P), bicarbonate, and Hcy. Albuminuria was not used as a predictor, as patients had normal urinary protein excretion at baseline.Variables with > 25% missing data were excluded. Missing values for included variables were imputed using the random forest (RF) method .Seven machine learning algorithms implemented in the Python package 3.3.8: light gradient boosting machine (LightGBM) , eXtremeLightGBM is a new member of the boosting family of algorithms, which is an accurate and efficient implementation of GBDT, similar to XGBoost. Both LightGBM and XGBoost take the negative gradient of the loss function to fit the residuals and find the optimal solution. Compared with XGBoost, LightGBM has faster training efficiency, lower memory, higher accuracy, and it can handle large-scale data and provide direct support of categories. The AdaBoost algorithm is a boosting method that combines multiple weak classifiers into a single strong classifier. The neural network model represents a (significant) enhancement of the logistic regression method. Decision tree models break down data sets into smaller subsets and develop an associated decision tree. The SVM algorithm is a binary classifier that maps input data into a high-dimensional feature space with a non-linear transformation. The logistic regression algorithm builds linear models with built in attribute selection.A binary outcome for the prediction model was defined as the presence or absence of DKD. Every subset of data included the baseline values (at patients' first visit) for the predictor variables as well as DKD outcomes at 3 years of follow-up. Data were randomly allocated into separate training and validation data sets for each time window using the Python package (Scikit-learn) . 80% of P value < 0.05 was considered statistically significant.Analyses were conducted using Python version 3.8.3 and SPSS software . Normally distributed continuous variables were compared using the student's t test. Non-normally distributed continuous variables were compared using the Wilcoxon rank sum test. Categorical variables were compared using the chi-square test. Tests were two-sided. A Performance of the predictive models generated by the seven machine learning algorithms were evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, accuracy, and the F1 score / ); range from 0 (worst score) to 1 (best score)) . Shapley. At baseline, patients with no DKD at the 3-year follow-up were significantly older and had significantly higher eGFR, ALB, and Hb and significantly lower HbA1c, compared to patients with DKD at the 3-year follow-up.A total of 816 patients were included in this analysis. Of these, patients had a median age of 56 years , and 585 (67.7%) patients were male. The incidence of at least one macrovascular or microvascular complication  was 52.6%. Baseline demographic and clinical characteristics of patients with or without DKD (n = 408 each) at the 3-year follow-up are shown in Table 1Recursive feature elimination (RFE) with RF was used to select variables as inputs for the 3-year DKD risk prediction model . UltimatThe eight selected variables were used as inputs for the seven machine learning algorithms to predict 3-year DKD risk. Performance evaluation of the models generated by the seven machine learning algorithms is shown in Table SHAP was used to interpret the results of the LightGBM model by computing the contribution of each variable to the prediction. The importance matrix plot and SHAP summary plot for the LightGBM model are shown in Fig. The importance matrix plot ranked the variables contributing to 3-year DKD risk prediction from most to least important as patients’ baseline age, Hcy, HbA1c, BMI, Alb, eGFR, bicarbonate, and LDL Fig.  identifiSHAP force plots illustrate profiles of patients at high or low risk for developing an outcome and show how a predictive model based on EMR can facilitate individualized care planning. SHAP force plots for the LightGBM model are shown in Fig. In the study population, the risk of developing DKD over the next 3 years was 49.6%. Figure This study identified predictive risk factors for DKD and constructed a 3-year DKD risk prediction model in patients with T2DM and normo-albuminuria using machine learning and clinical variables easily extracted from EMR. The performance of predictive models generated by seven machine learning algorithms were compared. Findings showed the LightGBM model had the highest AUC, sensitivity, positive predictive, and negative predictive values. LightGBM is a high-performance gradient boosting framework , 29 thatEMR has increased access to large amounts of patient data. This, combined with machine learning, is facilitating the development of sophisticated prediction models , 32. Pre2, poor glycemic control, and high or low BMI had a high 3-year risk of developing DKD. Accordingly, older age was identified as a risk factor for DKD progression, independent of diabetes duration, in patients with T2DM [2 (hyperfiltration) had a high 3-year risk of developing DKD. While more research is required, evidence suggests that glomerular or whole kidney hyperfiltration is a major contributing factor to the development of DKD in patients with type 1 or T2DM [Machine learning has confirmed that several biomarkers have prognostic use and may help investigators identify novel risk factors and provide insight into disease pathogenesis . Ongoingith T2DM ; a prospith T2DM ; and pooith T2DM . eGFR, g or T2DM , 42. Spe or T2DM .The relationship between lipid profile and DKD is complex. Previous reports suggest dyslipidemia as a potential risk marker for DKD, but it is unclear which lipids or lipoproteins should be targeted for intervention . In thisHomocysteine, Alb, and bicarbonate are not traditionally associated with increased risk for DKD. However, one study in Chinese patients with diabetes indicated a causal relationship between elevated circulating homocysteine levels and risk of DKD ; in hosp2 or ESRD [This study has several strengths. First, we used RWD derived from EMR, which is likely more representative of the diverse T2DM patient population than data derived from clinical trials. Second, among the other algorithms, the LightGBM model performed the best. LightGBM is a highly optimized gradient boosting decision tree algorithm that can incorporate multiple clinical variables Third, we identified risk factors that have not been traditionally associated with increased risk for DKD. Fourth, most studies have targeted patients with CKD and an eGFR < 60 ml/min/1.73m or ESRD . We inclThis study was associated with some limitations. It was conducted at a single institution, included a small sample size, and the missing information  in our EMR-derived data represented a potential bias. However, we believe our rigorous methodology generated a robust predictive model of 3-year DKD risk in patients with T2DM and normo-albuminuria. External validation using another data set is required to establish stability in the performance of our prediction model.In conclusion, we identified baseline demographic and clinical variables as predictive risk factors for DKD and constructed a 3-year DKD risk prediction model in patients with T2DM and normo-albuminuria using machine learning and EMR. We established the LightGBM model as a tool with potential to facilitate population management strategies for T2DM care in the EMR era.


Objective: The trajectory patterns of estimated glomerular filtration rates (eGFR) in chronic kidney disease (CKD) older adults with malnourishment and their association with subsequent patient outcomes have not been elucidated. We aimed to assess the eGFR trajectory patterns for predicting patient survival and kidney failure in the elderly without or with malnourishment.Materials and Methods: Based on a prospective longitudinal cohort, CKD patients aged 65 years or older were enrolled from 2001 to 2013. Among the 3,948 patients whose eGFR trajectory patterns were analyzed, 1,872 patients were stratified by the absence or presence of malnourishment, and 765 patients were identified and categorized as having malnourishment. Four eGFR trajectory patterns  were classified by utilizing a linear mixed-effect model with a quadratic term in time. The malnourishment was defined as body mass index < 22 kg/m2, serum albumin < 3.0 mg/dL, or Geriatric Nutritional Risk Index (GNRI) < 98. This study assessed the effectiveness of eGFR trajectory patterns in a median follow-up of 2.27 years for predicting all-cause mortality and kidney failure.Results: The mean age was 76.9 ± 6.7 years, and a total of 82 (10.7%) patients with malnourishment and 57 (5.1%) patients without malnourishment died at the end of the study. Compared with the reference trajectory T0, the overall mortality of T1 was markedly reduced . In patients with trajectory, T3 was associated with a high risk for kidney failure  compared with the reference, especially higher risk in the presence of malnourishment. Patients with high GNRI values were significantly associated with a lower risk of death and kidney failure, but patients with malnourishment and concomitant alcohol consumption had a higher risk of kidney failure.Conclusions: Low baseline eGFR and progressively increasing eGFR trajectory were high risks for kidney failure in CKD patients. These findings may be attributed to multimorbidity, malnourishment, and decompensation of renal function. Longitudinal eGFR change in patients with CKD is often nonlinear, and most people with CKD have major clinical events and die before reaching kidney failure. In previous observational studies, patients with CKD experienced the possibility of non-progression of renal function, stable kidney disease with accelerated deterioration, and relentlessly fast eGFR decline into kidney failure –3. HowevMalnourishment, which was caused by CKD, respiratory disease, cancer, and cardiovascular disease, was reported to possibly contribute to high eGFR mortality, especially in older adults , 13. TheClinically, great diversity in longitudinal eGFR measurements exists. These patterns reveal different clinical pictures of kidney function. Taking these characteristics of longitudinal eGFR profiles into account would provide more information on the condition of kidneys compared with using baseline eGFR or decline rate. Therefore, we conducted a prospective longitudinal cohort study using the eGFR trajectory to predict patient survival and renal outcome in CKD older adults without or with malnourishment.n = 3,948) from five counties and cities in central Taiwan from December 1, 2001, to July 31, 2013. Among the 3,948 patients, 2,076 patients without complete data of malnourishment criteria were excluded. 1,872 participants whose eGFR trajectory patterns were analyzed and were stratified by the absence or presence of malnourishment, and 765 patients were identified and categorized as having malnourishment. The patients in the TCVGH_CKD cohort had at least 3 outpatient eGFR records per year, based on data obtained from the Taiwan Society of Nephrology (TSN). However, before January 01, 2014, serum creatinine was measured by the Jaffe method using a Beckman Synchron CX5 analyzer (USA) calibrated under the standards of the Chinese National Laboratory Accreditation program. After January 01, 2014, the enzymatic method (CYGNUS AUTO CRE) and spectrophotometry were used. Patients were excluded if they had undergone kidney transplantation or had irreversible kidney failure with or without dialysis before the index date. The TCVGH_CKD database included patients with early CKD  and pre-kidney failure , and all participants were followed up for longer than 6 months, until February 07, 2014, to prevent lead-time bias.Data from the CKD cohort were obtained from patients' medical records at Taichung Veterans General Hospital    Study equation , 23. Thoper year , was defper year . Thirty-per year  combinin effects . Traject in GFR)  were als2, serum albumin < 3.0 g/dL, or GNRI < 98 , hypertension (HTN), cardiovascular diseases, malignancy, malnourishment components , 28, theMortality was obtained from the death registry system and coded from death certificates according to the International Classification of Diseases (ICD)-9 or ICD-10. The primary outcome was all-cause mortality, and the secondary outcome was kidney failure. Patients were identified as having kidney failure if they had undergone maintenance dialysis or short-term dialysis before death.post-hoc analysis was conducted to compare all pairs of subgroups. These calculations were conducted using SAS PROC MI and PROC MIANALYZE. Multinomial logistic regression analysis was applied to evaluate the associations between eGFR trajectory patterns and factors, including demographic variables, comorbid conditions, lifestyle, and nutritional status of older people. The primary outcome, all-cause mortality, and the secondary outcome, kidney failure, were analyzed using cause-specific hazard models for competing risk data. All variables, including the classification of eGFR trajectory patterns, were adjusted in the survival analysis. In all tests, a p < 0.05 was considered statistically significant. Statistical analyses were implemented using R statistical software, version 3.4.2, and SAS, version 9.4 .Based on the empirical Bayes estimates of all random effects, each patient's eGFR profile was estimated. The results revealed four patterns of eGFR trajectories. Each patient was classified into one of the four trajectory patterns according to his/her estimated eGFR profile. To construct eGFR trajectories, the longitudinal eGFR pattern was followed for nearly 140 months . The baspost-hoc test comparing all pairs of subgroups. Baseline eGFR in the T3 group was lower than that in the other subgroups, and a higher proportion of patients in the late stages of CKD were also found in the T3 group , 1.16–4.45]. A total of 333 individuals (8.4%) died at the end of the study .Because the presence of certain parameters may be correlated with increased or decreased odds of trajectory classes , we thenDuring the 12-year study period, 1,872 older adults had complete data with which to identify the status of malnourishment. Among these 1,872 patients, 765 (40.9%) were identified as having malnourishment. The study participants were predominantly male (66.7%), and the mean age was 76.9 years. The most common comorbidities were hypertension (77.7%) and DM (38.8%). Compared with the participants with malnourishment, those without malnourishment were younger, predominantly male, and more likely to have diabetes and/or hypertension. Participants without malnourishment also had higher alcohol consumption, HbA1c, and more prescriptions for hyperlipidemia and hypertension drugs .p = 0.007) after adjusting for all other covariates (p = 0.035) (p = 0.08)  , but the = 0.08) .p < 0.001) compared to the reference  or net reclassification improvement , 38 for There were some potential limitations in the present study that should be addressed. Firstly, there were not enough variables for comparison due to the large size of the cohort. Other possible confounding factors included several concordant and discordant comorbid conditions. Since albuminuria and proteinuria were not included in our dataset, the accuracy of nutritional indicators such as albumin and GNRI is questionable. Especially in patients with nephrotic proteinuria, these nutritional indicators may not adequately reflect nutritional status. Secondly, this study included mostly Taiwanese individuals with a highly selected population, and thus the results may not be generalizable to less narrowly defined populations. Thirdly, old age seemed to have protective effects on kidney failure in the CKD cohort, and this finding was consistent with previous findings. The age distribution was the same between the results obtained using multiple imputations and those without any imputations . Fourth,In conclusion, eGFR trajectories were shown to be a valuable prognostic indicator for predicting outcomes in older adults with CKD. An integrated kidney disease care program could have a notable beneficial effect on patients' mortality and kidney failure, based on a comparison with gradual eGFR decline. Increasing eGFR trajectory in the later period was shown to be a high-risk factor for kidney failure in older CKD patients. These phenomena may be due to multimorbidity, abnormal BMI status, and malnutrition.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics Committee of Taichung Veterans General Hospital . The patients/participants provided their written informed consent to participate in this study.S-CW wrote the manuscript. C-MC, Y-CC, M-JW, and D-CT conceived and designed the experiments and contributed to the discussion and manuscript revision. C-MC performed the analyses. S-CW, M-JW, and D-CT performed the experiments and collected the data. M-JW and D-CT conceived the study and are the guarantors of this publication. All authors reviewed the manuscript, contributed to the article, and approved the submitted version.We are also deeply indebted to Taichung Veterans General Hospital, Taichung for providing the grants for this study . This study was also supported by Taiwan's Ministry of Science and Technology (MOST 106-2314-B-075A-003) and the Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and the Foundation for Poison Control.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Patients with acute decompensated heart failure are prone to recurrent exacerbation leading to poor quality of life when they do not respond to an optimal medical regimen. Due to the lack of linear positive inotropy response to increasing preload in heart failure patients, increasing preload is associated with poor outcomes. Partial occlusion of either IVC or SVC is a proposed novel treatment that can improve cardiac function or quality of life by altering preload/pressure in heart failure (HF) patients unresponsive to diuretics.PubMed, Ovid (MEDLINE), and Cochrane database we searched using the MeSH terms including “Superior vena cava occlusion,” “Inferior vena cava occlusion,” “Heart failure exacerbation.” The inclusion criteria included studies that enrolled patients > 18 years with diagnosed NYHA II-IV HF with reduced ejection fraction (HFrEF) on optimal medical treatment (OMT).The analysis involved two studies with 14 patients; the mean age was 64.4 ± 10 and 100% males. The difference in the mean pulmonary pressures between pre-and-post VCO devices were 1.56 . There was no heterogeneity among the study of mean pulmonary pressures. With the use of VC occlusion devices, the mean difference in pulmonary artery systolic pressure decreased by 1.70  . The heterogeneity of mean pressure was minimal 14%.In conclusion, VCO can help decrease pulmonary pressure that can indirectly prevent heart failure exacerbations and possibly hospitalization in this cohort of patients. •Patients with acute decompensated heart failure are prone to recurrent exacerbation when they do not respond to an optimal medical regimen.•Partial occlusion of either IVC or SVC is a proposed novel treatment that can improve cardiac function or quality of life by altering preload/pressure in heart failure (HF) patients.•The choice of vena cava for device implantation is also essential. However, it is not well discussed in the literature.•This meta-analysis aims to bridge the gap in literature that precludes the uptake of partial VCO as a routine treatment modality for refractory heart failure. Preload volume is a vital contributor to a heart failure exacerbation. The increase in preload is associated with the stretching of myocardial fibers. Due to the lack of linear positive inotropy response to increasing preload in heart failure patients, increasing preload is associated with poor outcomes. Partial occlusion of either IVC or SVC is a proposed novel treatment that can improve cardiac function or quality of life by altering preload/pressure in heart failure (HF) patients unresponsive to diuretics ,2. This 2PubMed, Ovid (MEDLINE), and Cochrane database we searched using the MeSH terms including “Superior vena cava occlusion,” “Inferior vena cava occlusion,” “Heart failure exacerbation.” The inclusion criteria included studies that enrolled patients > 18 years with diagnosed NYHA II-IV HF with reduced ejection fraction (HFrEF) on optimal medical treatment (OMT). They underwent intermittent occlusion of IVC or SVC in artificial or natural ways. The OMT included symptomatic or mortality lowering doses of diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and beta-blockers (BBs). The primary outcome was to evaluate the change in pulmonary artery pressure as an indirect means of lowering the worsening of heart failure exacerbations.3The analysis involved two studies with 14 patients; the mean age was 64.4 ± 10 and 100% males. The difference in the mean pulmonary pressures between pre-and-post VCO devices were 1.56  A. There Safety measures and adverse effects of IVC and SVC occlusion using preCARDIA catheter were discussed in Kapur et al. Acute IVC occlusion reduced left ventricular systolic and diastolic pressures, LV volumes, cardiac output (CO), and systemic blood pressure; in contrast, SVC occlusion reduced LV diastolic pressure and volumes without affecting cardiac output or systemic blood pressure. SVC therapy using preCARDIA was well tolerated with stable MAP and CO without evidence of damage to SVC, lungs, heart, or brain. However, in one animal study, spontaneous sinus bradycardia and hypotension were observed after 14 hours of SVC therapy, but no damage to SVC, RA, RV, brain, or lungs was noted. A large anterior wall myocardial infarction due to LAD ischemia and reperfusion injury was also documented at autopsy. However, in all three animal studies in Kapur et al., SVC occlusion increased IJ pressure, reduced RA, mean PA, PCWP pressure; CO remained stable. One potential concern is the impact of elevated jugular venous pressure on the cerebral function, but no neurologic deficits were identified during or up to 7 days of follow-up after SVC occlusion [3. The quality of the studies was moderate—Quality assessment was done as per the “Cochrane systemic reviews” method4The non-invasive inferior vena cava occlusion by exercise is reviewed by Kaiser et al. enrolled six patients that underwent particle occlusion of IVC by exercise. The study found that mean pulmonary artery pressures dropped significantly with occlusion with no additional neurological or cardiovascular complications. The study found that IVC obstruction lowers left ventricular filling pressure, decreasing cardiac workload, and improving myocardial contractility . AnotherAdditionally, none of the patients reported any adverse neurological or cardiovascular sequelae immediately after the procedure. The potential concern is the impact of elevated jugular venous pressure. However, after 1 week, follow-up divulged that none of the patients developed cerebrovascular accident, myocardial infarction, neurologic complications of thrombosis secondary to the procedure, demonstrating a very low risk of grave post-procedural outcomes.The results delineated by Kapur et al. depicted that partial VCO can be a safe therapeutic procedure that can be efficaciously employed in heart failure patients. The Kapur et al. study results were significant and got expedited approval of the device by the USA's food and drug administration (FDA) . These sOn the other hand, the device implantation in Inferior vena cava precludes two-third of blood supply and might lead to profound hypotension. It also increases pressure in the splanchnic and renal vein that may lead to renal injury and reduces oral medications' absorption. Still, more studies are needed in this therapeutic strategy since it is a relatively novel approach.Our study analyzed both studies to see the mean pressure difference as an indirect effect on pulmonary congestion. The mean difference of pulmonary pressures and mean systolic pressures between pre-and-post VCO were 1.56  and 1.70 , respectively. Given the drop of 1.70 mmHg in PASP, mild clinical improvement in pulmonary hypertension, the results are limited to see the long-term effect of this change. Nevertheless, the study has several limitations. Kaiser et al. was published as abstract, so baseline characteristics are not available. The power of the study is very low for the generalization of results. The long-term outcome of the procedure is yet to be evaluated, and the studies had a very short follow up period. Since the study has shown promising preclinical results, more randomized trials with adequate follow-up are needed to evaluate the treatment option better.5In conclusion, VCO can help decrease pulmonary pressure that can indirectly prevent heart failure exacerbations and possibly hospitalization in this cohort of patients. Therefore, in patients with refractory heart failure unresponsive to appropriate medical intervention, partial VCO might be the way forward.NA.NA.YS, MM, TA: conceived the idea, designed the study, and drafted the manuscript.DS, WU, HMP: conducted literature search and created the illustrations.MZ, IYE FM,: revised the manuscript critically and refined the illustrations.YS, MCA revised the final version of the manuscript critically and gave the final approval.NAName of the registry: NA.Unique Identifying number or registration ID: NA.Hyperlink to your specific registration (must be publicly accessible and will be checked): NA.Talal Almas.RCSI University of Medicine and Health Sciences.123 St. Stephen’s Green.Dublin 2, Ireland.Talalalmas.almas@gmail.com+353834212442.Not commissioned, externally peer reviewed.None.


Introduction: Systemic lupus erythematosus (SLE) is associated with premature cardiovascular disease (CVD) and mortality, unexplained by traditional risk factors. Impairment of microcirculation and vascular hemodynamics may represent early signs of vascular affection. We hypothesized that studies of microcirculation and pulse waves may provide additional information, compared to ultrasound (US) alone, for the detection of early vascular disease in SLE.Methods: Sixty well-characterized SLE-patients  characterized by lupus nephritis , antiphospholipid syndrome  or skin and joint involvement (n = 20) and 60 healthy controls were included. Microcirculatory peak oxygen saturation (OxyP) was evaluated using a novel combined laser Doppler flowmetry/diffuse reflectance spectroscopy method. Pulse waves were recorded in the radial artery by the aid of applanation tonometry in order to calculate central augmentation index (AIx75). Intima-media thickness (IMT) and plaque occurrence were evaluated using high frequency US, in carotid and central arteries.Results: Lower OxyP  and higher AIx75  were seen in the SLE cohort. OxyP was inversely correlated with IMT in internal carotid artery (ICA), . AIx75 correlated with IMT in common carotid artery (CCA), , common femoral artery (CFA), , and ICA . AIx75 correlated negatively with OxyP . SLE-patients with plaque had lower OxyP values  and higher AIx75  compared to those without plaque.Conclusion: Impaired microcirculation and vessel hemodynamics were observed in SLE. These methods correlated with IMT and plaque occurrence. The importance of early macro- and micro-circulatory vascular affection for increased risk of CVD in SLE will be followed-up in future studies. Systemic lupus erythematosus (SLE) is a multi-organ autoimmune inflammatory disease primarily affecting young females . PatientTo evaluate the risk of CVD, ultrasound (US) with measurements of intima media thickness (IMT) constitutes a validated and established method to assess early atherosclerosis . PreviouArterial stiffness in large arteries is considered as a decisive factor for systolic pressure and is a predictor of cardiovascular events . Pulse wAccording to prior studies , an incrSeveral tools to assess microcirculation have been used clinically, i.e., capillaroscopy, infrared thermography and different laser techniques measuring microcirculation perfusion . StudiesFor evaluation of microcirculation in the skin, we employed a novel fiber-optic system that combines laser Doppler flowmetry (LDF) and diffuse reflectance spectroscopy (DRS). The system estimates red blood cell tissue fraction, speed resolved perfusion and oxygen saturation , 22. PreThe aim of this study was to assess vascular hemodynamics in relation to macrocirculation in patients with SLE. We hypothesized that microcirculation and pulse waves may provide additional information, compared to ultrasound (US) alone, for the detection of early vascular disease in SLE.The study population  has prevAcquired organ damage was assessed by the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) damage index (SDI) and disease activity by the SLE disease activity index 2000 (SLEDAI-2K) for each patient, recorded from their closest regular visit to rheumatologist , 30. MeaSixty healthy age- and sex-matched , non-medicated (except for contraceptives) controls without clinical signs of inflammatory or atherosclerotic disease, were examined using the same protocol  as for the patients. The healthy controls were all of Caucasian ethnicity and hospital employees.Height, weight, waist circumference and sagittal abdominal diameter were measured in all subjects. Variables concerning age, sex, smoking habits, physical activity, and ongoing pharmacotherapy were collected by oral request and medical records. Physical activity was defined as activity with increased heart rate (occasions/week). Blood pressure was determined with oscillometric technique .Microcirculatory oxygen saturation was assessed with PeriFlux 6000 EPOS system . A sphygmomanometer cuff was placed on the left upper arm, the probe (with both DRS and LDF) of the EPOS system  was atta® system, model MM3, AtCor Medical, Sydney, Australia), of the right radial artery. The locally recorded peripheral pressure waveform is traced by partly compressing the artery with an external high fidelity pressure probe (tonometer). Augmentation index adjusted to heart rate 75 (AIx75) was calculated. AIx is defined as [(Difference between the second and first systolic peak pressure)/Pulse Pressure] x100. This index denotes the relative aortic pulse pressure amplification in late systole from reflection waves  with L2-9 MHz and C1-6 MHz transducers. IMT was measured in the common carotid artery (CCA), internal carotid artery (ICA), subclavian artery (SCA), axillar artery (AxA), common femoral artery (CFA), superficial femoral artery (SFA) and the aortic arch. Both sides were investigated. The procedure of IMT measurements has been described previously . The IMTAs previously described , standarThe participant had to rest 15 min before the test, which was performed in a room with a temperature of 25°C, dim lighting and no outer disturbances. A standardized examination procedure was used in all individuals. The examination procedure started with US measurements followed by bilateral blood pressure measurements and pulse wave analysis of the right radial artery. The examination procedure ended with evaluation of microcirculation.All participants were asked to refrain from coffee and nicotine use 4 h prior to the measurements.The same vascular sonographer performed all physiologic examinations and the following off-line measurements. The sonographer was blinded to which subgroup of SLE the patients belonged, but not to whether the participants were patients or controls.t-test. χ2 test was performed for categorical variables. Differences between subgroups were calculated using one-way ANOVA with Bonferroni post hoc test. Pearson's correlation test, as well as univariate linear regression were used to test any relationship between AIx75 and OxyP and each of the variables in p ≥ 0.05) variables until a multiple model with only significant variables remained. For missing data, no imputation analysis was performed. Statistical analyses were performed using SPSS version 25.0 .AIx75, OxyP and IMT are presented as mean ± SD. Differences between the whole SLE group and controls were calculated using Student's Oral and written informed consent was obtained from all patients and healthy controls. The study protocol was performed according to the Declaration of Helsinki and approved by the Regional Ethics Board in Linköping .n = 5) showed LDL levels ≤2.7 mmol/L. No significant differences were seen between SLE and controls except for body mass index (BMI), waist circumference, sagittal abdominal diameter, diastolic blood pressure and smoking habits.Basic demographics, laboratory data and ongoing medical therapies are shown in p = 0.01). No significant differences with regard to the phenotypic SLE subgroups were found, although the LN group had the lowest values (82 ± 10 %). AIx75 values were increased in SLE patients compared to controls . No significant differences with regard to the phenotypic subgroups were found, although the APS group showed the highest values (18.8 ± 15.2 %). When comparing gender, no significant differences were found for OxyP, whereas AIx75 differed significantly. AIx75 in females was 19.0 ± 13.7 vs. men 6.8 ± 10.7 % (p < 0.001). In controls, AIx75 for females was 11.6 ± 13.3 vs. men −0.6 ± 15.8 % (p = 0.02).The average OxyP of the entire SLE group was significantly decreased compared to controls 84 ± 8 vs. 87 ± 5 % .A significant inverse correlation was observed between OxyP and AIx75 . IMT in other vessel areas was not correlated with OxyP.OxyP was inversely correlated with IMT in ICA, (p = 0.001). As demonstrated in We observed a difference in OxyP between (1) controls, (2) patients with normal IMT in the aortic arch without plaque, (3) patients with increased IMT in the aortic arch without plaque, and (4) patients with plaque , CFA  and ICA . Other vessel areas showed no significant correlation with AIx75.AIx75 correlated with IMT in CCA (p = 0.04). AIx75 differ significantly between controls and patients with plaque  and higher AIx75  compared to those without plaque.When comparing patients with or without plaque, regardless of normal or increased IMT in the aortic arch, the group with plaque had lower OxyP values  and statin therapy (p = 0.001) were negatively associated with OxyP (R = 0.51).Relation between OxyP and traditional and disease associated risk factors are shown in OxyP was not associated with age , duratioSelf-reported physical activity (occasions/week) were not associated with OxyP, neither in SLE nor in controls.Relation between AIx75 and traditional and disease associated risk factors are shown in p < 0.001), female sex (p < 0.001) and diastolic blood pressure (p < 0.001) remained as significant risk factors for AIx75 (R = 0.63).When all significant variables were included in a multiple linear regression model, age , (p < 0.n = 31), for physical activity 1–3 times/week 18.31 ± 2.5 % (n = 23), and for physical activity ≥4 times/week 3.1 ± 17.1 % (n = 6), (p = 0.02). In the controls, no significant differences were seen.There was a significant difference in AIx75 in relation to self-reported physical activity in SLE. For no physical activity AIx75 was 19.4 ± 13.1 % (p < 0.001). Increased AIx75 levels were found in three of four age groups .As OxyP was lower, and AIx75 was higher, in SLE patients compared to controls, and as OxyP tended to decrease with age in SLE but not in controls , we analThis study of well-characterized SLE patients with clinically low disease activity showed impaired microcirculatory reactivity assessed by OxyP, and signs of premature arterial aging assessed by pulse wave recordings, when compared to healthy controls. Significant correlations with IMT in different vascular areas and plaque occurrence were also detected.For assessment of microcirculation in SLE, prior studies have used different methods such as capillaroscopy, laser imaging techniques and infrared thermography .In this study we used a novel fiber-optic method combining LDF/DRS for estimating oxygen saturation in the microcirculation of the skin in absolute units , 22. MicWe observed that patients with SLE had impaired microcirculation as reflected by OxyP, compared to healthy controls. In healthy controls, the OxyP value were relatively stable regardless of age, whereas OxyP tended to decrease with age in patients with SLE. Stücker et al., using high-resolution two-dimensional laser Doppler perfusion imaging in a healthy group could not find age-related differences in microcirculatory perfusion .Jonasson et al. demonstrated that microcirculatory perfusion is reduced in diabetic patients independent of microvascular changes in the kidneys and large-vessel stiffness . In the Our study showed that reduced OxyP was negatively correlated with waist circumference, sagittal abdominal diameter, presence of Raynaud's phenomenon, as well as ARB/ACE inhibitor and statin therapy in the univariate analysis. In the multivariate analysis only presence of Raynaud's and use of statins remained as negatively correlating factors. However, it should be noted that statin therapy in the study population was prescribed as either primary or secondary prophylaxis. Mosdósi et al. investigated skin perfusion in finger with laser Doppler technology in adolescents with Raynaud's and reported altered heat-induced cutaneous hyperaemia responses . Thus, mStatin therapy has been reported to impair hyperemic blood flow measured with laser Doppler . One expThe possible mechanism of microvascular abnormalities in SLE include autoantibodies forming immune complexes that deposit in small vessels and activate endothelial cells . Howevern = 20), our study could not detect any association of APS and these parameters. Brodszki et al. demonstrated that vascular stiffness was associated with SLE irrespective of secondary vasculitis or not. They suggested that other mechanisms such as shifts in the collagen/elastin ratios, besides atherosclerosis might be involved in the pathogenesis of arterial stiffness in SLE  by physical activity in univariate analysis. This finding should be further investigated.Peak oxygen saturation correlated inversely with arterial stiffness (AIx75) implying that both methods could add valuable information regarding vascular status in SLE.Although our study population was well-characterized, the number of included subjects remained limited. Nevertheless, the included number of patients were comparable with many other studies investigating the increased risk of cardiovascular disease in SLE . We admit that both BMI and smoking habits were different among SLE patients compared to the controls. It cannot be excluded that these differences might have affected the results over all. The present study was based on the identical study population as our previous study . The patients/participants provided their written informed consent to participate in this study.CSv, PE, CSj, and HZ contributed to the conception of this study and the study design. CSv collected and assembled data and wrote the original draft. CSv, PE, CSj, HZ, HJ, TS, and NB contributed to the analysis and interpretation of the data. All authors contributed to the critical revision of the article for important intellectual content and gave final approval of the article for submission. All authors have seen and approved the final text.The study was supported by Region Östergötland (ALF grants), the Swedish Rheumatism Association, the King Gustaf V's 80-year Anniversary Foundation, the King Gustaf V and Queen Victoria's Freemasons Foundation, the Gustafsson Foundation, and Linköping University Hospital Research Funds.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.