Systolic blood pressure (SBP) negatively correlated with retinal vascularity. The superficial retinal vascular plexus density in the whole image showed a significant negative correlation with 24 h SBP , day-SBP , and night-SBP . pEVs did not show significant associations with microvascular damage , endothelial function , or psychosocial status (anxiety and depression). Our results indicate that the pEV levels were associated with macrovascular damage measured by PWV, whereas no significant association between pEVs and microvascular damage, endothelial function, or emotional status could be detected. The potential utility of pEV in clinical practice in the context of HMOD may be limited to macrovascular changes.Elevated circulating platelet-derived extracellular vesicles (pEVs) have been associated with arterial hypertension. The role of hypertension-mediated organ damage (HMOD) to induce EV release is still unknown. We studied the micro- and macro-vascular changes , endothelial function , and assessed the psychosocial status (anxiety and depression) in hypertensive patients to determine their relationship with EV release. Pulse wave velocity showed a significant positive correlation with pEVs (r = 0.33;  Hypertension (HTN) is one of the most prevalent cardiovascular risk factors. The increased mechanical stress induces structural and/or functional changes in major organs, leading to hypertension mediated organ damage (HMOD) . AlthougIn the past decades, extracellular vesicles (EV) have emerged as a potential early biomarker in cardiovascular disease. EVs are small cell vesicles derived from the cell membrane of different cells in response to stress, injury, or cell activation. EV could have an important role on HTN as they have been associated with the underlying mechanisms causing HMOD such as vascular integrity, endothelial function, inflammation, and thrombosis . The constant high-pressure flow in HTN has been shown to affect the microcirculation, endothelial function, and promote a thrombogenic state. The latter may be particularly important given that thrombotic events represent one of the most detrimental complications of hypertension ,3,4. As While the association of pEV and classical clinical characteristics has been investigated previously, the evaluation of pEV with subclinical damage can provide a better insight into their role as an early biomarker. In order to investigate the potential use of pEV in HTN, we used state-of-the-art techniques in hypertensive patients to evaluate early HMOD and psychosocial status. We evaluated macrovascular damage by pulse wave velocity (PWV), the gold standard to evaluate arterial stiffness. Furthermore, we assessed microvascular changes evaluated by vascular density in different layers of the retina using optical coherence tomography–angiography (OCT–A), a modern technology to complement retinal assessment and reliably detect early microvascular damage. Additionally, we used non-invasive techniques to measure endothelial function  and finger plethysmography (EndoPAT)) . These sThe baseline demographics of the study population are summarized in p = 0.03). Normotensive participants showed less pronounced macrovascular damage with significative lower PWV and AIx than hypertensive patients. PWV showed a significant positive correlation with pEVs . PWV showed a significant correlation with systolic blood pressure (SBP) measured in the office , 24 h , day-time , and night .The mean level of the platelet-derived EVs were higher in patients with hypertension compared to normotensives , parafovea zone (p = 0.58), and whole image (p = 0.66)) or the deep vascular plexus density (fovea zone (p = 0.67), parafovea zone (p = 0.86), and whole image (p = 0.89)  .p < 0.01), day-SBP , and night-SBP . Office BP did not show a significant association. The parafoveal superficial vascular plexus density also showed a significant negative association with 24 h SBP  and day-SBP , but not with night-SBP or office BP. No other significant associations were found in the rest of the retinal areas. Interestingly, the superficial vascular plexus density in the whole image showed a significant negative correlation with 24 h SBP   and did not show any correlation with EV  . The pat = 0.15) . p = 0.84). Patients were evaluated for endothelial dysfunction according to the levels of RHI. Interestingly, only nine patients fulfilled the criteria for endothelial dysfunction (RHI < 1.67) [Similarly, RHI evaluated by finger plethysmography was not correlated with the levels of pEV   with finp = 0.02). In contrast, the anxiety score did not show any significant correlation with systolic AOBP , 24 h-BP , or day-BP . The anxiety score (state) did not show any significant correlation with systolic AOBP, 24 h-BP, day-BP, or night-BP. No significant correlation was found between the EV and anxiety scores.Finally, we evaluated the emotional status in the hypertensive spectrum. Night-SBP showed a significant negative correlation with anxiety score (trait)  showed a trend to lower values of BP, this difference was significant in systolic blood pressure levels at night-time. In contrast, patients presenting high anxiety levels (state) did not express this pattern, furthermore, diastolic blood pressures during night-time showed significantly higher levels in patients with high anxiety. Patients with high anxiety levels (state) showed a trend to higher levels of pEV. Stress markers did not show any statistical associations .The depression score did not show any significant correlation with blood pressure levels, pEV, or stress markers. There was no significant difference between the depression categories in any parameter.The major findings of our study are: (a) patients with hypertension showed higher levels of pEV than normotensive participants; (b) PWV showed a significant correlation with pEVs and SBP; (c) parafoveal and whole superficial vascular density were inversely associated 24 h SBP and day SBP. Nocturnal SBP was also inversely associated with whole vascular density. (d) pEVs did not show significant associations with microvascular damage , endothelial function , and psychosocial status (anxiety and depression).Using gold standard BP evaluation (office and ambulatory BP). we have previously demonstrated a positive correlation between the pEV levels and BP and PWV ,14,15. OArterial stiffness has been widely recognized as a surrogate for cardiovascular disease, and current guidelines recommend the assessment of arterial stiffness to evaluate HMOD and underlying arteriosclerosis, especially in patients who appear to be asymptomatic. A PWV >10 m/s is considered to represent significant alterations in the arterial elastic properties and determine subclinical HMOD ,17,18. SIn contrast, when we evaluated the microvascular damage by retinal vascular density, we did not find a significant association with the levels of pEVs. While no significant differences were found in the vascular density between the normotensive and hypertensive groups, a significant correlation was found between the superficial vascular density and ambulatory systolic BP measurements in the whole image and in the parafoveal portion, but not in the deep vascular plexus. Retinal evaluation is recommended in hypertension for its prognostic significance and should be performed routinely in grades 2 or 3 hypertension . New imaEndothelial dysfunction is considered as an early feature of atherosclerosis. There is now overwhelming evidence associating endothelial function with cardiovascular risk factors, which has motivated its use as a therapeutic target for cardiovascular disease prevention ,29,30,31Finally, we investigated the association between emotional status and pEV release. Anxiety and depression have been commonly described in patients with cardiovascular disease and may significantly influence their overall health and quality of life. The link between emotional status and cardiovascular disease is complex and is not fully understood. The emotional status may be a normal response to the patient’s current situation; however, excessive and long-standing emotional stress is considered detrimental ,38. ChroOur study had some limitations. First, given the sample size and the cross-sectional nature of this analysis, a causal relationship cannot necessarily be inferred and can only be interpreted as hypothesis-generating. Second, as we used state-of-the-art techniques  as a surrogate of HMOD, studies including hard outcomes are required to fully understand their prognostic value. We acknowledge the inherent limitations of this investigation due to its observational nature.In conclusion, our results indicate that the pEVs levels were associated with macrovascular damage measured by PWV. We did not find any significant association between pEVs and microvascular damage, endothelial function, or emotional status. While recent investigations indicate that pEVs have a role in the underlying mechanisms of cardiovascular disease, their use in clinical practice is still limited and may be restricted to specific subpopulations.Patients between 18 and 85 years old were recruited from the outpatient hypertension clinic of the Royal Perth Hospital Medical Research Foundation. The study complied with the Declaration of Helsinki and received approval from the University of Western Australia research ethics committee. All participants provided written consent for the study. Clinical baseline data were collected from the patients including medical history, medication history, serum pathology, and blood pressure (BP) evaluation by office and ambulatory blood pressure measurements . All patients were referred to undergo extended testing including macro- and microvascular damage, endothelial function, and emotional evaluation, however, if the test could not be completed  or the quality of the data was insufficient for a correct interpretation, the patient was excluded from the specific test analysis.In the first analysis, we investigated pEV levels along with microvascular and macrovascular damage in the blood pressure spectrum . We included 62 subjects, 10 normotensive and 52 hypertensive subjects. HTN was defined by the elevated office and/or ambulatory blood pressure or history of hypertension with ongoing antihypertensive medication. Retinal vascular density was evaluated in the superficial and deep vascular plexus by optical coherence tomography–angiography (OCT–A). Urine albumin–creatinine ratio was measured as a surrogate of renal microvascular damage. Arterial stiffness was used as a marker of macrovascular damage and was determined by PWV. In view of the absence of established reference values for vascular density and EV, the normotensive group served as a reference group to put vascular density and EV values from our cohort into perspective and enable clinical interpretation.In the second analysis, we analysed endothelial function in 39 hypertensive patients. Participants underwent endothelial function testing by flow-mediated dilatation (FMD) and finger plethysmography (EndoPAT). The patients were subsequently divided into two groups according to the presence of endothelial dysfunction using the previously reported cutoff values for each test ,12.In the third series, we assessed the pEV levels in relation to the emotional status (anxiety and depression) in 49 hypertensive patients. Additionally, we assessed cortisol and high sensitivity C-reactive protein as biological stress-related markers. +/Annexin V+) were analysed by flow cytometry according to the expression of surface antigens. Patients who had heart failure NYHA class III–IV, chronic kidney disease (eGFR of <30 mL/min/1.73 m2), or active autoimmune disease requiring treatment with corticosteroids or other immunosuppressive agents were not eligible to be included in any of the studies.Platelet EV . Unattended automated office blood pressure (AOBP) was defined as the average of the three measurements.Office blood pressure from the brachial artery was measured according to international guidelines. Automated blood pressure was measured after 5-min of resting in the sitting position three times with one minute rest periods between measurements (HEM 907 Automatic Blood Pressure MonitorAmbulatory blood pressure monitoring (ABPM) was performed throughout 24 h with clinically validated devices . The device was set to measure BP every 15 min during day-time (6:00 h–22:00 h) and every 30 min during night-time (22:00 to 6:00 h). The 24 h-BP, day-BP, and night-BP were reported as the average of successful readings recorded during the period. Participants were instructed to follow their usual daily activities but remain still during the measurement. Daily activities were documented in a printed diary including bedtimes (adjustment of awake and asleep periods was made if required) and medication intake. Only patients with successful readings were included in the 24 h-BP, day-BP, and night-BP analysis (minimum of 70% successful readings including 20 day-time and seven night-time) . ® spectral-domain optical coherence tomography–angiography (OCT–A) device . Vascular density (VD) was estimated non-invasively with OCT–A technology via time-dependent signals from the laser reflection of flowing erythrocytes. VD was defined as the percentage of sample area (whole scan size was 6 × 6 mm) occupied by vessel lumens following the binary reconstruction of images. An automated analysis tool of AngioVue software (version 2018.1.0.43) Fremont, CA, USA was used to calculate the VD in the superficial and deep vascular plexus. The fovea centre was automatically determined, and VD was determined in the whole image (6 × 6 mm), inner and outer rings representing the foveal (1 mm diameter around the fovea) and parafoveal (ring from 1–3 mm around the fovea), respectively.Retinal imaging was performed using the Optovue AngioVueOCT–A scans were reviewed by a trained operator to ensure sufficient image quality. The average of both eyes was used to define the individual VD for each section. If the scans of any of the eyes could not be performed  or the quality was too low for assessment, only the scans of the remaining eye were used .Arterial stiffness was assessed by non-invasive pulse wave analysis (PWA) and pulse wave velocity (PWV) performed with the SphygmoCor XCEL system  in accordance with the manufacturer’s recommendations. PWA was performed after a 5 min rest period in the supine position, and an automatic 10 s PWA reading was used for data acquisition. Simultaneous measurements through applanation tonometry over the carotid and femoral artery provided the pulse transit time. The time that elapsed between the carotid and femoral artery sites was used to calculate the pulse wave velocity. The capturing time for the PWV assessment was set to 10 s with a PWV distance and subtraction method. PWV assessments were performed twice, and their average was used for further analysis. PWV was expressed as the distance/transit time (m/s). Several hemodynamic parameters were documented including central mean arterial pressure (cMAP), aortic augmentation pressure (AP), and augmentation index (AIx). AIx was normalized for a heartbeat of 75 beats per minute to enable comparations and was expressed as a percentage.baselineD) to a postischaemic maximal diameter (maxD) expressed as a percentage of baselineD:FMD was performed on patients who fasted for 6 h, in a temperature-controlled room after 15 min of supine rest. FMD was assessed by high-resolution B-mode ultrasound, images were recorded every second and analysed with an automated analysis system . The patient’s arm was extended and positioned at an angle of 80° from the torso. A forearm blood-pressure cuff was placed distal to the cubital fossa. Baseline diameter was measured before cuff inflation for a period of 1 min. The forearm cuff was inflated (>200 mmHg) for 5 min. Diameter and flow recordings were resumed 30 s before cuff deflation and continued for 3 min after. All images were stored as AVI files for offline analysis. The brachial maximal diameter was determined as the 5 s average peak diameter observed during the plateau phase after cuff deflation. FMD was defined as the difference in arterial diameter from the baseline diameter . Digital pulse amplitude was measured with a pulse amplitude tonometry (PAT) device placed on the tip of each index finger . PAT was assessed in response to reactive hyperaemia. Measurements were obtained for 5 min at baseline followed by 5 min of occlusion of one arm, with a blood pressure cuff inflated on the upper arm to supra-systolic pressure (60 mmHg above systolic pressure or 200 mmHg) and then released to induce reactive flow-mediated hyperaemia, which was measured for 5 min. The reactive hyperaemia index (RHI) was calculated as the ratio of the average amplitude of the PAT signal over a minute time interval, one minute post deflation divided by the average amplitude of the PAT signal taken for 3.5 min during the baseline, corresponding to the automatic algorithm provided by Itamar Medical. The emotional status was determined using the Beck Depression Inventory (BDI-II) to assess symptoms of depression. Patients were subsequently classified according to their score as normal (1–10), mild mood disturbance (11–16), borderline clinical depression (17–20), moderate depression (21–30), severe depression (31–40), and extreme depression (>40).The Spielberger’s State and Trait Anxiety inventories were used to determine the level of anxiety. Patients were categorized as having no or low anxiety (20–37), moderate anxiety 38–44), and high anxiety (45–80) [, and higg for 10 min and double centrifugation at 2500× g for 15 min at room temperature (RT). PFP was immediately frozen and stored at −80 °C until processing for isolation and quantification. All samples were processed identically and within 1 h after extraction. Samples that failed to accurately measure pEVs  were excluded from the analysis.Platelet EV subpopulations were evaluated by flow cytometry according to the expression of platelet markers (CD41) as described previously by our group.  Briefly,g for 2 min to remove fibrin clots/aggregates. The supernatant (400 μL) was collected for subsequent high-speed centrifugation at 20,000× g for 20 min. The supernatant was discarded, and the remaining pEV-enriched pellet was re-suspended in 300 μL ultrafiltered PBS. Re-suspended pEVs were incubated for 60 min with fluorochrome-labelled antibodies (CD41-PE-Cy7). The mix was subsequently incubated with Annexin V-FITC at 5% for 10 min and diluted with ultra-filtered annexin binding buffer  before being immediately analysed on an AttuneTM NxT Acoustic Focusing Cytometer. Equivalent concentrations of the respective isotype controls were used to determine the degree of non-specific binding. The acquisition was performed using the lower flow rate (12.5 μL/ min). Forward scatter (FSC), side scatters (SSC), and fluorescence data were obtained with the settings in the logarithmic scale. The concentration of pEVs was determined by volumetric cell count in 50 µL of the sample within the gate limits established by ApogeeMix (Apogee Flow Systems). The lower detection threshold was set using the 80 nm fluorescent/180 nm silica beads signal. pEVs within the established gate limits were identified and quantified based on their binding to Annexin V and reactivity to CD41-PECy7 to define platelet-derived extracellular vesicles . A p-value < 0.05 was considered statistically significant for all comparisons. Statistical analysis was performed using R 4.0.3 software. For the baseline characteristics, continuous variables were expressed as the mean ± SD and categorical variables as the frequencies and percentages. Qualitative variables were compared with the chi-square test or Fisher’s exact test if the application conditions were not fulfilled. Differences in quantitative variables between groups were made with an unpaired


Iron deficiency (ID) is prevalent and adverse in chronic heart failure (CHF) but few human studies have explored the myocardial mechanism(s) that potentially underlie this adversity. Because mitochondrial oxidative phosphorylation (OXPHOS) provides over 90% of the hearts adenosine triphosphate (ATP), and iron is critical for OXPHOS, we hypothesized that patients with CHF and ID would harbour greater cardiac energetic impairments than patients without ID.in‐vivo cardiac energetics, in CHF patients and healthy volunteers. Cardiac structure and function was assessed from magnetic resonance short stack cines. Patients with (n = 27) and without (n = 12) ID, and healthy volunteers (n = 11), were similar with respect to age and gender. The PCr/ATP ratio was lower in patients with ID (1.03 [0.83–1.38]) compared to those without ID  and healthy volunteers . This was despite no difference in cardiac structure and function between patients with and without ID, and despite adjustment for the presence of anaemia, haemoglobin levels, cardiac rhythm, or New York Heart Association (NYHA) class. In the total CHF cohort, the PCr/ATP ratio correlated with ferritin levels , and was higher in NYHA class I than class II or III patients (p = 0.02).Phosphorus magnetic resonance spectroscopy was used to quantify the phosphocreatine (PCr) to ATP (PCr/ATP) ratio, an index of Iron deficiency is associated with greater cardiac energetic impairment in patients with CHF irrespective of anaemia and cardiac structure and function. Suppression of cardiac mitochondrial function might therefore be a mechanism via which ID worsens human CHF. Iron deficiency (ID) is prevalent and adverse in chronic heart failure (CHF),The heart requires a continuous supply of adenosine triphosphate (ATP) to power contractile function and early diastolic relaxation, and to maintain ion channels that orchestrate normal sinus impulse propagation. Mitochondrial oxidative phosphorylation (OXPHOS) provides over 90% of this ATP by coupling fuel substrate oxidation  to ATP synthesis via the electron transport chain (ETC).in‐vitro and pre‐clinical animal models, cellular iron deprivation downregulates Krebs cycle, antioxidant and ETC proteins, blunts mitochondrial respiration (a proxy for cellular energetics), and, when severe, induces lethal murine cardiomyopathy even in the absence of anaemia.ex‐vivo using cardiac homogenates in this study, it is still unclear whether ID is linked to lower myocardial energetics in CHF patients.Iron is theoretically indispensable for mitochondrial ATP generation as iron‐containing prosthetic groups (haem and iron–sulfur clusters) are functional components of haemoglobin (Hb) and myoglobin, and of enzymes of the Krebs cycle, β‐oxidation pathway, and the ETC.31P‐MRS) is the gold‐standard means of quantifying cardiac energetics in vivo and has revealed low PCr/ATP ratios in CHF.Phosphorus magnetic resonance spectroscopy  <45% within the last 6 months, non‐ischaemic cardiomyopathy, stable CHF for 4 weeks with no drug/dose changes in the prior 2 weeks, New York Heart Association (NYHA) class I to III symptoms, no contraindications to magnetic resonance imaging (MRI), no use of erythropoiesis‐stimulating agents, immunosuppressive agents or chemotherapy in the prior 3 months, and no active infection, inflammation, renal replacement, or severe chronic obstructive pulmonary disease. Medical and drug histories were obtained from patients and their medical records. A ferritin <100 µg/L or 100–300 µg/L with a transferrin saturation (TSAT) <20% defined ID. A Hb <120 g/L in females and <130 g/L in males defined anaemia. Healthy age‐ and gender‐similar controls with no known medical or drug history were also recruited. The local research ethics committee and institutional review boards approved the study which complied with the International Conference on Harmonization for Good Clinical Practice and the Declaration of Helsinki. All subjects gave written informed consent prior to inclusion.This was a prospective observational cohort study involving a screening visit and a single 31P‐MRS was performed on a 3 Tesla Achieva MR scanner using a 14 cm diameter linearly polarized transmit‐receive 31P surface coil . Participants were positioned supine , with a total acquisition time of ∼25 min. Spectral locations were overlaid onto an anatomical image and the slice containing the interventricular septum was used for quantification . Spectral analysis was performed offline using jMRUI v5.2 and applying the AMARES algorithm with prior knowledge .Data are presented as mean ± standard deviation, median [interquartile range], or frequencies (%). Normality of distribution was assessed using the Shapiro–Wilks test. Continuous variables were compared using a Student's Table Of 11 healthy volunteers, 12 patients without ID, and 27 patients with ID who were recruited, one patient with ID did not tolerate the MRI, two patients with ID did not have a discernible PCr peak on their spectra, and two patients with ID had poor quality spectra that was presumed to be due to obesity. The baseline characteristics of the study groups were broadly similar Table 1. All h31P‐MRS spectra are shown in Figure p = 0.99) in healthy volunteers (0.28 [0.22–0.34]) and patients without (0.28 [0.24–0.34]) and with (0.28 [0.22–0.34]) ID. This suggests that the degree of spectral blood contamination was comparable between groups. The PCr relative signal intensity progressively declined (p = 0.05) from healthy volunteers (0.47 ± 0.30) to patients without ID (0.39 ± 0.18), to patients with ID (0.29 ± 0.14). The γ‐ATP relative signal intensity was similar (p = 0.92) in healthy volunteers (0.20 [0.16–0.30]), and patients without (0.22 [0.15–0.28]) and with (0.22 [0.11–0.32]) ID. Calculated total ATP relative signal intensities progressively declined (p = 0.10) from healthy volunteers (0.33 [0.29–0.39]), to patients without (0.26 [0.16–0.30]) and with (0.20 [0.13–0.40]) ID.Representative p = 0.001, Figure p = 0.002) and healthy volunteers . In contrast, the PCr/ATP ratio did not significantly differ between patients without ID and healthy volunteers. The PCr/ATP ratio also did not differ when patients were stratified on the basis of anaemia , but not with Hb or TSAT levels. Stratification on the basis of NYHA class revealed that the PCr/ATP ratio was higher in class I  than class II  or III  patients (ANOVA p = 0.02). In a post‐hoc sensitivity analysis, inclusion of the two patients with suboptimal 31P‐MRS spectra did not alter the results.The PCr/ATP ratio significantly differed between the study groups , ethnicity (adjusted post‐hoc p = 0.005), Hb levels (adjusted post‐hoc p = 0.005), presence of anaemia (adjusted post‐hoc p = 0.002), presence of diabetes (adjusted post‐hoc p = 0.009), heart rhythm (adjusted post‐hoc p = 0.001), NYHA class (adjusted post‐hoc p = 0.02), and use of β‐blockers (adjusted post‐hoc p = 0.004).To assess whether the observed variance in the PCr/ATP ratio was due to Hb levels, the presence of anaemia or diabetes, or to intergroup differences in baseline characteristics, separate ANCOVA models were constructed. The PCr/ATP ratio remained significantly different between patients with and without ID after univariable adjustment for gender  after this adjustment.Despite a lower PCr/ATP ratio in CHF patients with ID compared to those without, there was no significant difference in measured indices of cardiac structure and function between these groups Figure 5. Althoex‐vivo mitochondrial respiration was assayed using cardiac homogenates. Here, we utilised 31P‐MRS which is the gold‐standard non‐invasive means of quantifying myocardial bioenergetics in vivo.Iron deficiency is prevalent in CHF and might escalate symptoms and exercise intolerance by suppressing cardiac energetics. Despite extensive animal data suggesting that ID impairs cardiomyocyte energy generation, only one study has attempted to corroborate this in humans.31P‐MRS, is diminished in CHF patients with ID compared to those without. This was evident despite no intergroup difference in cardiac structure and function, and persisted after adjustment for the presence of anaemia. The PCr/ATP ratio was also lower in iron‐deficient patients compared to healthy volunteers, but did not significantly differ between iron‐sufficient patients and healthy volunteers. In the total CHF cohort, lower PCr/ATP ratios related to lower ferritin levels, and to greater symptoms and disease severity as reflected by a higher NYHA class.To the best of our knowledge, this is the first study to show that cardiac energetics, as reflected by the PCr/ATP ratio on ex vivo using high resolution respirometry, was preserved in a prior study in iron‐deficient CHF patients.in‐vivo mitochondrial assessments (e.g. with 31P‐MRS) are, in principle, better than ex‐vivo assessments. Due to variability in the acquisition and analysis of published PCr/ATP ratios, it is difficult to compare across studies but our ratios were within the range of values reported for healthy subjects and CHF patients,Cardiac energetics, as measured Iron is quantitatively the most important biocatalyst in oxidative metabolism, so greater cardiac energetic impairment with ID is biologically plausible. Of the ATP needed by the heart to function optimally, OXPHOS provides over 90%. Iron is implicated at every step of OXPHOS. It functions in Krebs cycle and fatty acid β‐oxidation enzymes, in complex I to IV of the ETC, in Hb and myoglobin, and in catalase which limits redox inactivation of ATP synthase and creatine kinase.Left ventricular hypertrophy, dilatation, and dysfunction due to ID could enhance myocyte ATP demand to reduce the PCr/ATP ratio.Poorer cardiac energetics was observed in patients with a higher NYHA class, implying that cardiac mitochondrial dysfunction due to ID could be a mechanism for dyspnoea, exercise intolerance, and disease progression in CHF, and that improved cardiac energetics may be a route via which intravenous iron repletion is beneficial.et al.Several other findings deserve mention. First, anaemia did not correlate with the PCr/ATP ratio likely due to its myriad causes in CHF that may not all similarly impact energetics. Moreover, ID was linked with the PCr/ATP ratio irrespective of anaemia, in line with CHF data showing that ID is ominous independently of anaemia,31P‐MRS, but it also has limitations. First, it is observational so causality cannot be inferred. Second, we were likely underpowered for many secondary analyses, but were adequately powered for the primary comparison which was that of the PCr/ATP ratio between patients with and without ID. Third, patients with ID were more symptomatic and less likely to be in sinus rhythm than those without ID, but the difference in cardiac energetics between these groups persisted even after ANCOVA adjustment for NYHA class, cardiac rhythm, and other potential confounders such as Hb levels, anaemia, and diabetes. Fourth, we did not scan patients at 1.5 Tesla which would have enabled optimal quantification of cardiac iron content (T2*) to inform this study. Fifth, iron status and Hb were not measured in healthy volunteers, but their absence does not detract from our main findings. Sixth, skeletal  muscle contamination of cardiac 31P‐MRS signals can occur but the discordance between our results and those obtained in skeletal muscleOur study's strength is the use of Our study has clinical ramifications. First, it reinforces the importance of clinicians actively seeking, aggressively investigating, and promptly correcting, systemic ID in CHF which has been shown to augment myocardial iron content.31P‐MRS, is diminished in CHF patients with ID compared to those without. This was evident despite no intergroup difference in cardiac structure and function, and persisted after adjustment for anaemia. Lower PCr/ATP ratios related to greater symptoms and disease severity as reflected by a higher NYHA class in CHF patients.In conclusion, we show for the first time that cardiac energetics, as reflected by the PCr/ATP ratio on


No differences were found in obtaining an excellent functional result at 3 months . Tenecteplase showed worse neurological results after 24 h . No significant differences were identified in mortality; 17.5% with rtPA and 20% with TNK (p = 0.79), nor in the appearance of intracranial hemorrhage ICH (15.2% with rtPA vs. 30% with TNK (p = 0.12). In our series, there were not significant differences shown regarding effectiveness and safety between tenecteplase and alteplase.Not all hospitals have interventional radiology services. This fact implies that in centers where this resource is not available, the treatment of stroke in the acute phase must be adapted and individualized. The aim of the study is to determine and compare the combined effect of thrombolysis and thrombectomy effectiveness and safety of tenecteplase versus alteplase in the acute treatment of ischemic stroke in patients who are candidates for endovascular therapy according to clinical practice guidelines. This paper details a retrospective multicenter cohort study of patients with ischemic stroke admitted in three hospitals between 2018 and 2020. The main outcome variables were the degree of recanalization and the functional outcome at 3 months; safety variables were mortality and the occurrence of intracranial hemorrhage (ICH). In total, 100 patients were included, 20 of which were treated with tenecteplase (TNK) and 80 with alteplase (rtPA). Of those treated with TNK, 75% obtained a successful recanalization compared to 83.8% in those treated with rtPA (OR 0.58; 95% CI 0.18–1.88;  Stroke is a disease of great importance due to its high mortality rate and its high socio-sanitary burden ; two thiWe conducted a multicenter, retrospective and observational cohort study in which included patients were treated in the Emergency Departments (ED) of 3 s-level hospitals with diagnosis of ischemic stroke due to large-vessel occlusion and indication for fibrinolysis plus thrombectomy, so they required a transfer to a fourth reference hospital. The study period was between January 2018 and January 2021, both inclusive. Two groups were formed according to the thrombolytic used in the acute phase of stroke: group 1, patients treated with alteplase 0.9 mg/Kg, up to a maximum of 90 mg, initially administered 10% of the dose as an intravenous bolus, and then the rest of the dose as an intravenous infusion over 60 min; and group 2, treated with tenecteplase administered by a single intravenous bolus of 0.25 mg/kg, maximum 25 mg. The inclusion criteria were: patients ≥ 18 years old with a diagnosis of ischemic stroke and who had received systemic thrombolysis and subsequent endovascular thrombectomy due to large vessel occlusion: middle cerebral artery , carotid artery (ICA) or basilar artery seen on CT or MRI. Were excluded patients with a pre-stroke disability (mRS ≥ 3), terminally ill patients with expected survival of less than 3 months, those with significant head injury, those having had a prior stroke in the previous 3 months, and pregnant women. We classified dependent variables into effectiveness and safety variables. Effectiveness variables were: the degree of reperfusion of the ischemic territory after fibrinolysis and thrombectomy (mTICI), the value of the modified Rankin scale at 90 days after thrombolytic application (mRS90), the differential value of NIHSS scale at 24 h (ΔNIHSS24-0) of thrombolytic application compared to the premorbid value (NIHSS0) and number of days of hospital stay. The first three were dichotomized so that successful recanalization was considered as TICI 2b-3, excellent result as mRS90 0–1 and significant neurological improvement as NIHSS24 = 0 or reduction of 4 or more points compared to the baseline NIHSS prior to thrombolytic treatment. Safety variables were death from any cause within 90 days after the thrombolytic treatment and the presence of intracranial hemorrhage (ICH) in the first 48 h. The latter defined according to the European Cooperative Acute Stroke Study (ECASS) as: (i) blood at any site in the brain on the CT scan, clinical deterioration or adverse events indicating clinical worsening  or causing an increase in the NIHSS score of 4 or more points (ECASS II criteria); (ii) any apparently extravascular blood in the brain or within the cranium associated with clinical deterioration (defined by an increase in the NIHSS score of 4 or more points) or death, and that is identified as the predominant cause of the neurological deterioration (ECASS III criteria) [SPSS v25.0 was applied for statistical analysis; based on previous literature, our goal was to detect 35% more of successful recanalization (mTICI 2b-3) in subjects treated with TNK versus those treated with rtPA , with a confidence level of 95%. For a sample size of 100 patients, a power of 83% was obtained. Qualitative variables were represented by absolute value and percentage. The analysis of the quantitative variables has been carried out both in a general and stratified ways by the treatment group. We performed normality tests on these variables (Kolmogorov-Smirnof test for rtPA group and Shapiro-Wilk for TNK group), demonstrating non-normal distribution, so the median was used as a measure of central tendency and the interquantile range (IQR) as a measure of dispersion. The analysis of the relationship between qualitative variables was carried out using Pearson’s Chi square, using Yates’ correction when founding at least one expected value <5, and the Odds Ratio (OR) to quantify this association. Mann-Whitney U test was used to analyze the association between quantitative and qualitative variables. For the variables mRS90 and ΔNIHSS24-0, binary logistic regressions were used to control the confounding factors.p = 0.016), and NIHSS0, with a median of 6 points higher in those treated in that group (p = 0.021). The clinical and epidemiological characteristics of the patients and the differences between groups are shown in We analyzed 100 patients, , treated in the ED meeting the admission criteria; 20 of which were treated with tenecteplase and 80 with alteplase. These patients had a median age of 73 (IQR: 66.25–80.5) and a median of 2 cardiovascular risk factors (CVRF) (IQR: 1–3), the most frequent being hypertension (68%), followed by dyslipidemia (50%). Most did not show any type of disability before the onset of the event (93% mRS0 ≤ 1). Regarding the location of the occlusion, we found that the involvement of the middle cerebral artery in its M1 segment accounts for more than half of the total (55%), followed by tandem occlusion (24%); 75% were treated with fibrinolytic therapy within 3 h or less from the last time the patient was seen asymptomatic, and the median NIHSS0 was 16 points (IQR: 10–21). In the stratified analysis of the independent variables according to the treatment group, we found no statistically significant differences, with the exception of gender, with 20% of women in the TNK group (p = 0.56) were detected between both treatment groups (rtPA 83.8% vs. TNK 75%). In the study of hospital stay, no significant differences were found (p = 0.21) in terms of days of admission (8 days in the rtPA group—IQR: 5–13 vs. 11 days in the TNK group—RIC: 6–20). Regarding the Rankin scale at 90 ± 7 days after thrombolytic application, although the percentage of excellent results is lower in patients treated with TNK (35% vs. 58.8%), these differences were not statistically significant (p = 0.38) after performing the binary logistic regression model. In our series, the most influential factors in predicting an unfavorable outcome (mRS90 2–6) were diabetes and ICH. Diabetic patients and those with ICH are about 4 times more likely to have an unfavorable outcome (p = 0.008). In this way, those treated with TNK are approximately 5 times more likely to have an unfavorable result in the variable ΔNIHSS24-0 than those treated with rtPA (OR: 5.4 CI95% 1.57–18.6), regardless of the remaining confounding factors  after thrombectomy. However, only half (50%) presented a significant neurological improvement at 24 ± 6 h after the application of the thrombolytic. Patients were hospitalized for a median of 8 days (IQR: 5–15). After 90 ± 7 days of the application of the thrombolytic, 54 patients (54%) did not present any type of disability, thus obtaining an excellent result (mRS90 ≤ 1). When analyzing the differences in the degree of reperfusion of the ischemic territory, no statistically significant differences  nor in the appearance of ICH (15.2% with rtPA vs. 30% with TNK (p = 0.12). When analyzing the population that presented hemorrhagic complication, we observed that diabetes predominated and a higher score of the NIHSS0 at admission. Subject’s mortality in the first 90 days was 18% (18) and the frequency of intracranial hemorrhage in the first 48 h after the application of the fibrinolytic was 18.2% (18). We did not observe statistically significant differences between the two treatment groups, neither in terms of mortality , thus avoiding the risk of extravasation or loss of the VA. It would also avoid the possibility of withdrawal of the fibrinolytic treatment in case of oscillations in blood pressure during the infusion. Therefore, the demonstration of non-inferiority, even in the absence of superiority, place TNK as an attractive alternative. Our study opens the door to new lines of research which would imply a continuity in the analysis of these indicators and new ones, such as the most appropriate dose, time saved in the administration of the fibrinolytic agent, or the facilities that the administration of TNK involves. The off-label use of TNK that we present in real clinical practice has just been endorsed with the recently published results of the AcT study  that pro


Participants in the highest quartile of TMAO levels (>8.38 µmol/L) presented relatively elevated serum creatinine levels and a higher number of people with CKD than those in the lower quartiles. TMAO levels were significantly correlated with kidney function biomarkers, including estimated glomerular filtration rate and urinary albumin to creatinine ratio. The association between TMAO and CKD was evident (p < 0.0001) and remained significant after adjusting for risk factors of kidney disease, including age, gender, body mass index, duration of diabetes, and smoking. These findings suggest the association between plasma TMAO and CKD in patients with T2D.Previous studies have linked elevated plasma trimethylamine N-oxide (TMAO) levels to poor renal function. The relationship between TMAO and chronic kidney disease (CKD) in type 2 diabetes (T2D) is still unclear. We investigated the association between plasma TMAO levels and CKD in patients with T2D. A cross-sectional study of 133 patients with T2D with or without CKD has been conducted. Blood biomarkers of kidney function, diabetes, and inflammation were assessed in the study participants. Plasma TMAO levels were quantified using UPLC-MS/MS. People with T2D and CKD exhibited significantly higher plasma TMAO levels [10.16 (5.86–17.45) µmol/L] than those without CKD [4.69 (2.62–7.76) µmol/L] ( Chronic kidney disease (CKD) has been recognised as a major public health issue, with a high morbidity and mortality burden worldwide . DiabeteRecently, the gut microbiota has been identified as playing a critical role in a number of chronic diseases . TMAO isCross-sectional, case-control, and longitudinal studies have consistently demonstrated the significant contribution of high blood TMAO levels to CKD progression ,20,21,22Diabetic patients are more likely to develop microvascular complications such as nephropathy, which can worsen blood and urinary biomarkers of kidney function . Most stn = 133) were recruited in a prospective case-control study as previously described  , as previously described ,36. The All data analyses were conducted using SPSS  and graphs were created using GraphPad Prism (version 9). Participants’ characteristics were summarised according to T2D cases with or without CKD. Laboratory parameters and biomarker values were described using percentages for categorical variables, mean ± standard deviation (SD) or medians (IQR), and 25th to 75th quartiles range for continuous variables. For normally distributed data, the unpaired t-test and one-way ANOVA test evaluated the differences between study groups. Nonparametric tests were used for the measurements of non-normally distrusted data. The Mann–Whitney U test was used to compare data between the two patient groups, while the Kruskal–Wallis test compared patient data between plasma TMAO quartiles. Comparisons between categorical variables were analyzed by Pearson’s chi-squared test or Fisher’s exact test. Spearman’s rank correlation coefficient was applied to assess the association between TMAO and biomarkers of kidney disease. Multiple linear regression analysis was performed to examine the association between TMAO and CKD, adjusting for demographic variables  as well as biomarkers of kidney function  using a backward stepwise approach. The variables included in Model 2 were incorporated in the nomogram to predict CKD risk using “rms” package in R software version 4.2.2. A significance level of 0.05 was used for all analyses.n = 12, and without CKD, n = 121) are displayed in p = 0.02), had T2D for a median of 20 years, were more likely to be smokers , and were more likely to have macroalbuminuria . No significant differences were observed between study participants with and without CKD in terms of BMI, gender, FPG, ALP, calcium, phosphorus, total bilirubin, UACR, urine creatinine, and hs-CRP. HbA1c, haemoglobin, serum creatinine, BUN, eGFR, albumin, K, Na, and GGT levels were significantly higher in CKD participants than in those without CKD.Characteristics and metabolic parameters of study participants  as presented in Patients with CKD exhibited significantly higher plasma TMAO levels [10.16 (5.86–17.45) µmol/L] than patients without CKD [4.69 (2.62–7.76) µmol/L] , serum creatinine , BUN , and UACR   as shown in Plasma TMAO levels were positively correlated with age (r= 0.046) . Howeverp < 0.0001) as well as in Model 2 which adjusted for risk factors of CKD, including age, gender, BMI, duration of diabetes and smoking  (p = 0.063) and Model 4 ].Plasma TMAO levels were significantly associated with CKD in the non-adjusted Model 1  . HoweverA nomogram was created to optimise the statistical predictive models into a single numerical probability estimate of CKD in the form of a graph. The nomogram was based on five parameters that were significant in multivariable analysis (Model 2) to predict the risk of CKD in T2D patients, including age, gender, BMI, diabetes duration, and smoking. The total point, which ranges from zero to two hundred and twenty, was computed by summing the points from each variable to determine CKD probability. The risk of CKD by total points was shown in the nomogram. The risk of CKD was lower than 10% for those below 90 points, and higher than 50% for those with over 200 points. The nomogram is shown in 2, diabetes duration of more than 20 years, and smokers.Patients with more than 100 total points, for example, may have a 15% to 50% probability of developing CKD: TMAO levels greater than 7 µmol/L, age over 40 years, female gender, morbid obesity, BMI greater than 35 kg/mThis study explored the association between plasma TMAO levels and CKD in patients with T2D. Patients with CKD demonstrated higher levels of plasma TMAO than non-CKD patients. Plasma TMAO levels were positively correlated with biomarkers of renal function, including serum creatinine, BUN, and UACR, and were inversely correlated with eGFR. No significant relationship was found between plasma TMAO and other markers, including urine creatinine, serum electrolytes, ALP, total bilirubin, GGT, and hs-CRP. Elevated plasma TMAO levels were associated with CKD in the unadjusted model as well as when risk factors of CKD were adjusted for. However, the significant association was lost after further adjustment was made for CKD biomarkers, including UACR and eGFR. A simple monogram, based on the five variables that were significant in the multivariable analysis in Model 2 including TMAO level, age, BMI, gender, diabetes duration, and smoking demonstrated that TMAO levels contribute to the identification of T2D patients at high risk of developing CKD.TMAO has been shown to aggravate kidney function decline and tubular interstitial injury, activate the inflammatory pathway via increasing p38 phosphorylation and human antigen R (HuR) level, upregulate NADPH oxidase 4 (NOX4), promote oxidative stress and nod-like receptor family pyrin domain containing three (NLRP3) inflammasome activation . It has Uncontrolled hyperglycaemia, particularly diabetes mellitus, remains a critical risk factor for CKD . We 33]33] and oAccumulating evidence has demonstrated a significant association between TMAO and CKD ,20,21,22The study observations are in line with several previous studies in patients with cardiovascular diseases ,25,26,27The association between plasma TMAO and CKD has been confirmed in the unadjusted model as well as after adjusting for CKD risk factors, including age, gender, BMI, diabetes duration, and smoking. However, when the model further adjusted for biomarkers of kidney disease such as UACR and eGFR, the association between TMAO and CKD was attenuated. This finding proposed a potential interaction between TMAO and biomarkers of kidney disease, suggesting TMAO as a surrogate marker for GFR and urine albumin as a predictor of poor outcomes in CKD patients . FurtherThe present study is the first in the Middle East to investigate the association between TMAO and blood markers of kidney disease in patients with T2D. We were able to understand the renal implications of TMAO and its correlation with poor renal outcomes in T2D patients. In this cross-sectional study, we have included only patients with a clinically confirmed diagnosis of T2D to control for any potential confounding produced by differences in diabetes diagnosis. The observational nature of the present study prohibits any inferences on the causality of TMAO and CKD in T2D patients. Patients from only one medical centre in the capital city of Saudi Arabia were included, limiting the generalizability of the findings. Further studies with a larger number of patients are warranted to verify the association between circulating TMAO levels and CKD with T2D.In conclusion, our study has confirmed the association between circulating TMAO levels and CKD in a Saudi Arabian population where the dietary habits are different from the countries where the association has been previously established. Plasma TMAO levels are significantly associated with CKD, aggravated further in people with T2D, and correlated with biomarkers of renal function such as serum creatinine, eGFR, BUN, and UACR. Longitudinal and randomised controlled studies are warranted to establish if the progressive increase in TMAO and CKD is the cause or consequence of renal impairment in people with T2D. Identification of dietary and other lifestyle factors that can influence circulating TMAO levels may further enhance investigations into the prevention of T2D and CKD.


Hypertension is the most common modifiable risk factor for cardiovascular and cerebrovascular diseases. In the last two decades, the guidelines have evolved tremendously from areas with no recommendations for screening or treatment to targeted recommendations for some at-risk groups. We sought to go through the literature that provided guidelines for the management of hypertension at any point in time over the last 22 years from 2000 to 2022. We searched four databases: PubMed, Embase, Google Scholar, and Cochrane, using specified search terms. The keywords used were "hypertension" and "guidelines." We combined them using the Boolean operators  and searched for articles. A total of 2461 publications were initially identified; 348 publications were excluded after screening for full-text availability. The full-text articles were further filtered based on title and abstract screening. Following this, a total of 1443 articles were excluded. The remaining 670 full-text articles were assessed for eligibility. Of the 670 full-text articles, 480 were excluded based on exclusion criteria, and following the full-text article screening, 190 articles met the final inclusion criteria. Most of these guideline evolutions concerned establishing and adjusting thresholds for the subgroups of the elderly population and patients with diabetic kidney disease, chronic kidney disease, and stroke. Furthermore, the medications of choice are now guided by the stage of disease, presence or absence of comorbidities, and other relevant information, as opposed to ethnicity, which was previously a heavy yardstick for medication choice. Hypertension is a common risk factor for several life-threatening cardiovascular and cerebrovascular diseases, including myocardial infarction, cardiomyopathies, and cerebrovascular accidents . MaintaiDespite these recommendations, achieving BP control has remained a major concern for healthcare providers and patients. Hence, these guidelines have continued to evolve to accommodate this ever-growing knowledge. This has made keeping up with these organizations' recommendations difficult . This reBackgroundAccording to the 2015 guidelines from the United States Preventive Services Task Force (USPSTF) [The 2003 World Health Organization (WHO) and the International Society of Hypertension (ISH) guideline BP reference was systolic BP of 140 mmHg in low-risk patients and lower thresholds in higher-risk patients. The 2014 American Society of Hypertension/International Society of Hypertension guideline goal for diagnosing hypertension was systolic BP > or =140, diastolic BP > 90, or both. This BP goal was based on major clinical trials showing the benefits of treating people with these BP levels [The Joint National Commission 8 (JNC 8) guidelines also include treatment recommendations for different age groups, races, and disease conditions . ThiazidMethodologyWe searched four databases: PubMed, Embase, Google Scholar, and Cochrane, using specified search terms. Our keywords were "hypertension" and "guidelines." We combined the keywords using the Boolean operators . We searched for articles written from 2000 to 2022.A total of 2461 publications were initially identified; 348 publications were removed after screening for full-text availability. The full-text articles were further filtered based on title and abstract screening. A total of 1443 articles were excluded. The remaining 670 full-text articles were assessed for eligibility. Of the 670 full-text articles, 480 were excluded based on exclusion criteria, and following the full-text article screening, 190 articles met the final inclusion criteria.Inclusion and Exclusion Criteria1. The reviewed hypertension guidelines that were written between 2000 to 2022: The guidelines documents reviewed were: (a) Amaerican College of Cardiology (ACC)/AHA hypertension guidelines, (b) JNC guidelines, (c) USPSTF recommendations for hypertension, (d) the National Kidney Foundation hypertension guidelines, (e) ISH guidelines, (f) The American Diabetes Association (ADA) guidelines, (g) the European Society of Hypertension (ESH) guidelines.2. Publication with full-text access indexed in PubMed, EMBASE, Google Scholar, and Cochrane.We excluded systematic reviews and meta-analyses from this review.The ACC/AHA guidelinesThe Threshold for Defining HypertensionThe AHA/ACC started synthesizing evidence and publishing guidelines specific to hypertension in 2013. The AHA/ACC hypertension guidelines were initially done in collaboration with the Centers for Disease Control and Prevention (CDC). The AHA/ACC/CDC, in 2013, set a BP goal of 139/89 mmHg for all adults and revised it in 2014 to a screening threshold of 140/90mmHg for all adults . The guiThe 2017 ACC/AHA guideline eliminated the classification of prehypertension and divided hypertension into three levels: (1) Elevated BP with a systolic BP between 120 mmHg and 129 mmHg and diastolic BP <80mmHg, and (2) Stage 1 hypertension with a systolic BP between 130 and 139 mmHg, and diastolic BP between 80 and 89mmHg and stage 2 hypertension (systolic BP ≥140 mm Hg OR diastolic BP ≥90 mm Hg). A prominent feature in the 2017 guideline was lowering the definition of hypertension from ≥ 140/90mmHg to ≥ 130/80 mmHg ,9. The sThe ACC/AHA guidelines also pay great attention to accurate BP measurement by recommending standard measurement conditions using appropriately sized BP cuffs and validated BP measurement devices. It also provides new recommendations for out-of-office blood pressure measurement and confirms the diagnosis of hypertension .The Chronology/Changes in RecommendationsIn November 2013, the ACC/AHA/CDC collaboration made the following recommendations:● In stage 1 hypertension, the treatment threshold for adults (systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg) may be treated with lifestyle modifications and, if needed, a thiazide diuretic.● Stage 2 hypertension (systolic BP > 160 mmHg or diastolic BP > 100 mmHg): can be treated with a thiazide diuretic combined with an ACEI, an ARB, or a calcium channel blocker.The recommended BP goal should be 139/89 mmHg or less.● For individuals who do not attain BP goals, medication dosing may be increased, or medication with a different mechanism of action can be added to the treatment [The AHA/ACC/ASH collaboration released a guideline on the management of hypertension in patients with coronary artery disease in 2015 and made the following recommendations:● A BP control of <140/90 mm Hg was recommended for most CAD and hypertension patients.● A BP of 130/80 mm Hg was reasonable in individuals with CAD, its equivalent, and stroke.● In individuals with hypertension and CAD, a BP target of <140/90 mm Hg for secondary prevention of cardiovascular events seemed reasonable, and tighter control of 130/80 mmHg was acceptable in some of these patients with a previous stroke, transient ischemic attack, myocardial infarction (MI), or CAD risk equivalents .● Medications recommended for patients with hypertension and chronic stable angina include ACEIs or ARBs, beta-blockers (history of MI), and thiazide. They also mentioned that medications with mortality benefits in patients with acute coronary syndrome (ACS) were beta-blockers, ACEIs or ARBs, and possibly aldosterone antagonists.● In patients with CAD with elevated diastolic BP and myocardial ischemia, BP reduction should be gradual. Caution should be taken when lowering diastolic BP to less than 60 mmHg in the elderly and individuals with diabetes mellitus. Lowering systolic BP in older patients with hypertension and wide pulse pressures may reduce diastolic BP (less than 60 mmHg) [Limitations to ACC/AHA Considerations2 and proteinuria > 1 g/day), diabetes, and population in nursing homes or had dementia resulting in lack of generalizability  [The SPRINT and ACCORD clinical trials were two significant studies that shaped the most recent ACC/AHA guidelines. They, however, had certain limitations that may have affected their results: (1) The SPRINT trial showed a better cardiovascular outcome among the treatment group that received intensive treatment (aiming for systolic BP < 120 mmHg) compared with a standard treatment group (systolic BP < 140 mmHg), excluded individuals with end-stage chronic kidney disease /ESH GuidelinesThe Threshold for Defining HypertensionBefore 2013, the ESH and the ESC did not have a particular guideline on hypertension, as they were working with and endorsed guidelines of the ISH Liaison Committee/World Health Organization (WHO) ,16. TheyThe treatment intervention levels for cardiovascular risk factors such as BP, blood cholesterol, and blood sugar have been based on different arbitrary points of the individual risk factors; the current approach to management is to determine the threshold, at least for cholesterol and BP reduction, based on the calculation of estimated coronary risk over a defined period  ,18. In tThe Chronology/Changes in RecommendationsThe significant chronologic changes in the ESC/ESH guidelines for treating hypertension from 2001 to 2021 were in the areas of the threshold for drug initiation and target BP. The choice of drug classes effective in treating hypertension and the combination recommended for hypertensives with various comorbidities remained constant.2003 ESC/ESH Treatment Guidelines: The 2003 guidelines and recommendations on the threshold for the initiation of drug therapy include the following: Irrespective of the patient’s age, the decision to initiate antihypertensive therapy is governed by cardiovascular risk and the level of systolic and diastolic BP, with cardiovascular risk-taking precedence over BP . They reConcerning special conditions such as patient's age and comorbidities :● The initiation of antihypertensives should follow the general guidelines while paying attention to the patient’s risk factors and frailty, target organ damage, and associated cardiovascular conditions, irrespective of the patient’s age .● In diThe committee recommended that BP be lowered to ≤140/90mmHg in all patients and <130/80mmHg in people with diabetes while acknowledging that it may be challenging to achieve SBP <140mmHg in elderly patients . The 200Based on evidence from interventional studies, we found the following combinations to be beneficial: Diuretics plus ACE inhibitors or angiotensin II receptor blockers (ARBs), β-blockers, or calcium antagonists, ACEIs or ARBs plus calcium antagonists, β-blockers plus calcium antagonists . While mThe 2007 ESC/ESH Treatment GuidelinesBased on more recent studies after the 2003 guidelines were published, the ESC/ESH published a new set of guidelines in 2007 while still adhering to most of the recommendations in the 2003 guidelines. The ESC/ESH committee made the following recommendations concerning the initiation of antihypertensive therapy:● Again, the decision to initiate antihypertensives is governed by the presence of cardiovascular risk and the level of systolic and diastolic BP.● The ESC/ESH guidelines used the 10-year risk of having a cardiovascular event  to stratify risk into low, moderate, high, and very high risk. But an additional term "added risk"-was used to imply that the risk was higher than average in all strata .● In thThe 2007 guidelines and recommendations on using antihypertensives, choice, and treatment targets or goals were still the same as the 2003 guidelines in these areas. The notable changes were: The need to use peak and trough or ambulatory measurements to ensure 24 hours of BP monitoring. Also, in addition to calcium antagonists and thiazide diuretics, ACEIs and beta-blockers were recommended to treat hypertension in elderly patients. The ESC/ESH recommended a tighter BP target goal of 130/80 mmHg for patients with previous stroke and renal dysfunction (and even lower for patients who had > 1 g/day of protein in their urine) . They re2013 ESC/ESH Treatment GuidelinesIn the 2013 guidelines, the committee made some reversals in their earlier decisions to initiate drugs and treatment targets in elderly patients and patients with comorbidities like diabetes mellitus and post-stroke.The recommendations for the initiation of drug treatment in the 2013 guidelines are:● Based on new evidence, the committee recommended no intervention for patients with high normal BP compared to the previous guidelines, as most of the studies in support of intervention either classified patients already on antihypertensives as normotensive or had a tiny percentage of normotensive patients in their research .● It reIn the area of target BP, based on evidence from recent studies -26, the 2018 ESC/ESH Treatment RecommendationsIn 2018, the ESC/ESH committee made important changes based on new evidence from studies regarding when drug treatment should be initiated, target BP, and changes in the management of hypertension in patients with comorbidities and across the age spectrum.The Start of Therapy: The 2018 committee recommendations on drug treatment initiation for the different hypertension grades are shown in Table Treatment Objectives: The committee recommended the following treatment targets● To keep the office BP of these patients to <140mmHg office SBP and <90mmHg if tolerated.● When tolerated, SBP should be between 120 - 129mmHg for patients < 65 years.● 130 -139mmHg was recommended for patients >65 years● It advised diabetic patients to keep their blood pressure below 130 mmHg.● Target DBP for all patients should be <80mmHgTherapeutic strategies, drug choice, and other related therapeutic guidelines were unchanged. Research Trials Considered in the ESC/ESH Guidelines and Their LimitationsThe SCOPE study, cardiology vascular health study, atherosclerosis risk in a community study, the Hypertension Optimal Treatment (HOT) study, Australian blood pressure study, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), Lifestyle Interventions and Independence for Elders (LIFE) study, ASCOT study, SPRINT, and the Prevention and Treatment of Hypertension study ,23,27 arThe USPSTF guidelinesThe USPSTF is an independent, volunteer panel of national disease prevention and evidence-based medicine experts. The task force primarily makes evidence-based recommendations about disease prevention. Regarding hypertension, most of the USPSTF work was focused on screening strategies.In 1996, the USPSTF recommended only screening adults (21 years or older) for hypertension. At this time, no treatment guidelines/recommendations for hypertension were made by the task force . In 2003The USPSTF in 2007 sought to ask two questions: (1) What are the benefits of screening for high BP in adults? (2) What are the risks of early screening for and/or treating high BP? A literature search on studies on the benefits and harms of screening and treatment of hypertension was conducted by the task force. They included studies of nonpregnant adults in the United States and outside of the United States with a patient population generalizable to the United States. To meet their inclusion criteria, the USPSTF found no studies on the benefits or harms of screening for high BP. Five studies on the harms of early hypertension treatment met their inclusion criteria . In thesIn 2015, the USPSTF reaffirmed its recommendation to screen for high BP in adults older than 18. The task force also recommended that caregivers obtain BP measurements from outside the clinic to confirm the diagnosis of high BP before initiating treatment . This waUSPSTF also commented on first-line pharmacological therapy for different groups of patients. For non-Black patients, the initial treatment recommendation consisted of a thiazide diuretic, calcium-channel blocker, angiotensin-converting enzyme inhibitor, or angiotensin-receptor blocker. A thiazide diuretic or a calcium-channel blocker was recommended for Black/African American patients as the first-line treatment . For patThe NKFIn 1998, the NKF published the task force's report on CVD in chronic renal diseases. One of the objectives was to assess current knowledge about the association between high BP and CVD in chronic kidney disease. Also, the NKF published a report on managing hypertension in adults with diabetes and renal disease. In 2001, the NKF initiated a Kidney Disease Outcomes Quality Initiative (KDOQI) workgroup to conduct a review of evidence and develop clinical practice guidelines for the management of blood pressure in chronic kidney disease to prevent the progression of kidney disease and the development and progression of CVD in chronic kidney disease. The goal of this guideline was to relate high BP to adverse outcomes of chronic kidney disease and to describe the association of the level of glomerular filtration rate with high BP. Most of the time, they made decisions based on their findings through workgroups and Kidney International , if done in collaboration, from clinical trials and observational studies based on risk stratification. Some of their guidelines on managing hypertension in diabetic chronic kidney disease were consistent with the American Diabetes Association and JNC data. In addition, KDOQI used the glomerular filtration rate as the principal basis for staging chronic kidney disease and augmented the staging scheme by incorporating the cause of kidney disease and level of albuminuria in addition to the level of glomerular filtration rate. Many clinical trials on antihypertensive agents to prevent CVD excluded patients with reduced kidney function. In 2007 guidelines, Type 1 and 2 diabetes mellitus and chronic kidney disease stages 1-4 were included, while kidney transplant recipients were excluded; Table Chronology of the Changes in the NKF GuidelinesThere were a number of research trials in the NKF guidelines, each with its limitations.2002 Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification: In 2002, according to the NKF guidelines for chronic kidney disease, the recommendations for the general population were based on evidence from observational studies and clinical trials that related BP levels to mortality and CVD. This was seen in the HOT on diabetic kidney disease . There w2004 Hypertension and Hypertensive Agents in Chronic Kidney Disease : Numerous epidemiological studies showed a graded, independent, and strong relationship between arterial BP and CVD. Above a systolic BP of 115 mmHg and a diastolic BP of 75 mmHg, there is a risk of CVD, which double for every increment of the systolic BP by 20 mmHg or diastolic BP by 10 mmHg. In individuals above 50 years of age, systolic BP greater than 140 mmHg is a more critical CVD risk factor than diastolic BP . ControlThe onset of hypertension in persons with type 1 diabetes usually signifies the beginning of renal disease. In contrast, in those with type 2 diabetes, it may occur without kidney disease(Guideline 8). Several prospective studies have shown a strong correlation between BP and an increased risk of renal failure in diabetic kidney disease .Generally, multiple antihypertensive agents are required to reach target BP levels. Nevertheless, ACEIs are more effective than other antihypertensive classes in slowing the progression of kidney disease with macro-albuminuria due to type 1 diabetes. Also, ARBs are more effective than other antihypertensive classes in slowing the progression of kidney disease with macro-albuminuria due to type 2 diabetes .2005 KDOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients: The rationale for the recommendations was from the reviews that linked hypertensive heart disease to cardiovascular morbidity and mortality . People 2007 American Journal of Kidney Disease, Clinical Practice Guidelines and Clinical Recommendations for Diabetes and Chronic Kidney Disease: The guidelines for antihypertensive agents in kidney disease due to diabetes and other causes do not conflict. ARBs and ACEIs were compared with other classes of antihypertensive agents. These studies frequently used diuretics as additional antihypertensive agents to achieve BP control .2012 KDOQI United States Commentary on the 2012 KDIGO Clinical Practice Guidelines for the Management of BP in Chronic Kidney Disease: Per the National Health and Nutrition Examination Study (NHANES) data, chronic kidney disease and nondiabetic chronic kidney disease are often associated with resistant hypertension. The choice of agents for treatment must be made according to the comorbidities, especially renovascular disease, volume depletion, or potential drug interactions .The concept that diuretics complement ACEIs/ARBs in combination is well supported. While the metabolic side effects of thiazide diuretics are well known, these are usually easily managed. Interest in chlorthalidone was on the rise as the diuretic of choice, as most of the large clinical trials used chlorthalidone. Beta-blockers are still utilized in hypertensive patients with chronic kidney disease. In primary hypertension, beta-blockers were no longer considered first-line therapy in hypertension without indication .For BP control in chronic kidney disease nondiabetics, evidence was scarce for these recommendations that suggested that except in the individuals with severely elevated albuminuria, there was no compelling reason to use or not use specific agent classes in these patients .Based on the Hypertension in the Very Elderly Trial (HyVET), a target BP of 140-145 mmHg was recommended for octogenarians. Because elderly patients with nondiabetic kidney disease may require less aggressive BP reduction, the above-average blood pressure target may apply to these individuals .The Limitations of These StudiesThe 2002 Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification: The 2002 survey done by the NKF showed that the knowledge base for chronic kidney disease was limited. The formulation of this guideline was also limited by other factors, such as the fact that a number of the studies were difficult to compare as they used different measures for kidney function including glomerular filtration rate or creatinine clearance, estimation equations for glomerular filtration rate or creatinine clearance, or simply serum creatinine . SecondlThe 2004 Hypertension and Hypertensive Agents in Chronic Kidney Disease : There were few studies on treating hypertension in chronic kidney disease. Most clinical studies in patients with chronic kidney disease were designed to evaluate the efficacy of therapy in slowing the progression of chronic kidney disease rather than reducing the risk of CVDs . These rThe KDOQI 2005 Guidelines for CVD in Individuals with Renal Impairment on Dialysis: Many of the recommendations supported by the ADA on the care of diabetes are based on extensive clinical studies that provide strong evidence for the particular recommendation, but those studies do not target dialysis patients .The 2007 American Journal of Kidney Disease, Clinical Practice Guidelines and Clinical Recommendations for Diabetes and Chronic Kidney Disease: Combining ACEIs with ARBs effectively slowed the progression of nondiabetic kidney disease, an observation related to a further reduction in proteinuria rather than BP lowering. No trials with clinical outcomes had evaluated such a combination for treating diabetic kidney disease. Other combinations, such as aldosterone blockade with ACE inhibition, may have reduced albuminuria independent of blood pressure changes in diabetic kidney disease. To date, all studies evaluating combinations of renin-angiotensin-system (RAS) inhibitors had been performed in hypertensive patients with diabetes with advanced chronic kidney disease and microalbuminuria .The 2012 KDOQI United States Commentary on the 2012 KDIGO Clinical Practice Guidelines for Managing BP in Chronic Kidney Disease: There has been a lack of evidence for most of the guidelines. One of the more controversial recommendations was to treat patients with chronic kidney disease, with or without diabetes, who have moderately to severely increased albuminuria to a systolic BP of 130 mmHg. Although this may result in less albuminuria than a less stringent goal of 140 mm Hg, it is hard to show the benefit of the 130 mmHg systolic goal, which conflicted with the JNC's recommendations at the time .The ADA guidelinesThe "Standards of Medical Care in Diabetes" is a component of the ADA guidelines, which outline the current recommendations for the clinical management of diabetes. These include the components of care for diabetes patients, treatment goals, and tools to assess the quality of care . With thAmong young people, type 1 diabetes is the most common type of diabetes. Individualized nutritional therapy is recommended for this population as a crucial part of the treatment plan. The recommended pharmacologic therapy for people with type 1 diabetes includes intensive insulin treatments. Diabetes is also prevalent in older adults, especially people over 65 years of age. This population commonly has coexisting chronic illnesses, which should be assessed at the initial visit and annually, as needed .The aimFor many years, the ADA has recommended that people with diabetes get their blood glucose tested two to four times a year using an A1C (glycated haemoglobin) test. One of the major highlights of the 2021's guideline update was that sodium-glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide 1 (GLP-1) agonists (if SLGT-2 is not well tolerated) be used in people with diabetes with comorbid conditions such as chronic kidney disease and heart failure, irrespective of HbA1C or metformin use.The ADA 2021 guidelines were updated to include the following recommendations:● Individuals with diabetes and concomitant hypertension at higher cardiovascular risk or 10-year ASCVD risk > 15% are to be treated to a BP target of < 130/80 mmHg, whereas a BP target of < 140/90 mmHg is to be achieved by people with diabetes and hypertension at lower cardiovascular risk or 10-year ASCVD risk < 15% .● ACEIsHypertension guidelines have metamorphosed over the last 22 years to include a more extensive at-risk population with the adoption of various blood pressure cutoffs per population. The evolution of anti-hypertension medications has also seen huge success following multiple clinical trials. We envisage that the future of the hypertension guideline will encompass BP control targets, specifically according to ethnicity, body muscle mass, sex, and geographical location, to further individualize its clinical application in the near future.


Objective: This study aimed to determine whether the combination of pregnancy-associated endothelial cell-specific molecule 1 (ESM-1), the placental growth factor (PLGF) in the first- and second-trimester maternal serum, and the uterine artery Doppler pulsatility index (PI) in the second trimester can predict preeclampsia (PE). Methods: The serum levels of ESM-1 and PLGF in 33 severe preeclampsia (SPE) patients, 18 mild preeclampsia patients (MPE), and 60 age-matched normal controls (CON) were measured. The Doppler ultrasonography was performed, and the artery pulsatility index (PI) was calculated for the same subjects. Results: The 2nd PLGF level was significantly lower and the 2nd PI was higher than those in the MPE group. Combining the 2nd PLGF with the 2nd PI yielded an AUC of 0.819 (83.33% sensitivity and 70.00% specificity). In the SPE group, the 1st ESM-1 level and the 2nd PLGF level were significantly lower, and the 2nd ESM-1 level and the 2nd PI were significantly higher in the SPE group. The combination of the 1st ESM-1, the 2nd PLGF, and the 2nd PI yielded an AUC of 0.912 (72.73% sensitivity and 95.00% specificity). Conclusions: The 1st ESM-1 and the 2nd PLGF levels and the 2nd PI were associated with PE. The combination of serum biomarkers and the PI improved the screening efficiency of the PE prediction, especially for SPE. Preeclampsia (PE) is a major cause of morbidity and mortality among pregnant women and infants, resulting in an estimated 76,000 maternal deaths and 500,000 fetal and newborn deaths every year . The etiEndocan, an antiangiogenic factor which is also called endothelial cell-specific molecule-1 (ESM-1), was originally identified in cultured endothelial cells . SeveralPlacental growth factor (PLGF), produced by villous syncytiotrophoblasts, is thought to induce nonbranching angiogenesis, leading to a low-resistance placental vascular network ,8. LimitSpiral artery transformation failure in PE could lead to an increase in uterine artery blood flow resistance , which cThe objective of our study was to evaluate the maternal serum ESM-1 and the PLGF levels in the first and second trimesters and the uterine artery Doppler PI in the second trimester and to determine whether the integration of these biomarkers with the 2nd PI would be helpful in the prediction of PE.This was a prospective study. Women with singleton pregnancies who presented at the International Peace Maternity and Child Health Hospital, Shanghai, China, from 2020 to 2021 for prenatal examination were eligible for inclusion. The exclusion criteria were multiple pregnancies, chronic hypertension, chronic renal disease or pre-existing proteinuria, diabetes, malignancy, autoimmune disorders, acute systemic inflammation, fever, premature rupture of membranes, preterm labor, or major congenital fetal anomaly. The study was conducted according to the Declaration of Helsinki guidelines and the approval of the National Ethics Committee for Science and Technology (number: GKLW2020-03). All the participants were followed from the first trimester to delivery, with pregnancy outcomes recorded and written informed consent provided.(1)Blood pressure ≥160/110 mm Hg on two occasions at least 4 h apart (unless antihypertensive therapy was initiated before this time);(2)9/L;Thrombocytopenia: platelet count <100 × 10(3)Renal insufficiency: serum creatinine concentrations >1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal diseases;(4)Impaired liver function: elevated blood concentrations of liver transaminases to twice the normal concentration;(5)Pulmonary edema;(6)New-onset headache unresponsive to medication and not accounted for by alternative diagnoses or visual symptoms.The definition of the severe preeclampsia (SPE) group was as follows:(1)Blood pressure ≥140/90 mmHg on two occasions at least 4 h apart after 20 weeks of gestation in a woman with previously normal blood pressure;(2)Three hundred milligrams or more per 24 h of urine collection (or this amount extrapolated from a timed collection) or a protein/creatinine ratio ≥ 0.3 mg/dL or a dipstick reading of 2+.The mild preeclampsia (MPE) group was described as follows:+6 weeks of gestation, and the second trimester, at 24–28 weeks of gestation. All the blood samples were centrifuged at 3000 rpm for 10 min, and the serum samples were stored at −80 °C until use.Peripheral venous blood samples were collected from all the participants during two different periods: the first trimester, at 9–13All the samples from the subsequently diagnosed PE patients based on the ACOG guidelines  and gestThe patients without fetal defects on routine ultrasound performed at 22–28 weeks of gestation also underwent a bilateral uterine artery Doppler assessment. The uterine artery PI was determined as the average PI from three continuous similar waveforms. All the examinations were evaluated by ultrasound by simultaneous B-mode scanning . The carrier frequency was from 1 to 5 MHz for the transabdominal probers.t-tests or chi-square tests. A p value < 0.05 was considered statistically significant.The data analysis was performed using SPSS 25.0  and MedCalc (version 11.4.2.0). The data are presented as the mean ± SD or median (min-max). Logistic regression analysis was used to evaluate the combination of these indicators. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value. Statistically significant differences were estimated utilizing the Student’s In total, 2086 pregnant women were recruited for the study. Among them, 1927 pregnant women completed the study, and 159 (7.6%) did not give birth in our hospital and were lost to the follow-up. Fifty-one women developed PE (severe preeclampsia (SPE) 33 cases and mild preeclampsia (MPE) 18 cases), with an incidence rate of 2.6%, which was consistent with that in the literature [p < 0.001). The gestational age at delivery and the fetal weights were significantly lower in the PE group, especially in the SPE group (p < 0.001). The placental weights were lower in the SPE group (p < 0.05). However, there was no significant difference in maternal age, pre-pregnancy BMI, or the 5′ Apgar scores among the groups.The clinical and demographic characteristics of the participants are presented in p < 0.001) in the SPE group was significantly lower. There was no significant difference in the ESM-1 level between the control and the MPE groups (p = 0.0032) in the SPE group was significantly higher and the PLGF level  in the SPE group was significantly lower (p < 0.001) in the MPE group (p < 0.001) in the SPE group and the 2nd PI  in the MPE group were also significantly higher , 0.802 , and 0.843 , respectively. Logistic regression analysis was used to evaluate the combination of these indicators. In the SPE group, the AUCs for the combinations of the 1st ESM-1 and 2nd PLGF, the 1st ESM-1 and 2nd PI, and the 2nd PLGF and 2nd PI were 0.856 (93.90% sensitivity and 66.70% specificity), 0.876 (84.85% sensitivity and 80.00% specificity), and 0.890 (69.70% sensitivity and 95.00% specificity), respectively. The combination of the 1st ESM-1, the 2nd PLGF, and the 2nd PI yielded an AUC of 0.912 (72.73% sensitivity and 95.00% specificity) . Furthermore, the details of the AUCs are shown in p < 0.0001) and 0.748 , respectively. In the MPE group, combining the 2nd PLGF with the 2nd PI yielded an AUC of 0.819 (83.33% sensitivity and 70.00% specificity).The ROC curves for the biomarkers in the MPE prediction are presented in Accumulative evidence has revealed that inflammation and endothelial dysfunction are vitally important to the pathophysiology of PE . ESM-1 mThe results showed that the ESM-1 level in the maternal plasma was lower during the first trimester (12–16 weeks of gestation) but increased in the second and third trimesters (≥24 weeks of gestation) in the SPE group ,26. MoreAs an explanation for the lower 1st ESM-1 level in PE, some researchers have suggested that ESM-1 functions as a protective cytokine by inhibiting leukocyte aggregation to protect tissues and organs from inflammatory damage and is consumed in early pregnancy . It was +6 weeks of gestation, the PLGF expression was significantly lower in PE pregnancies than in the CON pregnancies [PLGF, which is expressed in the human placenta, heart, and lungs, is a member of the VEGF family . It can gnancies . Anothergnancies . The stugnancies , and anognancies . Moreovegnancies . Our stugnancies .Some studies have shown that uterine artery PI is a significant marker for predicting PE. The Doppler ultrasound of the maternal uterine artery PI might be the most effective method for screening women with PE in the second trimester . In our Many recent studies have suggested that the combination of biochemical indicators and the uterine artery Doppler could improve the screening efficiency for the prediction of PE ,37. NotaThe 1st ESM-1, 2nd PLGF levels and the 2nd uterine artery Doppler PI were associated with PE. The combination of serum biomarkers and the uterine artery Doppler PI strengthened the screening efficiency for the prediction of PE, especially for SPE. Our study is the first to assess the predictive combination of the 1st ESM-1, the 2nd PLGF, and the 2nd uterine artery Doppler PI for PE. Unfortunately, due to the COVID-19 outbreak, the blood samples of the participants in the third trimester were lost, resulting in a lack of data on the serum concentrations of ESM-1 and PLGF. Further studies are needed in a larger population to determine the potential for use of the aforementioned indicators.


The hypertensive group (67.6%) was significantly older and exhibited significantly lower eGFR than the normotensive one. Increased left ventricular mass index (LVMI) was seen in 2.0%, mitral valve prolapse was observed in 3.4%, mitral valve regurgitation in 15.3%, tricuspid valve regurgitation in 16.0%, and aortic valve regurgitation in 4.8% of the whole sample. The present study suggested that the prevalence of mitral valve prolapse was much lower than previously reported, and increased LVMI was not seen in most adult ADPKD patients.Cardiovascular abnormalities, such as left ventricular hypertrophy and valvular disorders, particularly mitral valve prolapse, have been described as highly prevalent among adult patients with autosomal dominant polycystic kidney disease (ADPKD). The present study aimed to assess echocardiographic parameters in a large sample of both normotensive and hypertensive ADPKD patients, regardless of kidney function level, and evaluate their association with clinical and laboratorial parameters. A retrospective study consisted of the analysis of clinical, laboratorial, and transthoracic echocardiograms data retrieved from the medical records of young adult ADPKD outpatients. A total of 294 patients  with a median estimated glomerular filtration rate (eGFR) of 75.5 mL/min/1.73 m Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic kidney diseases, with an estimated prevalence between 1 to 2500 through 1 to 1000 individuals . End-staThis is a retrospective study based on the medical records of ADPKD patients followed at the outpatient Polycystic Kidney Disease (PKD) Unit of the Nephrology Division of the Universidade Federal de São Paulo (UNIFESP) from March 2002 through June 2018, whose transthoracic echocardiograms (TTE) were available as part of their routine evaluation. Exclusion criteria were age < 18 years, malignant diseases, and ESKD on dialysis. The diagnosis of ADPKD was confirmed by positive family history and renal cysts according to ultrasonographic diagnostic criteria by Pei et al. .The study was reviewed and approved by the Research Ethics Advisory Committee of the Universidade Federal de São Paulo (UNIFESP) (CAAE: 01521418.2.0000.5505).2 × length/2. Hypertension at admission was defined based on office or clinic levels of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg [Demographic, anthropometric, and serum biochemistry data were retrieved from patients’ electronic records. Biochemical parameters considered for the present analysis were serum creatinine, sodium, potassium, uric acid, fasting glucose, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol (HDL), and triglycerides. Creatinine was determined by an isotope dilution mass spectrometry (IDMS) traceable method and the estimated Glomerular Filtration Rate (eGFR) was calculated using the CKD-EPI equation. Total Kidney Volume (TKV) was calculated and defined as the mean of both kidneys based on renal ultrasound using a standard formula of a modified ellipsoid for each kidney as follows: Renal volume = 4/3 π (anteroposterior diameter/4 + width/4) 90 mmHg  or use o2  and 111 g/m2 . Valvular disorders included Mitral, Aortic and Tricuspid Valve Regurgitation, Mitral Valve Prolapse (MVP), and Diastolic function. Based on the 2003-Guideline from the American Society of Echocardiography [Transthoracic echocardiograms (TTE) was performed on a Philips IE33 echocardiography device  using a S5–1 (1–5 mHz) transducer, capable of obtaining two-dimensional images and analysis of the flow velocity with color and flow mapping techniques and Spectral Doppler. The measurements were obtained as recommended by the American Society of Echocardiography  and the iography , the seviography .p < 0.05 was considered significant. Variable distributions were evaluated by the Kolmogorov–Smirnov test. Normally distributed variables were expressed as mean ± standard deviation (SD) and non-normally distributed ones as median (interquartile range). Differences between groups were tested by Mann–Whitney U pairwise or Student t-test according to their distribution. Categorical variables, presented as n (%), were compared using a Chi-square test. A logistic binary regression using left ventricle impaired relaxation (yes or no) as a dependent variable, and a multivariable linear regression using LVMI as a dependent variable, were additionally performed.Statistical analyses were performed using IBM SPSS version 23.0 . In all analyses, From a total of 557 ADPKD patients referred for care at the outpatient PKD unit, TTE data were available for 346. Of these, 52 did not meet inclusion criteria, resulting in 294 subjects for the present analysis. p < 0.001), but hypertension was no longer associated with an impaired LV relaxation when performing a logistic binary regression analysis adjusted for age, BMI and eGFR .A significantly higher mean percentage of patients with impaired LV relaxation was noticed in the hypertensive versus normotensive groups , and tricuspid regurgitation . Aortic regurgitation was significantly higher among hypertensives , whereas MVP was higher among normotensives .As shown in Structural and functional cardiovascular alterations, particularly those detected by echocardiography, have been described to be associated with ADPKD ,13,26,27Present rates of 3.4% of MVP are similar to the ones described in the general population, around 2.5–3.0% ,32,33,34p = 0.08). Interestingly, a very recent small retrospective study with patients who underwent echocardiography and whose genotype was confirmed by genetic testing showed a higher prevalence of mitral valve regurgitation in patients with PKD-1 genotype than in those with PKD-2 or non-PKD-1 (46.9% vs. 8.3% vs. 19.0%), with no other cardiac valve complications [Mitral valve regurgitation was disclosed in 15.3% of the present sample, with no differences between hypertensive and normotensive patients contrasting with the description of up to 31% of ADPKD patients in the literature ,37. Despications .The prevalence of 4.8% of aortic valve regurgitation disclosed in our sample, more common among the hypertensive group, was nevertheless lower than the one reported in the general population of similar age (9%)  and alsoFinally, we observed tricuspid valve regurgitation in 16% of patients , in line with rates reported by Hossack et al.  (15%), bGiven that the pathophysiology and epidemiology of cardiac valvar abnormalities, particularly MVP, remain not fully understood even in the general population , the undp = 0.09). Of note, when we compared the mean values of LVMI between our normotensive patients with the cohort of healthy individuals reported by Ângelo et al. [p = 0.28) and aged 40–49 years old , respectively. Moreover, only 2.0% of the present cohort exhibited increased LVMI. Left ventricular hypertrophy (LVH) is highly frequent among pediatric and adult patients with ADPKD [In the present study, the dimensions of the cardiac chambers and aorta, as well as parameters related to myocardial mass, were within limits established by the American Society of Echocardiography Guidelines, elaborated in conjunction with the European Association of Echocardiography . The majo et al. , there wth ADPKD ,41,56,57th ADPKD ,57 or noth ADPKD . Accordith ADPKD . Howeverth ADPKD  down to th ADPKD . Noteworth ADPKD  in the Hth ADPKD  involvinth ADPKD ,62, as sBeyond the impact of hypertension on echocardiographic alterations in the current study, the hypertensive sub-group was also significantly older, presented higher BMI, TKV and kidney length, more diabetes or features of metabolic syndrome , and lower kidney function when compared to the normotensive group, suggesting a longer duration of the disease. A recent review of LVH beyond hypertension in ADPKD showed that there are factors other than hypertension that contribute to LVH . Insulinp = 0.09).The prevalence of impaired left ventricular relaxation of 25.8% in the present series suggesting diastolic dysfunction, much higher than observed in the general population (11%) , was staIt seems that more accurate assessment of cardiac diastolic function, such as TDI, spectral Doppler, and speckle strain echocardiography are still needed  as more appropriate surrogate markers of diastolic assessment as opposed to a single parameter measurement Limitations of our study include the characteristic observational and retrospective design, the lack of a control group, no PKD1 or PKD2 genotyping, and determination of kidney volume by ultrasound. However, its strength relies on the larger sample size when compared to the previous reports.In conclusion, the present study disclosed a lower prevalence of mitral valve prolapse and did not show increased LVMI in adult ADPKD patients contrasting with previous reports. Further prospective studies on other populations are warranted to confirm these findings.