In patients with non-communicating hydrocephalus impairment of cerebral compliance can occur pre- but also intraoperatively.In such patients (n = 6) undergoing endoscopic third ventriculostomy (ETV), the present study aimed to investigate the effect of ETCO2 (e.g 40 mmHg and 60 mmHg) and positive end-expiratory pressure (PEEP) (e.g. 6 cm and 12 cm H2O) on intraventricular pressure (IVP).Before but not after ETV, hypercapnia in contrast to PEEP increased IVP(PEEP-6/ ETCO2-40: 2.6 ± 2.4 mmHg) vs. (PEEP-6/ ETCO2-60: 12 ± 6.4 mmHg*); (PEEP-12/ ETCO2-40: 4.2 ± 4.1 mmHg) vs. (PEEP-12/ ETCO2-60: 13.7 ± 7.6 mmHg*), * significant, P ≤ 0.05;(PEEP-6/ ETCO2-40: 2.0 ± 1.2 mmHg) vs. (PEEP-6/ ETCO2-60: 4.4 ± 3.1 mmHg); (PEEP-12/ ETCO2-40: 1.6 ± 1.3 mmHg) vs. (PEEP-12/ ETCO2-60: 6.6 ± 2.6 mmHg), * significant, P ≤ 0.05).Patients with non-communicating hydrocephalus showed that hypercapnia but not PEEP increases significantly IVP before but not after ETV. To create a near physiological communication between the third ventricle and the basal subarachnoidal spaces endoscopic third ventriculostomy (ETV) has become the treatment of choice for these patients ,7,9. The2Following approval by the local University Ethics Committee and written informed consent, patients  scheduled for ventriculostomic therapy of symptomatic, obstructive third-ventricular hydrocephalus were enrolled in this pilot study.All patients were premedicated with midazolam . A bolus of propofol (2 – 3 mg/ kg) and remifentanil (0.2 – 0.4 mcg/ kg / min) was given to induce anesthesia. An additional remifentanil bolus (3 - 5 mcg/kg) facilitated intubation of the trachea . We usedThe patient was in a supine position with the neck slightly flexed. ETV was performed as previously described . A rod lHeart rate (HR) and invasive mean arterial blood pressure (IMAP) were monitored intraoperatively.3Pilot study with a sample size of six patients. Data are presented as mean ± SD. Data were tested for normal distribution using the Kolmogorov-Smirnov Test. Analysis of variance (ANOVA) for repeated measurements was used to compare the IVP values during the four respiratory settings established.The statistical computer package SPSS ® 11.0.1 for Windows was used for statistical analysis.4All enrolled patients / male (1); age: 52 ± 18 years; weight: 74 ± 11 kg; height: 170 ± 9 cm) completed the study without complication. Technical problems prevented measurement of IVP after ventriculostomy (ETV) in patient No. 6.Before ETV, increasing PEEP from 6 cm to 12 cm H2O at a constant ETCO2 (e.g. 40 mmHg or 60 mmHg) had no effect on IVP . In contChanges in PEEP, ETCO2 or both following ETV had no effect on IVP .Hemodynamic parameters remained stable throughout the whole procedure.5In patients with symptomatic, non-communicating hydrocephalus an increase in PEEP (e.g. from 6 cm to 12 cm H2O) had no effect on IVP during normo- or hypercapnia. An increase in ETCO2 (e.g. from 40 mmHg to 60 mmHg), however, increased IVP at 6 and 12 cm H2O PEEP.A previous study in young, healthy volunteers assessed the effect of increased mean airway pressure e.g. 12 cm H2O) on cerebrospinal fluid (CSF) drainage from the third to the fourth cerebral ventricle by measuring systolic cerebrospinal fluid peak velocity (CSFVPeak) in the aqueduct of Sylvius  cm H2O o. Given tChanges in arterial carbon dioxide partial pressure paCO2), which correlate well with ETCO2 ,2 cause , which cIn summary an increase in CBV, e.g. by hypercapnia, much more so than an increase in Pcsf, e.g. by increasing mean airway pressure, is clearly seen to increase IVP due to the increased pressure on the cerebral ventricles. These findings are consistent with those of others, who reported a PEEP of 15 – 20 cm H2O to not significantly increase intracranial pressure (ICP), for example in head trauma patients .Immediately following ETV the present study’s IVP measurements taken during normo- and hypercapnia were repeated at 6 and 12 cm H2O PEEP. Similar to the readings before ETV, increasing PEEP from 6 to 12 cm H2O had no effect on IVP. Surprisingly, in contrast to before ETV, hypercapnia now did not increase IVP, neither at 6 cm nor at 12 cm H2O PEEP. Obviously, the ventriculostoma allowed sufficient CSF drainage from the third ventricle, so that hypercapnia-induced increases in CBV compressed the third ventricle without concomitantly increasing IVP. Since CSF drainage by way of a patent aqueduct of Sylvius was previously shown to not be able to compensate hypercapnia-induced compression of the third ventricle (e.g. CSFVPeak increased)  it is loPropofol and remifentanil were used to induce and maintain anesthesia in our patients. Any confounding effect of either anesthetic agent on our results can largely be excluded for two reasons. Firstly, propofol but also remifentanil are known to preserve cerebral autoregulation,16,17 anFrom a practical, clinical point of view it is important to emphasize that hypercapnia should be strictly avoided in patients with symptomatic, non-communicating hydrocephalus, especially before successful ETV, whereas an increase in mean airway pressure is well tolerable.The present study’s patients showed stable hemodynamics throughout the procedure. It is, however, noteworthy that in about 7% of ETV procedures a Cushing reflex can occur in response to increased ICP . EspeciaIn conclusion, we here show that in patients with non-communicating hydrocephalus hypercapnia but not PEEP significantly increased IVP before but not after ETV.


Hypertension is a global public health issue and the most important preventable cause of cardiovascular diseases. Despite the clinical availability of many antihypertensive drugs, many hypertensive patients have poor medication adherence and blood pressure control due, at least partially, to the asymptomatic and chronic characteristics of hypertension. Immunotherapeutic approaches have the potential to improve medication adherence in hypertension because they induce prolonged therapeutic effects and need a low frequency of administration. The first attempts to reduce blood pressure by using vaccines targeting the renin-angiotensin system were made more than half a century ago; however, at the time, a poor understanding of immunology and the mechanisms of hypertension and a lack of optimal vaccine technologies such as suitable antigen design, proper adjuvants, and effective antigen delivery systems meant that attempts to develop antihypertensive vaccines failed. Recent advances in immunology and vaccinology have provided potential therapeutic immunologic approaches to treat not only infectious diseases but also cancers and other noncommunicable diseases. One important biotechnology that has had a major impact on modern vaccinology is virus-like particle technology, which can efficiently deliver vaccine antigens without the need for artificial adjuvants. A human clinical trial that indicated the effectiveness and safety of a virus-like particle-based antiangiotensin II vaccine marked a turning point in the field of therapeutic antihypertensive vaccines. Here, we review the history of the development of immunotherapies for the treatment of hypertension and discuss the current perspectives in the field. Hypertension is a global public health issue and the most important preventable cause of cardiovascular disease worldwide , 2. AnnuIn the treatment of hypertension, the lack of clinical symptoms is thought to result in poor medication adherence and the cessation of therapy at the patients' own judgment . Poor meImmunotherapeutic approaches for the treatment of hypertension, which are often referred to as “hypertension vaccines,” have the potential to improve health outcomes, reduce healthcare costs, and increase medication adherence because they induce prolonged therapeutic effects and have a low frequency of administration . TraditiIn 1898, Tigerstedt and Bergmann first reported that intravenous injection of extract from rabbit kidney into other rabbits induced an increase in blood pressure , 11.Although the first half of the 20th century produced many new insights into the pathogenesis of hypertension, especially with respect to the RAS, the development of treatments for hypertension was lacking. Early experiments targeted renin for the treatment of hypertension, but few chemical compounds were known to directly and strongly inhibit the function of renin . TherefoHere, we review the history of the development of immunotherapies for the treatment of hypertension  and discIn the 1940s, the first attempts were made to develop an immunotherapy to control hypertension. Page et al. succeeded in reducing blood pressure in hypertensive humans, dogs, and rats by subcutaneously or intramuscularly injecting extracts of pig kidney . In theiIn a subsequent clinical study, vaccination of hypertensive patients with pig renin twice a week for several weeks or months induced the production of anti-renin antibodies in some vaccines but did not induce a reduction in blood pressure . This faAdjuvants were also used to amplify the immunogenicity of homologous renin. Freund's complete adjuvant (FCA) and Freund's incomplete adjuvant (FIA) are commonly used adjuvants in animal research. FIA is essentially paraffin oil containing mannide monooleate as a surfactant, and FCA is FIA with the addition of heat-killed mycobacterium . When a Because the pathogenesis of the autoimmune diseases caused by immunization with renin or AN1792 could not be fully elucidated, the development of renin vaccines was stalled for a long time. However, recently, the use of partial renin peptides has been examined for the development of a safe and effective hypertension vaccine. The active site of human renin is a deep cleft between the N- and the C-terminal domains . Human rSkeggs and colleagues first isolated angiotensin-converting enzyme  in 1956 . In the 5) Ang I vaccine (with Freund's adjuvants) on blood pressure in bilateral-kidney-wrap rabbits but reported that this vaccine did not suppress the pressor response to kidney wrapping [μg of Ang I-TT mixed with aluminum hydroxide at 0, 14, and 28 days induced the highest anti-Ang I antibody titer and suppressed Ang I-induced pressor responses in Sprague Dawley (SD) rats [μg of Ang I-KLH adsorbed on an aluminum hydroxide adjuvant) was evaluated in patients with essential hypertension; it was found that immunization with PMD3117 increased plasma renin and decreased urinary aldosterone, suggesting blockade of the RAS, but failed to decrease blood pressure [In 1970, Johnston et al. first evaluated the effect of an asparaginyl-5-valine  rats . In a suSD) rats . EpitopiSD) rats . In a supressure .5-Ang II coupled to rat albumin together with FCA three or four times at intervals of at least two weeks did not reduce blood pressure but did suppress vasopressor responses against the administration of exogenous Ang II in SD rats [5-Ang II vaccine revealed that it also had suppressive effects on Ang II-induced vasopressor responses in renovascular hypertensive rabbits [In 1968, Oken and Biber reported the antihypertensive effects of an Ang II vaccine: immunization with Val SD rats . Subsequ rabbits  and that rabbits . However rabbits , 44, ren rabbits , 45, or  rabbits .β (AngQβ) reduced blood pressure (systolic blood pressure reduced by up to 21 mmHg) without serious adverse events in SHRs [μg of AngQβ to healthy volunteers elicited anti-Ang II IgG antibodies with no serious adverse events, but most participants showed local adverse events such as erythema, edema, pain, and induration at the injection site [β in hypertensive patients (AngQβ study 1) was conducted and successfully showed that AngQβ has antihypertensive effects [μg of AngQβ, or placebo, at 0, 4, and 12 weeks. The titer of IgG antibodies against Ang II was strongly increased after the second injection in vaccinated subjects, and the half-life of antibody titer after the final immunization was 17 weeks. In the participants given 300 μg of AngQβ, the mean ambulatory blood pressure at 2 weeks after the final vaccination was significantly reduced by 9.0/4.0 mmHg compared with the placebo. In particular, morning blood pressure was markedly lowered by 25/13 mmHg, suggesting that AngQβ has particularly strong efficacy against the morning surge in blood pressure.Virus-like particles (VLPs) are a new immunological approach for the induction of B-cell responses that has been applied to the development of a hypertension vaccine , 48. Bec in SHRs . Thereafion site . In 2008β testing an accelerated treatment regimen with injection of 300 μg of AngQβ at 0, 2, 4, 6, and 10 weeks was conducted (AngQβ study 2). Although the antibody titers induced by this intensive regimen were 5 times those observed in study 1, the reduction in blood pressure (−2.5/−0.9 mmHg) was much lower [β administered following the accelerated treatment regimen , antibody titers were also higher than those observed in study 1 but the reduction in blood pressure was much lower and did not achieve statistical significance compared with placebo. Contrary to expectations, antibody affinity  was lower in studies 2 and 3 than in study 1 [β was discontinued.Next, a phase II study of AngQch lower . In an a study 1 . One posIn 1999, Zelezna et al. demonstrated that immunization against angiotensin II type 1 receptor (AT1R) attenuated the development of hypertension in young SHRs . Their A182, of AT1R is an important part of the Ang II binding pocket [μg of AT1R-KLH in combination with FCA at first administration and FIA at following administrations to SHRs at 4, 6, and 8 weeks of age attenuated the elevation of blood pressure (systolic blood pressure of vaccinated rats −44 mmHg vs. control rats); this attenuation of hypertension was equivalent to that provided by continuous administration of candesartan cilexetil (0.1 mg·kg−1·day−1) and was sustained for 25 weeks after the final immunization [Because the second extracellular loop, especially residue Pheg pocket , we and g pocket –57. Subcg pocket , 56. Sing pocket . In contg pocket . Three dnization .β were also used to develop a vaccine targeting AT1R [β and immunized SHRs with 100 μg of AT1R peptide conjugated to VLP Qβ (ATRQβ-001) in combination with aluminum hydroxide at 6 and 8 weeks of age. ATRQβ-001 vaccination decreased systolic blood pressure by 19 mmHg and attenuated left ventricular hypertrophy [β-001 was sustained for 84 days after the final immunization.VLPs derived from bacteriophage Qing AT1R . Chen etertrophy . The antμg of AT1R-KLH in combination with Freund's adjuvant prevented hypertensive kidney damage caused by NG-nitro-L-arginine methyl ester- (L-NAME-) induced endothelial injury in SHRs at a level equivalent to continuous administration of candesartan cilexetil, whereas no renoprotective effect against L-NAME-induced kidney damage was observed in hydralazine-treated SHRs that had blood pressure controlled to a level almost equal to that of the AT1R-KLH-vaccinated SHRs, indicating that ATR1-KLH vaccination prevents hypertensive kidney damage independent, at least partially, of the vaccine's antihypertensive effects [μg of ATRQβ-001 in combination with aluminum hydroxide reduced blood pressure and concomitantly prevented podocyte injury and renal fibrosis and inflammation, resulting in decreases in urine protein and serum creatinine levels in streptozotocin-induced diabetic SD rats [Recently accumulated evidence has clearly indicated that vaccination targeting the RAS induces not only a reduction in blood pressure but also attenuates hypertensive organ damage, including that in the kidney, heart, brain, and arteries. Previously, we reported that three doses of subcutaneous vaccination with 100  effects . Subsequ SD rats .μg/dose) of Ang II-KLH-conjugate vaccine in combination with Freund's adjuvants prevented cardiac dysfunction and attenuated cardiac fibrosis after myocardial infarction in SD rats [β-001, when subcutaneously injected twice before and three times after the induction of myocardial infarction, attenuated myocardial inflammation and fibrosis in C57BL/6 mice, resulting in improvement of cardiac function and survival [The cardioprotective effects of Ang II vaccine and AT1R vaccine have also been reported. Three subcutaneous immunizations  have also been used in hypertension vaccine development. DNA vaccines have several advantages over traditional vaccines, including prolonged antigen expression, improved stability, and more rapid production . Koriyam6 months . Further6 months . Followiμg of vaccine antigen at one-week intervals induced the production of AT1R-specific serum IgG antibody and attenuated the elevation of systolic blood pressure (−16.8 mmHg vs. control) in SHRs [Streptococcus pneumoniae [Our group created a nasal AT1R vaccine using a nanoparticle-based vaccine delivery system . All pre in SHRs . Intereseumoniae . The conEvidence accumulated over more than half a century regarding the efficacy of therapeutic hypertension vaccines indicates that vaccines targeting the RAS can decrease blood pressure and attenuate hypertensive organ damage. The immunotherapeutic approach has advantages over traditional antihypertensive agents in that it can improve medication adherence; this is because it induces prolonged therapeutic effects and so needs a low frequency of administration. Vaccines against the RAS offer a promising means of reducing the economic burden caused by hypertension and its related disorders while increasing the rate of patients with adequate blood pressure control. Although no vaccine product is clinically approved as a therapeutic vaccine against hypertension, Ang II DNA vaccine is currently under clinical investigation  and expected to be proven its safety and effectiveness. In the near future, the immunotherapeutic approach may result in the development of novel hypertension therapies.


Patients with diabetes are at high risk of developing renal insufficiency and chronic kidney disease (CKD). As a result, screening for CKD is essential in diabetic patients as part of their care. This study investigated the prevalence of renal insufficiency, CKD, and correlates of CKD in diabetic patients attending Integrated Chronic Care Clinics in Neno District, Malawi.2. 8.8%  had CKD based on eGFR of less than 60 ml/min/1.73 m2 measured twice at least 3 months apart. In bivariate analysis, CKD was associated with older age, high systolic blood pressure and lower fasting blood sugar. Despite the low sample size, the study showed a moderately high prevalence of renal insufficiency and CKD in a rural cohort of diabetic patients in Malawi.Of 203 diabetic patients, 148 (73%) were screened for CKD by measurement of serum creatinine and urinary protein between April 2016 and January 2019. 39.2% (n = 58) of the patients had abnormal estimated glomerular filtration rate (eGFR), as estimated by CKD Epidemiology Collaboration formula and/or ≥ 2+ urine protein. 13.5%  of the patients had renal insufficiency based on eGFR of less than 60 ml/min/1.73 m The burden of chronic kidney disease (CKD) is increasing in Africa, in part due to the increased burden of non-communicable diseases (NCDs), in addition to the existing high burden of communicable diseases , 2. AlthDue to differences in geographical areas, study population, definitions of CKD, and laboratory measurements, the prevalence and correlates of CKD in diabetic patients in sub-Saharan Africa varies widely between studies , 3. For In Malawi, the burden of NCDs continues to increase, with the prevalence of diabetes estimated to be as high as 6% in adults aged 15–64 years old , 10. DesRoutine screening for CKD in diabetic patients is a cost effective way of detecting CKD early , allowinDue to differences in prevalence and correlates of CKD in other settings, it is important to investigate prevalence of CKD in Malawi, especially in rural Malawi where no data exists . To fillThis study is a retrospective audit of diabetic patients enrolled in an Integrated Chronic Care clinic in Neno District, Malawi. Neno, located in the southwest zone of Malawi, is a rural and impoverished district, with a population of about 138,000 in 2018 . MedicalThe Integrated Chronic Care clinic manages patients with HIV and/or a chronic NCD(s) , and is currently providing services in all 14 health facilities in Neno District. The clinics, managed by the Ministry of Health with support from a Non-Governmental Organisation called Partners In Health, are free-of-charge for all patients. Patients are followed every 1–3 months by a multidisciplinary team of midlevel providers, nurses and support staff . By JanuAll diabetes mellitus patients aged 18 years and above, enrolled in care for at least 3 months, with at least one visit in 2018, and at least one serum creatinine and/or urine protein result were included. Patients with a pre-existing diagnosis of CKD were excluded from the study.Data was extracted from Neno District’s electronic medical record (EMR), which services all chronic conditions including HIV and NCDs. Clinic encounters in the Integrated Chronic Care Clinic are recorded on the Malawi Ministry of Health hypertension/diabetic master card, a standardised paper-based patient chart. At Neno the clinical information is replicated in the EMR.All clinical and demographic measurements in the Integrated Chronic Care Clinic are protocol based, and these protocols are explained elsewhere . For ser2 and/or urinary protein 2+ or more, measured on two occasions at least 3 months apart. Renal insufficiency was defined as eGFR less than 60 ml/min/1.73 m2 measured on one occasion only. The eGFR was estimated based on serum creatinine using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula without using the factor of race. This formula was chosen as it has demonstrated better prediction of eGFR in Malawian adults in comparison to CKD-EPI with factor of race, Cockcroft-Gault, and Modification of Diet in Renal Disease 4 formulas [CKD was defined using Kidney Disease: Improving Global Outcomes (KDIGO) as an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 mformulas . EGFR waformulas .Demographic characteristics Age (years) and gender .History and clinical encounter measurements Type of diabetes (type 1 or type 2), number of years with diabetes and duration in clinic , most recent fasting blood glucose (FBG) (in mg/dl), diabetes mellitus patients with good FBG , most recent body mass index (BMI) (kg/m2), most recent diastolic blood pressure (DBP) and systolic blood pressures (SBP) (mmHg).Diabetes mellitus co-morbidities Current treatment for hypertension.Several other variables included in our analysis were extracted from routine patient encounters. These variable included:Some variables in our intended analysis had a high degree of missing data and variables that were missing in more than 90% of the participants were not included in the analysis; and these variables included history of smoking and alcohol intake and rare complications like stroke and cardiovascular diseases.All data were extracted to Microsoft Excel 2013 and exported to Stata version 14 for data cleaning and analysis. Missing data were re-collected using both electronic and physical patient charts.Descriptive statistics were used to describe all the variables. Bivariate analysis was used to show differences between patients with and without CKD. For categorical variables, Chi2 test or Fishers exact test were used as appropriate. For continuous variables, t-test were used for normally distributed data and the Mann–Whitney test for non-normally distributed variables. p < 0.05 showed statistical significance.A total of 148 diabetic patients, 16.9% type 1 (n = 25) and 83.1% type 2 (n = 123), were screened for CKD. This represented 73% of the 203 diabetic patients enrolled in care by January 2019 (Table 2), had a mean most recent FBG of 156.6 mg/dl, and median most recent SBP and DBP of 130 mmHg and 83 mmHg respectively. 32.1% (n = 42) and 29.8% (n = 39) had reasonable and strict blood glucose control respectively. Hypertension was the main co-morbidity .The majority of the patients were overweight .The initial median creatinine and eGFR were 0.7 mg/dl (IQR 0.6–0.9) and 96.9 (IQR 77.1–110.5) respectively. 60.8% of patients (n = 90) had normal eGFR, 1.4% n = 2) had stage G1, 25.7% (n = 38) had stage G2, and 12.3% (n = 18) had eGFR stage G3a to stage G5 , and had higher most recent SBP . However, patients with CKD had a lower most recent FBG than patients without CKD . Although not statistically significant, most recent DBP and hypertension diagnosis were higher in the CKD group in comparison to those without CKD. No differences in the other risk factors were observed between the groups.This is the first study to investigate renal insufficiency and CKD in a cohort of diabetic patients attending NCD clinics in rural Malawi. Almost two-thirds of the patients were females and this pattern of higher health service utilization by women is common in Malawi . In MalaThe prevalence of CKD in diabetic patients was about 9%, lower than some recent estimates in Africa. Two recent systematic reviews and meta-analysis report the prevalence of CKD in diabetic patients at 22% and 25% in Africa . HoweverIn this study, increased age and higher SBP were associated with CKD. Other studies have found similar associations with CKD , 29, 30.The study has research and clinical implications. Neno District plans to continue screening for CKD and patients with severe CKD are now enrolled in an advanced NCD clinic for care. Based on findings of this study, diabetes clinics should invest in screening for CKD. Finally, we propose a repeat of the study in rural and urban sites with larger patient cohort to further inform clinical practice and policy.Although the sample size was small, we found moderately high renal insufficiency and CKD, 13.5% and a minimum of 8.9% respectively, in a diabetic cohort attending Integrated Chronic Care clinics in rural Malawi. In bivariate analysis, CKD was associated with older age, high SBP and lower FBG.The study excluded all diabetic patients younger than 18 years, patients that were lost to follow up, and patients that have diabetes and are not getting care in Neno, Malawi.The data quality depended on how accurately the data was recorded in the chart.The study may not be representative of communities in Neno District and other districts of Malawi.The Correlates of CKD chosen for this study depended on the available data and may have excluded other risk factors.The study does not establish the temporal sequence between CKD and diabetes or any of the risk factors.As a facility-based clinical audit that used routinely collected data;


Patients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes. The timing, relative to disease onset, and degree of glycemic control that reduces the risk of adverse cardiovascular events remains uncertain. Coronary microvascular dysfunction is prevalent in patients with type 2 diabetes mellitus and is linked to adverse cardiovascular events. We assessed the association between endothelial-dependent and endothelial-independent coronary microvascular dysfunction and glycemic control in patients presenting with chest pain and nonobstructive coronary disease at angiography.Patients presenting with chest pain and found to have non-obstructive CAD (stenosis < 40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial –dependent microvascular function. Endothelial-independent microvascular function was assessed by comparing the coronary flow velocity, measured using a Doppler guidewire, in response to intracoronary infusion of adenosine to calculate the coronary flow reserve ratio in response to adenosine (CFRAdn Ratio). A CFRAdn Ratio ≤ 2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction defined as a %ΔCBFAch of ≤ 50%. Patients were classified by normal versus abnormal CFRAdn Ratio and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained prior to catheterization and compared between groups.Between 1993 and 2012, 1469 patients  underwent coronary angiography and invasive testing for coronary microvascular dysfunction, of which 129 (8.8%) had type 2 diabetes. Fifty-one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn Ratio. Conventional cardiovascular risk factors and cardiovascular or diabetic medication use did not vary significantly between groups. Females with an abnormal CFRAdn Ratio or abnormal %ΔCBFAch had a significantly higher HbA1c compared to patients with a normal CFRAdn Ratio or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p = 0.035 and 7.3 (1.9) vs. 6.4 (1.2), p = 0.022, respectively. Female patients with an abnormal CFRAdn Ratio had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn Ratio: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p = 0.035. This was not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any coronary microvascular dysfunction both in a univariate and multivariate analysis: odds ratio  1.69 (1.01–2.86) p = 0.049; and a fasting serum glucose > 140 mg/dL was significantly associated with an abnormal CFRAdn Ratio, 4.28 (1.43–12.81).Poor glycemic control is associated with coronary microvascular dysfunction amongst female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting microvascular dysfunction as an integrated index of cardiovascular risk.The online version of this article (10.1186/s12933-019-0833-1) contains supplementary material, which is available to authorized users. Patients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes –3, and dCoronary microvascular dysfunction (CMD) is prevalent in patients with type 2 diabetes mellitus , and is Studies have shown that diabetes is a stronger risk factor for cardiovascular mortality in women compared to men , 21. DifThis retrospective cross-sectional study was approved by the Mayo Clinic Institutional Review Board. Patients were referred to our institution by their physician for assessment of chest pain. All patients were then evaluated by a cardiologist at our institution and those with signs or symptoms suspicious of stable cardiac ischemic as per the clinical assessment of the evaluating cardiologist and/or had an abnormal non-invasive stress test were then referred for a clinically indicated elective coronary angiogram. Patients with the following were excluded: greater than 40% diameter stenosis of any coronary artery; acute coronary syndrome; acute renal failure; uncontrolled hypertension; left ventricular ejection fraction of 50% or less and left ventricular hypertrophy.Consecutive patients presented to the cardiac catheterization laboratory in the fasting state and all cardiovascular medications, including nitrates and calcium channel blockers, had been discontinued for at least 48 h. Routine diagnostic coronary angiography was performed on all patients using standard clinical protocols. Angiograms were reviewed prior to the infusion of any pharmacological agents. In cases where the severity of stenosis was uncertain, online quantitative coronary angiography was used. All patients underwent evaluation of microvascular endothelial-dependent and endothelial-independent coronary flow reserve as previously described , 28. FolBaseline mean peak velocity was recorded using the intracoronary Doppler wire after which intracoronary bolus injections of increasing doses (18–72 µg) of adenosine, an endothelial-independent vasodilator affecting predominantly the microcirculation  was admi−6, 10−5 and 10−4 M  for 3 min at each concentration to assess endothelial-dependent function as previously described [π (mean peak velocity/2)(coronary artery diameter/2)2. The maximal percentage increase in CBF in response to acetylcholine compared to the CBF at baseline was then calculated (%ΔCBFAch). For quality control, all measurements were performed in the segment 5 mm distal to the tip of the Doppler wire and following each infusion, the diameter was measured in the same segment of the vessel [After a 5-min equilibration period, acetylcholine was infused at concentrations of 10escribed –29. Infuescribed , 34. Endescribed , 29: CBFe vessel , 29–31.CMD was defined as the presence of abnormal endothelial-independent coronary microvascular function and/or abnormal endothelial-dependent coronary microvascular function. Impaired endothelial-independent microvascular function was defined as a coronary flow velocity reserve ratio in response to adenosine (CFRAdn Ratio) of 2.5 or less . ImpaireData was collected on conventional cardiovascular risk factors including hypertension, diabetes mellitus, hyperlipidemia, smoking status and body mass index (BMI); biochemical parameters including fasting blood glucose, HbA1c, serum total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides; and medication use including antiplatelet and antihypertensive medication, statins as well as diabetic medication including use of insulin. Diabetes was defined as a documented history of diabetes, for which the diagnostic criteria required at least one of the following: a fasting serum glucose ≥ 126 mg/dL; serum glucose after a 75 g oral glucose tolerance test of ≥ 200 mg/dL after 2 h; a random serum glucose of ≥ 200 mg/dL in conjunction with symptoms of hyperglycemia that may include polydipsia, polyuria, polyphagia, fatigue, and weight loss; or an HbA1c ≥ 6.5% . SmokingPatients with type 2 diabetes mellitus were retrospectively identified and were categorized as having normal versus abnormal endothelial-independent microvascular function measured using the CFRAdn Ratio and normal versus abnormal endothelial-dependent microvascular function measured using %ΔCBFAch. Continuous variables are presented as a mean (standard deviation) where data is normally distributed and as a median  for skewed data. Categorical variables are presented as frequencies (percentages). Differences between groups were analyzed using Student’s T test and Wilcoxon rank-sum test for continuous variables and Pearson’s Chi squared test for proportions. Indices of glycemic control, namely HbA1c and fasting serum glucose concentrations, were compared as continuous variables between patients with normal versus abnormal endothelial-dependent and endothelial-independent microvascular function after stratifying all patients by sex. Univariate and multivariate logistic regression models were then fitted to assess the association between glycemic control and endothelial-dependent and endothelial-independent CMD. Indices of glycemic control included HbA1c and fasting serum glucose concentrations as continuous variables, and an HbA1c > 7% and a fasting serum glucose > 140 mg/dL as categorical variables. These thresholds were used to denote suboptimal glycemic control. Multivariate analyses were adjusted for conventional cardiovascular risk factors which could potentially confound the relationship between glycemic control and CMD and included age, BMI, total cholesterol, and systolic blood pressure at the time of cardiac catheterization as continuous variables, and smoking status as a categorical variable. A p-value less than 0.05 was considered significant and all statistical analyses were performed using JMP 9 software .and abnormal %ΔCBFAch). Table Between 1993 and 2012, 1469 patients  underwent coronary angiography and invasive testing for CMD. One hundred twenty-nine patients had diabetes mellitus (8.8%) all of which were type 2. Patients were retrospectively divided into those with a normal versus abnormal CFRAdn Ratio and normal versus abnormal %ΔCBFAch. Forty-nine (38.0%) patients had an abnormal CFRAdn Ratio . Fifty-one (39.5%) had an abnormal %ΔCBFAch . Additionally, 93 subjects (72.1%) had any CMD , and 34 (26.4%) had both an abnormal CFRAdn Table Figure Table Amongst males, HbA1c was negatively associated with an abnormal %ΔCBFAch with borderline significance: odds ratio  0.67 (0.46–1.00) p = 0.049, though was not significantly associated with an abnormal CFRAdn Ratio. An HbA1c > 7%, and fasting serum glucose, as a continuous variable or as a categorical variable (fasting serum glucose > 140 mg/dL) were not significantly associated with an abnormal CFRAdn Ratio or %ΔCBFAch in diabetic men.Table In the current study we show that CMD is prevalent amongst an unselected population of type 2 diabetics who present with chest pain and non-obstructive CAD at coronary angiography. Patients with endothelial-dependent CMD were significantly older than those with normal microvascular endothelial function, and patients with endothelial-independent CMD were more likely to be female than those with normal endothelial-independent microvascular function. We also showed that HbA1c was significantly higher in females with diabetes who had endothelial-independent and endothelial-dependent CMD, an association not seen in men, and that fasting serum glucose levels were significantly higher amongst females with endothelial-independent CMD. Lastly, amongst females with diabetes HbA1c was significantly associated with endothelial-independent and endothelial-dependent CMD separately, and a fasting serum glucose ≥ 140 mg/dL was significantly associated with endothelial-independent CMD even after adjusting for confounders. These findings suggest a link between glycemic control and functional coronary microvascular abnormalities in females with diabetes, and may implicate CMD as a potential mediator of ischemia in diabetics with suboptimal glycemic control.Patients with type 2 diabetes mellitus are at an increased risk of angina and adverse cardiovascular events compared to those without diabetes –3, and dFurther, observational studies –8 have sIn the current study we showed that cardiovascular medication use, including statins, and vasoactive drugs such as beta blockers, calcium channel blockers, ACE-inhibitors and long-acting nitrates were not significantly associated with endothelial-dependent or -independent CMD. Whether these medications alter coronary microvascular function per se has not been consistently shown, though studies have indicated potential symptomatic value of various cardiovascular drugs in patients with CMD . Thus giDifferences in cardiovascular risk profile between men and women are well established. Women have fewer conventional cardiovascular risk factors compared to men and are more likely to experience cardiovascular events in the absence of obstructive CAD, which may be explained by a higher prevalence of functional vascular abnormalities such endothelial dysfunction and microvascular disease –24. FurtAs to which index of ‘optimal glycemic control’ is most important has remained an area of controversy. The current study shows that linear increments of HbA1c are associated with any CMD. Conversely, fasting serum glucose as a continuous variable was not associated with any dependent variable, but a fasting serum glucose > 140 mg/dL was associated with endothelial-independent CMD. HbA1c is an accepted reliable marker of overall, longer term glycemic control integrating fasting and postprandial states  as well This study has a number of limitations. First, the study population consists of type 2 diabetics presenting with chest pain who were referred for coronary angiography to a tertiary referral center, and so the prevalence, severity and reversibility of CMD may be different to other populations. Further, even though all patients in this study were referred for a clinically indicated coronary angiogram having presented with signs and symptoms suspicious for stable cardiac ischemia based on the clinical evaluation of a cardiologist at our institution, some patients in this group may ultimately have had non-cardiac chest pain as opposed to stable angina. Second, the cross-sectional design of this study makes determining a causal association between glycemic control and CMD not possible and also prevented us from evaluating the impact of temporal changes in glycemic control as well as the incidence of cardiovascular events in patients with type 2 diabetes. Equally we cannot show that CMD is a mechanism for the incidence of cardiovascular events in patients with diabetes, as hypothesized in this study. Thus the current study is hypothesis-generating and this question would be better investigated in prospective clinical trials. Third, some of our findings may be limited by relatively small sample sizes. Fourth, HbA1c and fasting glucose levels were only measured once prior to cardiac catheterization and so may not give a complete picture of glycemic control or the severity of glucose variability that has a strong role in cardiovascular risk in diabetic patients. Similarly, we did not collect data on the duration of diabetes, the presence of diabetic-related complications, or on renal parameters such as urine albumin creatinine ratios, all of which can influence cardiovascular risk and could therefore confound the potential association between glycemic control and coronary microvascular function.Poor glycemic control is associated with CMD in female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex-specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting CMD as an integrated index of cardiovascular risk.Additional file 1: Table S1. Summary of clinical characteristics between patients stratified by sex with normal versus abnormal endothelial-independent and endothelial-dependent microvascular function. Table S2. Summary of medication use at the time of coronary catheterization between patients stratified by sex with normal versus abnormal endothelial-independent and endothelial-dependent microvascular function.


Nutrition is known to exert an undeniable impact on blood pressure with especially salt (sodium chloride), but also potassium, playing a prominent role. The aim of this review was to summarize meta-analyses studying the effect of different electrolytes on blood pressure or risk for hypertension, respectively. Overall, 32 meta-analyses evaluating the effect of sodium, potassium, calcium and magnesium on human blood pressure or hypertension risk were included after literature search. Most of the meta-analyses showed beneficial blood pressure lowering effects with the extent of systolic blood pressure reduction ranging between −0.7  to −8.9 (−14.1 to −3.7) mmHg for sodium/salt reduction, −3.5 (−5.2 to −1.8) to −9.5 (−10.8 to −8.1) mmHg for potassium, and −0.2 (−0.4 to −0.03) to −18.7 (−22.5 to −15.0) mmHg for magnesium. The range for diastolic blood pressure reduction was 0.03 (−0.4 to 0.4) to −5.9 (−9.7 to −2.1) mmHg for sodium/salt reduction, −2 (−3.1 to −0.9) to −6.4 (−7.3 to −5.6) mmHg for potassium, and −0.3 (−0.5 to −0.03) to −10.9 (−13.1 to −8.7) mmHg for magnesium. Moreover, sufficient calcium intake was found to reduce the risk of gestational hypertension. Hypertension is the major leading risk factor for atherosclerosis and several diseases, especially renal and cardiovascular disorders, including myocardial infarction, stroke, and heart failure . Blood pIn addition to the blood pressure lowering effects of sodium reduction or higher potassium intake also in several studies and meta-analyses calcium supplementation has been shown to exert beneficial effects on the risk for gestational hypertension ,9, especFurthermore, from the electrolytes, magnesium is also effective in reducing blood pressure, especially by acting as a natural calcium channel blocker, increasing nitric oxide levels and improving endothelial dysfunction ,11.Early studies from the 1980s suggest that also chloride has an independent effect on blood pressure (reviewed in ). In the2S), it exerts antihypertensive effects in experimental models  for highest versus lowest category of calcium intake .Most of the meta-analyses showed that calcium supplements were associated with a reduced risk of gestational hypertension . Besidesn = 5) and observational studies (n = 3) were included to summarize the effects of magnesium on blood pressure or association with hypertension risk, respectively [Eight meta-analyses of randomized control trials  reduction and a higher intake of potassium have convincing blood pressure lowering effects. In addition, higher magnesium intake is suggested to possibly reduce blood pressure, especially in patients with hypertension. Moreover, sufficient calcium intake confers a protective effect regarding the risk for gestational hypertension. There are several mechanistical explanations for the association between high sodium intake and blood pressure like enhanced reabsorption and retention of filtered sodium through the renal tubules , or actiIn addition to blood pressure, in a recent systematic review and meta-analysis of randomized controlled trials it was analyzed that restriction of dietary sodium intake can reduce arterial stiffness, as expressed by carotid-femoral pulse wave velocity .In addition to sodium modification, several studies and meta-analysis showed that potassium supplements reduce blood pressure and also the risk of hypertension . Suggest2+ by inhibiting transmembrane calcium transport and calcium entry with low magnesium levels causing an increase in intracellular free Ca2+ concentration and subsequently vascular contraction [Besides the interdependent effect of sodium and potassium, calcium and magnesium have also been implicated in the regulation of blood pressure . Based otraction . On the other hand, low dietary calcium intake is shown to be a risk factor for the development of hypertension especially for women with a history of gestational hypertension . In thisLifestyle modifications including weight loss, exercise, and healthy diets are proved to be important predictors to lower blood pressure or the risk for hypertension, respectively. For example, the Canadian hypertension education program guidelines (2016) proposed health behavior management for the prevention of hypertension such as physical exercise, weight management, limited alcohol consumption, stress management, reduce sodium intake and recommended dietary modification as the preferred method of increasing potassium intake  to get additional nutritional benefits of whole foods over prescribed supplements . SimilarOur brief exploration of meta-analyses showed that lowering sodium and increasing potassium intake would exert convincing blood pressure lowering effects, especially in hypertensive patients. The maximum extent of systolic blood pressure lowering was approximately in the order of 8 to 9 mmHg, which roughly equals a monotherapy with an antihypertensive drug . This reWe did not find any meta-analyses summarizing the effects of chloride, phosphorus and sulphur on blood pressure or hypertension risk. In general, few studies are available, which assessed the effect of these electrolytes on blood pressure. There are indications from observational studies that there might be some effects, however robust evidence is missing. For example, a very recent systematic review from McClure et al. (2019) did not detected a consistent association between total dietary phosphorus intake and blood pressure .Relating to earlier studies replacing the chloride component of salt with other anions like bicarbonate or citrate might be a certain strategy, which could not only beneficially affect blood pressure but could show co-benefits regarding a (western) diet induced metabolic acid load . Obvious


To compare the efficacy of oral Labetalol versus oral Nifedipine for the treatment of postpartum hypertension.A prospective randomized controlled trial with parallel assignment was conducted in the department of Obstetrics and Gynecology, Dow University of Health Sciences Karachi, Pakistan, 124 patients with post partum hypertension were selected and randomized into two groups with 62 patients receiving Labetalol and 62 receiving long acting nifedipine. Initial blood pressures were recorded, and the respective drug was administered. Dose adjustments were performed in the initial 24 hours. The outcome was measured in the form of drug efficacy by lowering of systolic blood pressure less than 140mm of Hg and diastolic less than 90mm of Hg up to 48 hours after starting treatment. Data was entered and analyzed through SPSS version 20.Our study randomized 62 women to oral labetalol and 62 women to oral long acting nifedipine. The time required to achieve blood pressure control was 35.6±2.8 hours in labetalol group and 30.4±1.9 hours in nifedipine group (p=0.04).length of hospital stay, need of additional antihypertensive medications were same in both groups. Minor side effects were observed more in nifedipine group.We conclude that both oral labetalol and oral long acting nifedipine are effective and well tolerated interventions for the management of post-partum hypertension. However we found Nifidipine more effective in the management of postpartum hypertension. Hypertension complicates 6 – 10% of all Pregnancies and is a major cause of maternal morbidity and mortality.7Available pharmacological interventions for treatment of post-partum hypertension include intravenous hydralazine, intravenous or oral labetalol, nifedipine as short acting and extended long acting preparations, amlodipine and ACE inhibitors. NICE recommends that due to side effects of associated sedation, postural hypotension and depression methyldopa should be switched to an alternative agent in the post-partum period, although it was considered as the preferred drug in breast feeding mothers.13In our limited resourced healthcare setting we see a large number of women with hypertension during pregnancy or in the postpartum period. In these patient’s oral labetalol and oral extended release or long acting nifedipine would be the most convenient medications for management of post-partum hypertension. The aim of our study was to evaluate the efficacy of oral labetalol versus oral nifedipine for the management of post-partum hypertension.A prospective randomized controlled trial with parallel assignment was conducted in the Department of Obstetrics and Gynecology, Dow University of Health Sciences Karachi, Pakistan, between January, 2015 and December, 2015. The trial was registered at clinical trial.gov. registration no. NCT02426177.All women with any parity and age, who delivered at ≥20 weeks of pregnancy with persistent post-partum hypertension defined as systolic blood pressure (SBP) blood pressure of ≥ 150mmHg and/or diastolic blood pressure (DBP) of ≥100mmHg requiring an antihypertensive medication were included in the study. Eligible patients had persistent hypertension following gestational hypertension, pre-eclampsia, or had denovo post-partum hypertension without previous history. Exclusion criteria were women with a history of heart block or arrhythmias, heart failure, asthma, uncontrolled diabetes, hypothyroidism, chronic hypertension with history of other pre-pregnancy antihypertensive medication intake, renal disease with Serum Creatinine level >1mg/dl, those with allergies to either nifedipine or labetalol and those not willing to participate in the study.Eligible candidates provided written informed consent at enrollment and the study protocol was approved by the Dow University of Health Sciences Institutional Review Board. (Ref. No. IRB-S41/DUHS/-14).Participants of the study were randomized into two groups (1) labetalol and (2) long acting nifedipine. The study was not blinded due to different types of medications and their dosage schedule. However, the selection of drug was blinded as the patients enter the study after randomization. Envelopes with drugs were numbered consecutively and sealed and jumbled up, half containing labetalol and the other half containing nifedipine. The envelops were used in patients as they entered the study after simple randomization. The Patients initial blood pressure was recorded using a mercurial sphygmomanometer and the drug assigned to that patient was given. Serial blood pressure measurements were done hourly for six hours and then four hourly till 24 hours. Labetalol was initiated 100mg per orally Q1D and increased to 1200mg as needed to control blood pressure. Nifedipine long acting (nifedipine LA 30mg) was given 30 mg per orally once daily and increased to 90mg daily as needed to control the blood pressure. If blood pressure was not controlled with the maximum dose of one medication, the other medication was added at the lowest starting dose and incremental doses given accordingly till the desired blood pressure was achieved. Desired blood pressure taken as adequate control was systolic blood pressure below 150mmHg and diastolic blood pressure between 80 and 100mmHg. Additional medications as intravenous antihypertensive and magnesium sulphate for seizure prophylaxis were used as required on an individual patient according to decision of managing team.The primary outcome measure was drug efficacy in terms of time required to achieve blood pressure control (SBP < 150mmHg and DBO between 80 – 100mmHg), and sustained blood pressure control defined as absence of spikes of severe hypertension (SBP≤160mmHg &/or DBP ≤ 110mmHg) for at least 72 hours. Secondary outcome measures include the need of additional antihypertensive medications, length of hospital stay and drug related side effects.Baseline demographic data including age, parity, BMI family history of hypertension, mode of delivery were collected and recorded for all participants.Using open Epi method, the sample size was calculated with the efficacy of labetalol and nifedipine set to 81% and 58% respectively.Intention to treat analysis was performed and t-tests or analysis of variance were used for continuous variables and chi-square tests for categorical variables. Data was analyzed using IBM SPSS Version 20. P<0.05 was considered statistically significant.A total of 124 women were included in our study. Sixty-two women were randomized to the oral labetalol group and 62 to the oral long acting nifedipine group. The women ranged from 18 - 48 years of age. Baseline maternal characteristics were similar in both groups in terms of age, parity, body mass index and family history of hypertension. Vaginal delivery and cesarean section rates were also similar in two groups. .Women in both groups completed the study. The time required to achieve blood pressure control was 35.6 ± 2.8 hours in the labetalol groups and 30.4 ± 1.9 hours in nifedipine group (p=0.041) indicating nifedipine achieved control earlier that labetalol. Similarly, blood pressure control was maintained more effectively with initial starting dose for next 72 hours in the nifedipine group compared to the labetalol group. Labetalol group required more dose increments from 100mg QDS starting dose compared to the 30mg OD nifedipine starting dose. (p=0.001) . The neeth postnatal day for uncontrolled hypertension and received an ACE inhibitor for blood pressure control.In the labetalol Group-4 patients required the addition of nifedipine to control blood pressure and in the nifedipine group, three patients required the addition of labetalol once maximum drug dose was given. 58 women in labetalol group and 59 in the nifedipine group were discharged on the single agent treatment regimen initially started. The mean hospital stay was 3.5 ± 1.3 days for the labetalol group and 3.4 ± 1.5 days for the nifedipine group. Twelve women in labetalol group and 10 in in nifedipine group required one or two doses of intravenous antihypertensive drug for initial control of severe hypertension ≥ 160 / 110 mmHg. , but latNo major side effects were observed in either group. One woman in labetalol group had bronchospasm which was managed adequately. Headache, hypotension and palpitations were common side effects noted with nifedipine. .Our study compared oral labetalol and oral long acting nifedipine for the treatment of post-partum hypertension. We found that both interventions are effective in achieving good blood pressure control with the starting dose. However, oral nifedipine achieved control earlier than oral labetalol in our study. Side effects were found to be lower in women who were given labetalol than those given nifedipine. Both drugs have minimal excretion in breast milk.18Previously conducted trials compared the efficacy and safety of oral nifedipine and intravenous labetalol, hydralazine and methyldopa and found these medications effective.23Both studies reported no major side effects related to either drug.23The need for additional intravenous antihypertensive intervention for acute blood pressure control was nearly the same in both groups, as also noted in the study by Sharma et al.24A limitation of our study was the small number of patients and a difficulty in arranging post-discharge follow up. As a result, we cannot draw any conclusions regarding long-term management of women on either oral labetalol or nifedipine for post-partum hypertension. However, we present the first study where oral agents labetalol and nifedipine are used for the management of post-partum hypertension in a developing, resource-poor country. In addition, both patients and researchers were blinded to medication selection.We conclude that both oral labetalol and oral long acting nifedipine are effective and well tolerated interventions for the management of post-partum hypertension. However, nifedipine may be slightly superior due to earlier blood pressure control achieved and easier administration with once daily oral use.Oral agents are particularly appropriate in the out-patient setting of resource constrained institutions with busy delivery suites of public hospitals in developing countries. Hypertensive disorders of pregnancy and related complications can be a major cause of maternal morbidity and mortality in these settings. The use of oral labetalol and nifedipine for the management of post-partum hypertension reduces the risk of hypertensive complications and the burden of maternal morbidity and mortality.JAA: Designed the study, Data Analysis, Manuscript Writing.FJ: Literature search, Data collection, Data Analysis.SK: Data Collection, Manuscript Writing.


Objective: The objective of this study is to investigate the relationship between blood pressure changes and all-cause mortality, and between blood pressure changes and cardiovascular mortality, for maintenance hemodialysis (MHD) patients during dialysis.Methods: Data regarding general condition, biochemical indices, and survival prognosis of MHD patients who were treated at the Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital from July 2007 to December 2012 were collected, in order to evaluate the relationship between patients’ blood pressure changes during hemodialysis and mortality.Results: Among 364 patients, with an average age of 63.07 ± 13.93 years, an average dialysis vintage of 76.00  months, and a follow-up time of 54.86 ± 19.84 months, there were 85 cases (23.4%) of all-cause death and 46 cases (14.2%) of cardiovascular death. All-cause mortality and cardiovascular mortality were lowest  in patients whose systolic blood pressure difference (ΔSBP) before and after dialysis was between 7.09 and 14.25 mmHg. Kaplan–Meier analysis indicated that both all-cause mortality and cardiovascular mortality were markedly increased for patients with ΔSBPless than −0.25 mmHg . Cox regression analysis showed that ΔSBP< −0.25 mmHg, hemoglobin concentration, Kt/v  and albumin were independent risk factors for all-cause mortality in MHD patients.Conclusions: MHD patients whose blood pressure increased significantly after hemodialysis had a higher risk of dying; ΔSBP, hemoglobin concentration, Kt/v and albumin were independent risk factors for all-cause mortality in MHD patients. Mortality in maintenance hemodialysis (MHD) patients is high, especially cardiovascular mortality, which is 3–10 times higher than in the general population.Studies have shown that, for the non-dialysis population, blood pressure variability is a risk factor for cardiovascular events, stroke, and left ventricular hypertrophy.Four hundred and two patients, who were registered in the Shanghai Dialysis Registration System and have received ≥3 months of MHD treatment at the Shanghai Jiao Tong University Medical School-affiliated Renji Hospital from 1 July 2007 to 31 December 2012, were selected. Thirty-eight of them were excluded due to incomplete registration data, and the remaining 364 patients were included in the study.Patients’ demographic and clinical data were collected, including gender, age, height, dry weight, dialysis vintage, blood pressure before and after dialysis, biomedical indices, etc. All patients were treated with bicarbonate dialysis fluid and F80  or REXEED  polysulfone membrane dialyzer. The dialysis was conducted 2–3 times a week, lasting 4–5 h each time (10–12 h/week) with 200–350 ml/min blood flow. Filtration volume was exceeded every time, in order to reach clinical dry weight.2+), phosphate (P3+), intact parathyroid hormone (iPTH), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL), cholesterol, albumin (Alb), hemoglobin (Hb), and high-sensitivity C-reactive protein (hsCRP), were tested, and Kt/v were calculated for all patients.(1) Blood biochemical indices, including average values of corrected calcium (Ca(2) Blood pressure was recorded for all patients before and after hemodialysis at first hemodialysis of every season. Average value, standard deviation, and variation coefficient of SBP and DBP, average arterial pressure, ΔSBP[ΔSBP = SBP−SBP] and ΔMBP[ΔMBP = MAP−MAP] were also calculated.25); Group II: second quartile (P25≤ΔSBP < P50); Group III: third quartile (P50≤ΔSBP < P75); and Group IV: fourth quartile (ΔSBP ≥ P75). General conditions of patients in the four groups were compared with each other.Patients were divided into four groups, based on their relative ΔSBP level: Group I: first quartile  software  was used for statistical analysis. Normal distributed measurement data were represented by mean ± standard deviation, and the Bonferroni test was used for pairwise comparisons among groups. Measurement data that were not normally distributed were represented by median and quartile, and the Mann–Whitney Three hundred and sixty-four patients, 221 (60.7%) male, with an average age of 63.07 ± 13.93 years and an average dialysis vintage of 76.00  months, were selected. There were 85 cases (23.4%) of all-cause death and 46 cases (14.2%) of cardiovascular death , the risk of all-cause death for patients in Group II (−0.25 mmHg ≤ ΔSBP <7.09 mmHg) and Group III (7.09 mmHg ≤ ΔSBP <14.25 mmHg) was significantly lower. After correcting for age, gender, dialysis age, general individual conditions, and biochemical indices, the difference was still statistically significant. For patients in Group IV (ΔSBP ≥14.25 mmHg), the risk of all-cause death decreased by 25.2% compared with Group I (ΔSBP< −0.25 mmHg), but there was no statistically significant difference between the two groups see . Among tp = .001); hemoglobin concentration ; and Kt/v ; albumin .The primary outcome of the study was death from any causes . COX regression analysis showed that the following factors were independently associated with all-cause mortality in MHD patients: ΔSBP> −0.25 mmHg . Compared with patients in Group I (ΔSBP < −0.25 mmHg), the survival rate of cardiovascular death for patients in Group II (−0.25 mmHg ≤ ΔSBP <7.09 mmHg), Group III (7.09 mmHg ≤ ΔSBP <14.25 mmHg), and Group IV (ΔSBP ≥14.25 mmHg)was significantly higher . Among the patients who died of all-cause death, the survival rate was higher in Group III (7.09 mmHg < ΔSBP <14.25 mmHg) compared with Group I (ΔSBP < −0.25 mmHg) (p = .005). The difference was no statistically significant among Group II, Group IV, and Group I . This indicates that patients with higher SBP after hemodialysis had lower survival rate (see Kaplan–Meier analysis showed that, for patients with ΔSBP < −0.25 mmHg, all-cause mortality and cardiovascular mortality were all significantly higher than for those in the other three groups (Blood pressure increase or decrease frequently occurs among patients during hemodialysis. Physicians usually pay attention to the development of hypotension and other complications occurring during hemodialysis, while the significance of blood pressure increase or moderate decrease during dialysis is easily overlooked. In this study, 364 MHD patients were investigated, and the results showed that patients with ΔSBP< −0.25 mmHg during dialysis had higher mortality, while those patients whose SBP moderately decreased had a higher survival rate.The increase in SBP during hemodialysis was closely related to the increase in mortality, and SBP is increased in about 10–15% of patients after dialysis, according to some studies.,Blood pressure after dialysis compared with blood pressure before dialysis can be used to estimate cardiac stress during dialysis.,Large decreases in SBP or DBP during hemodialysis can also increase mortality, while patients with moderate decreases have a higher survival rate, according to previous studies.However, this study has certain limitations. First of all, it analyzed the relationship between survival and blood pressure decrease after dialysis, the extent of blood pressure decrease, and blood pressure increase after dialysis. Since the lowest blood pressure of patients might be lower than the blood pressure measured immediately after dialysis, the blood pressure value after dialysis may not accurately represent the impact of the lowest blood pressure during dialysis on patients’ survival. Moreover, blood pressure after dialysis might be influenced by multiple potential confounders. In addition, the use of antihypertensive drugs was not taken into account in this study, and the potential effects of various antihypertensive drugs on patient survival were not studied. Furthermore, this study did not consider the impact of residual renal function.To summarize, SBP changes before and after dialysis in MHD patients were closely related to both all-cause and cardiovascular mortality. Patients with moderate decreases of blood pressure after dialysis had a higher survival rate, while patients whose blood pressure decreased less than 0.25 mmHg or increased after dialysis compared with that before dialysis demonstrated significantly decreased rates of survival. Consequently, blood pressure changes occurring during dialysis could be used as a treatment target to improve the prognosis for MHD patients. However, the results of this study should be verified by prospective, randomized, controlled studies involving a large number of patients.


Evidences suggest that central hemodynamics indexes are independent predictors of future cardiovascular events and all-cause mortality. Multiple factors have been pointed to have potential influence on central aortic function: height, heart rate, left ventricular ejection duration and blood pressure level. Data related to the influence of gender and postmenopausal status on aortic waveform reflection is scarce. We aim to evaluate the impact of gender and menopause on central blood pressure of hypertensive patients.In a cross sectional study 122 hypertensive patients (52 men and 70 women) were studied. Hypertension was defined as blood pressure (BP) levels ≥140/90 mmHg or use of antihypertensive drugs. Central arterial pressure, augmentation index (AIx) and augmentation index normalized to 75 bpm (AIx75) were obtained using applanation tonometry. Menopause and postmenopause history were accessed by a direct series of questions. Postmenopause was defined as at least one year since last menstruation. Patients were paired by age, gender and menopausal status, and the data were compared considering gender and menopausal status.p < 0.01), AIx75  and central systolic blood pressure  were higher in women than men. The menopausal women (mean age of menopause = 48 years) had the worst indexes of aortic wave reflection, compared to men at the same age and younger women.Height and weight were significantly lower in women than in men at the same age. Conversely, AIx (32.7 ± 9.8% vs. 20.1 ± 11.7%, Hypertensive women had both higher reflected aortic pressure waveform and central blood pressure indexes than hypertensive men, and these findings were worsened by the menopausal status. Multiple factors have potential influence on large arteries functional properties: height [Evidences suggest that central hemodynamics indexes are independent predictors of future cardiovascular events and all-cause mortality. Central pressures do not exactly correspond to brachial pressures because of pressure pulse amplification from the aorta to the peripheral arteries . Compare: height , 3, hear: height  and bloo: height . HoweverWe enrolled 122 (52 men and 70 women) patients from approximately 468 individuals screened for this cross-sectional study. Patients from the Hypertension Unit of the Heart Institute of University of São Paulo (Brazil) were consecutively recruited from June 2013 to June 2015.The local ethics committee approved the protocol, and all participants agreed and signed the Informed Consent Form. The vascular evaluation was performed in the clinical research laboratory at the Heart Institute, room temperature controlled between 22 °C and 24 °C.Menopause and postmenopause history were assessed by a direct series of questions . Postmenopause was defined as at least one year since last menstruation . BecauseBrachial systolic and diastolic blood pressure was measured using the Omron automatic device (HEM-705 CP model), on the arm with the highest BP, after 5 min of resting. The mean of 3 measurements with a 1-min interval between each one was obtained for both systolic and diastolic blood pressure (SBP and DBP) according the recommendations of the VI Brazilian Guidelines on Hypertension. Hypertension was defined by SBP ≥ 140 mmHg and/or DBP ≥ 90 or use of antihypertensive drugs [The assessment of arterial pulse wave components was performed by a non-invasive applanation tonometry of radial artery a SphygmoCor device . Radial artery pressure waveforms were recorded in the left wrist using a pencil-type high-fidelity micromanometer . The reliability and reproducibility of this technique has been previously reported –10. The Carotid measurements were obtained in the right common carotid artery by a 7.5 MHz linear array probe 1 cm below the bifurcation at the site of distal wall. Carotid diameter and distension were recorded using a high-resolution echo-tracking system , which is based on a radio-frequency signal analysis previously validated and used in different clinical studies , 13. BriData were analyzed with SPSS software . Data distribution was determined using the Kolmogorov–Smirnov test. Continuous variables are presented as mean and standard deviation and were analyzed by the independent-samples t test and Mann–Whitney U test, when suitable. Categorical data are presented as percentages and analyzed by Chi-square test. An ANOVA test was used with Bonferroni post hoc comparisons to analyze differences between gender and age groups. The AIx, AIx 75 and brachial SBP were adjusted for height and weight and analyzed by an ANCOVA test. Pearson’s coefficient was used for bivariate correlations. Statistical significance was set at 5%.p < 0.01), AIx75  and central systolic blood pressure , respectively. There was a negative correlation between radial AIx  and AIx75  with the height of patients.In a cross-sectional study we evaluated 122 hypertensive patients. The average duration of hypertension was 9.99 ± 7.9 years and 47.1% had BP levels under control (< 140/90 mmHg). The Fig. p < 0.01) and AIx75  between women and men were maintained even after adjustment for height, weight and SBP. There were no differences among the groups according to hypertension duration and blood pressure level.Differences in AIx  and the lowest AIx75 (14.5 ± 6.98) than all other groups respectively: young women (25.4 ± 7.87), older men (21.8 ± 8.53) and older women (30.9 ± 6.57). Conversely, young women (group 2) had both AIx and AIx75 comparable to older men group . When all groups were compared, the menopausal women (group 4) had the worst indexes of aortic wave reflection (AIx: 34.9 ± 9.77 (group 4) vs. 16.5 ± 9.93 (group 1), 27.3 ± 8.74 (group 2), 23.2 ± 12.4 (group 3), p = < 0.01 and AIx75: 30.9 ± 6.57 (group 4) vs. 14.5 ± 6.98 (group 1), 25.4 ± 7.87 (group 2), 21.8 ± 8.53 (group 3), p = < 0.01) .Menopause was registered in 70% of women. Young men (group 1) had lower AIx than both young group 2) and older women (group 4)   had the lowest carotid diameter (6.68 ± 0.74 vs. 7.37 ± 0.69 (group 1), 7.49 ± 0.63 (group 3), 7.38 ± 0.92 (group 4), Concerning the use of antihypertensive drugs that could possibly interfere in central aortic pressures, including beta-blockers, no significant differences were observed among the four groups.The main finding of our study is that indexes related to an increase of wave reflection, radial AIx and AIx75, were higher in women than in men with hypertension, even after adjustments for the main recognized variables related to reflected waves as body height, weight and brachial SBP. Furthermore, postmenopausal women showed the highest indexes, compared to men at the same age or younger women.Arterial wave reflection originates from every branching of arterial vessels. The aortic length matches with body height, thus arterial wave reflection occurs later in taller individuals , 15. TheGatzka et al.  studied It has been demonstrated an increase in left ventricle pulsatile afterload  and chanEvidence have shown that menopause has a negative influence on atherosclerotic risk factors  and amplThe cross-sectional nature of this trial does not allow us to evaluate whether menopause has a direct role on aortic wave reflection and central blood pressure. Also, the patients were not submitted to echocardiogram, so correlations between left ventricular function and reflection indexes were not possible to evaluate. We did not have information about hormone replacement in postmenopausal women. Our study was carried out in a selected group of patients with hypertension referred to a tertiary hospital, limiting the application of our findings to other populations.Hypertensive women had an increased reflected aortic pressure waveform and a higher central blood pressure than men at same age. Postmenopausal hypertensive women had the highest values of indexes related to increased wave reflection. These findings highlight the influence of gender and the possible role of menopause on arterial stiffness.


Patients with chronic conditions, such as heart failure, swim regularly and most rehabilitation exercises are conducted in warm hydrotherapy pools. However, little is known about the acute effects of warm water immersion (WWI) on cardiac haemodynamics in patients with chronic heart failure (CHF).Seventeen patients with CHF  and 10 age-matched normal subjects were immersed up to the neck in a hydrotherapy pool (33–35 °C). Cardiac haemodynamics were measured non-invasively, and echocardiography was performed at baseline, during WWI, 3 min after kicking in the supine position and after emerging.p < 0.001), cardiac output  and cardiac index  with decreased systemic vascular resistance  and systolic blood pressure . The haemodynamic changes persisted for 15 min of WWI. In normal subjects, compared to baseline, WWI increased SV , CO  and CI .In patients with CHF, compared to baseline, WWI caused an increase in left atrial volume , without any changes in left ventricular size or function or amino terminal pro B-type natriuretic peptide.In patients with CHF, compared to baseline, WWI immediately increased stroke volume   Exercise training is recommended for patients with chronic heart failure (CHF) –4, not oWhether swimming is safe in patients with CHF has not been answered comprehensively in previous studies of water immersion or swimming . When noThe aim of the present study was to assess the acute hemodynamic, echocardiographic and amino terminal pro B-type natriuretic peptide (NTproBNP) changes during warm water immersion (WWI) in patients with CHF.Ambulatory patients with an established diagnosis of CHF, on stable treatment for more than 3 months were enrolled from a community heart failure clinic. Patients with severe symptoms (NYHA class IV), weight over 120 kilograms, hospitalised within last 6 weeks or with a contraindication to WWI  were excluded from the study. Controls were normal subjects, over 60 years of age, who were already consented to take part as healthy volunteers in a local observational research program. Normal subjects had to have a left ventricular ejection fraction (LVEF) ≥ 50% on echocardiography.The research conforms to the Helsinki declaration and ethics approval was granted by an external research ethics committee. The trial was registered on the ClinicalTrials.gov website (Identifier: NCT02949544) and all participants gave their written informed consent.The study was conducted in a hydrotherapy pool on the hospital site. The pool temperature was maintained between 33 and 35 °C and the outside temperature was maintained at 21 °C. A metal bed designed to be immersed in water was attached to a manual hoist fixed next to the pool. Participants remained in supine position on the bed throughout the study and the patients were immersed and removed from the water using the hoist.  were conducted after participants were comfortable on the bed for 10–15 min. A non-invasive haemodynamic monitoring device  was used to continuously monitor cardiac haemodynamics. This device has been validated against invasive methods of monitoring cardiac haemodynamics in studies of patients with heart failure and critically ill patients –18. An iThe participants were then gradually immersed up to their neck into the hydrotherapy pool in supine position. Echocardiography was repeated at 1 and 15 min following WWI with the ultrasound probe covered with a light polythene bag to ensure it remained water proof. After 15 min of WWI, the participants were asked to perform gentle exercise (3 min of kicking at an speed of 40 repetitions per minute) whilst remaining in supine position on the bed. The exercises performed was hip extension and flexion with a straight leg. At the end of 3 min of exercise, echocardiography was repeated. Once all the echocardiographic and haemodynamic readings were recorded the participants were lifted out of the water. Haemodynamic readings, symptom scores, blood sample for NTproBNP and echocardiography were repeated whilst participants remained in supine position on the bed 3 min after emerging from the hydrotherapy pool.All the electric devices used were checked by University engineers to ensure they were safe for use near water. Additional circuit breaking sockets were installed in case of any power surges or short circuits.From the non-invasive haemodynamic and central venous pressure monitoring devices, the following variables were recorded at baseline, 1 min WWI, 15 min WWI, 3 min after exercise and after 3 min recovery: heart rate (HR), blood pressure (BP), stroke volume (SV), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR) and central venous pressure. An average of five measured values for each haemodynamic variable was taken. All echocardiographic exams were performed by the lead cardiac sonographer in the Department of Academic Cardiology (AB), subsequently stored on DVDs, and finally reviewed off-line by a single experienced operator blind to the various phases of the study (PS).The following echocardiographic variables were measured: left ventricular end diastolic (EDV) and end systolic volumes (ESV), left ventricular ejection fraction (LVEF), left atrial diameter (LAD) and volume (LAV) tricuspid annular plane systolic excursion (TAPSE), systolic tricuspid regurgitation (TR) pressure gradient, inferior vena cava (IVC) diameter. Patients’ modified Borg score, Canadian cardiovascular society angina grading scale, fatigue symptom inventory symptom scores were taken at baseline and recovery.p < 0.05 (two tailed).Categorical data are presented as numbers and percentages; normally distributed continuous data as mean ± standard deviation (SD) and non-normally distributed continuous variables as median and interquartile range. The repeated measures ANOVA was used to assess the overall difference between related means of each variable and the Bonferroni correction was used for multiple testing errors. Log transformation of NTproBNP was used, given its not normal distribution. Primary and secondary endpoints are shown in graphs. All analyses were performed on SPSS (V.23.0), and statistical significance was assumed at Baseline characteristics of patients with CHF and normal subjects are shown in Table In patients with CHF, and compared to baseline measurements, WWI caused a significant, immediate (1 min) and sustained (after 15 min) increase in SV, CO, CI and decrease in BP and SVR, with no change in HR or CVP. The 3 min of kicking led to a further increase in HR, BP, CI and CO, with no change in SV, SVR or CVP Figs. , 3.In normal subjects, WWI caused a significant, immediate (1 min) and sustained (15 min) increase in SV, CO and CI with no change in HR, BP, SVR or CVP. The 3 min of kicking led to an increase in HR, CO and CVP with no change in BP, SV, CI or SVR Figs. , 3.In patients with CHF, WWI for 15 min led to a significant increase in LAV. The 3 min of kicking led to an increase in estimated pulmonary artery systolic pressure Figs. , 5.In normal subjects, WWI for 15 min significantly increased left ventricular EDV. There were no significant changes in echocardiographic variables after 3 min of kicking Figs. , 5.p = 0.21] or normal subjects . None of the subjects experienced any adverse events during water immersion. None of the patients reported any change in any symptom  during immersion or recovery.There was no significant difference in NTproBNP levels between baseline and recovery in patients with CHF [558 (IQR: 323–1140) to 642 (IQR: 309–1187) ng/L, We found that WWI in patients with CHF increases cardiac output. The mechanism for the haemodynamic changes is presumably that hydrostatic pressure increased cardiac preload and atrial volumes. WWI caused systemic vasodilation, leading to a fall in blood pressure which, in turn, causes a decreased left ventricular afterload.E/A ratio), with no effect on blood pressure [Our results are similar to those reported by other researchers. In a study of nine patients with CHF, WWI (34 °C) up to the xiphoid process increased central venous pressure, and as in our study, increased left atrial diameter (by echocardiography), CI and SV index with a decrease in SVR . In a stpressure . 5 min opressure . Similarpressure .All the previous studies of WWI on cardiac haemodynamic had patients in sitting or standing positions during WWI. We positioned the participants in supine position because this better replicates the posture during swimming –24.Warmer or colder water temperatures might lead to more pronounced, or different effects, on cardiac haemodynamics and heart function. Hot water immersion (41 °C) for 10 min significantly decreased left ventricular and atrial size, increased LVEF and decreased mitral regurgitation in a study of 34 patients with CHF and severe symptoms . The changes persisted for 30 min after emerging from water , 27.Swimming is a popular form of exercise in the United Kingdom . WhetherIn previous studies, warm water immersion up to the neck in standing position for 5–10 min, has increased central venous pressure , 31. We Our study was conducted in a controlled, indoor thermoneutral hydrotherapy pool, and therefore, the results cannot be translated to swimming in different environmental conditions. The studied population was small, and patients had only mild symptoms; thus, results of this study cannot be generalised to all patients with CHF, particularly to those with more severe disease. Although majority of the patients swim in prone, we were limited to investigate patients in supine position to enable echocardiography. The workload was not standardized and not adjusted for maximal exercise capacity. It was chosen to allow all participants to be able to conduct 3 min of exercise with continuous haemodynamic monitoring. We did not measure NTproBNP levels after a few hours from completing the study, or troponin levels, which might have provided further information about any delayed effect of WWI with exercise on the myocardium.In patients with CHF, WWI causes an acute increase in cardiac output and a fall in vascular resistance. The changes were well-tolerated. Whether swimming can be recommended as alternative to other forms of exercise or rehabilitation in patients with CHF needs to be studied further.


Some studies have been performed to assess the effects of levosimendan on cardiac function when administered to cardiac surgery patients with low cardiac output syndrome (LCOS) in the immediate postoperative period. Levosimendan is an inotropic agent for the treatment of low cardiac output syndrome that seems to have a protective effect on renal function.It is a quasi-experimental study. A total of 100 patients with LCOS received either beta-agonists or levosimendan. We assessed the incidence of postoperative kidney failure in cardiac surgery patients. In patients who had kidney failure at diagnosis of LCOS, we examined whether differences existed in the evolution of kidney failure based on the treatment administered for LCOS. The parameters measured included haemodynamics, oxygen supply, and renal function as assessed by the AKI scale. ANOVA, Student’s t-test and Wilcoxon or Friedman tests were used.p < 0.05).Up to 30% of cardiac surgery patients had kidney failure at diagnosis of LCOS. Kidney failure at discharge from the ICU was more frequent in patients who received beta-agonist drugs as compared to those who received levosimendan (The incidence of kidney failure decreased with the postoperative administration of levosimendan to cardiac surgery patients with LCOS, as compared to beta-agonists.46058317. Date of registration: 7/10/2019.Current Controlled Trials ISRCTN Retrospectively registered. One of the most common and serious complications of cardiac surgery is the low cardiac output syndrome (LCOS), which incidence in cardiac surgery patients ranges from 15 to 25%. This syndrome is associated with a mortality of 15%, reaching 70% in patients who develop cardiogenic shock. LCOS also increases pulmonary, renal and cardiac morbidity [Preoperative kidney failure is a predictor of perioperative risk in candidates to elective cardiac surgery . Kidney The gold standard treatment for LCOS is based on beta-agonist agents  . Yet, caOur group published recently a series of articles demonstrating the protective effects of levosimendan on renal function in patients with severe ventricular dysfunction at high risk for kidney failure. These effects are partially exerted by drug-induced renal preconditioning via the opening of mitochondrial KATP channels .The need to evaluate the possible nephroprotective effect of the drug in patients with low cardiac output syndrome, independent of its inotropic role is the objective of our study.We postulated that the use of levosimendan as compared to beta-agonists in cardiac surgery patients with LCOS and kidney failure exerts beneficial preconditioning effects on renal function that are independent from its cardioprotective effects. We collected data from cardiac surgery patients who developed LCOS from the more than 600 patients who underwent cardiac surgery in our unit in the last 3 years. We investigated the potential protective role of levosimendan against renal dysfunction in these patients.A three-year study was performed (January 2015–May 2018) in the Virgen de la Victoria hospital, Malaga, Spain. It was a quasi-experiment study used to estimate the causal impact of an intervention on target population without random assignment. Quasi-experimental research shares similarities with the traditional experimental design or randomized controlled trial, but it specifically lacks the element of random assignment to treatment or control. As it was a quasi-experimental study, recruitment was maintained until 50 patients were reached in each of the groups; patient recruitment from each of the groups was completed upon reaching the number of patients determined for the sample size, requiring 1 month more in the case of patients treated with levosimendan to reach the number of 50 patients. As it was not a randomized study, the recruitment ended more quickly in those patients in whom the responsible physician decided to use beta agonists, in our case. Subsequently, the number of cases with patients with renal dysfunction in each of them was collected, which was 15 patients per group, there being no randomization criteria here.Our study was both submitted to and approved by the ethics committee. Written Informed consent to participate in the study was obtained from participants.The study was approved by the local Ethics Committee .Patients older than 18 years who developed postoperative low cardiac output syndrome (LCOS) following heart surgery.2, or central venous saturation < 65% after volume replacement). It was checked by echocardiogram and Mostcare® (continuous cardiac index monitoring).LCOS Emergency surgeryPreoperative diagnosis of chronic kidney failure.Exclusion criteria were:2 and a central venous saturation > 65% following volume replacement.The administration of beta-agonists was maintained until LCOS resolution. The beta-agonists used for haemodynamic control were adrenaline or dobutamine, depending on whether vascular resistance concomitant to low cardiac output was low or high. Noradrenaline was added when necessary. Levosimendan was administered for 24 h at a rate of 0.1 mcg/kg/min to a target dose of 12.5 mg. The objectives of the therapy in the two groups were reaching a CI > 2 l/min/mRenal function parameters: Creatinine, stage of kidney failure as measured by the Acute kidney failure (AKI) scale, diuresis and use of diuretics (mg of furosemide). Requirement of renal replacement therapy.Hemodynamics: Heart rate (HR), multifocal atrial tachycardia (MAT), heart failure (HF), and ejection fraction of the left ventricle (EFLV), as monitored by an ultrasound specialist.MostCare®.Central venous saturation (SvcO2), central venous pressure (CVP). Heart rate and Cardiac Index was continuously monitored using Informed consent was obtained from all participants. The following data were collected from recruitment to ICU discharge: preoperative renal and cardiac function data  at diagnosis of LCOS, at 24 h and 48 h after diagnosis (24 h following completion of levosimendan therapy) and at Intensive Care Unit (ICU) discharge.Routine monitoring of all patients included continuous 5-lead ECG (leads II and V), invasive blood pressure in the radial artery, pulse oximetry and central venous saturation.We estimated that a sample of 100 patients with LCOS was required, assuming a reported incidence of 30% of kidney failure in these patients for a 95% confidential interval (CI) and a minimum precision of 10% to compare the effects of levosimendan vs beta-agonists in patients with kidney failure at diagnosis. The team conducting the statistical analysis was blinded to the group analyzed. Epidat 4.0 was the statistical software used.A descriptive statistical analysis was first conducted. Continuous variables were expressed in a table as means, standard deviations or medians based on normality of distribution. If continuous quantitative variables were normally distributed –as assessed by Shapiro-Wilk test– were measuerd by the ANOVA test. Differences between baseline values and values at 24 h and 48 h were assessed by Student’s t-test when normally distributed in each group. Normal distribution was tested by the Shapiro-Wilk test; otherwise, Wilcoxon or Friedman tests were used. The Wilcoxon and Friedman test are a non-parametric statistical hypothesis test used to compare two related samples, matched samples, or repeated measurements on a single sample to assess whether their population mean ranks differ (i.e. it is a paired difference test). It can be used as an alternative to the paired Student’s t-test  when the population cannot be assumed to be normally distributed .Kidney failure was classified using the Acute Kidney Injury (AKI) scale according to variations in creatinine levels and diuresis.In our study we finished the recruitment when 100 patients had a diagnosis of low cardiac output syndrome, these patients had an incidence of kidney failure at diagnosis of 30%. We studied both groups (levosimedan vs beta agonist), with 50 patients in each one Table p < 0.05). None of the patients required renal replacement therapy.Thirty patients developed kidney failure following cardiac surgery. Kidney failure persisted at discharge  only in some patients in the beta-agonist group, with significant differences between the two treatment groups  .In the levosimendan group, we investigated whether a relationship existed between the timing of administration (intra vs postoperative) and kidney failure, but no significant differences were found. Yet, a tendency was observed in the incidence of kidney failure to be lower in the group that was administered levosimendan intraoperatively vs postoperatively (p > 0.05).There were no significant differences between groups in the use of furosemide (only diuretic used in our study) (p > 0.05) Table There were no significant differences between groups in haemodynamics at diagnosis or at 24 h after completion of levosimendan therapy ; although sample size was not calculated for this variable.The most common and serious postoperative complications identified were low cardiac output syndrome and kidney failure. Perioperative cardioprotective and renoprotective strategies consist of maintaining organ perfusion and oxygen supply to tissues. Appart from diuretics, renal replacement therapy is another therapeutic option for acute kidney injury. When response to inotropic support is not adequate, intra-aortic balloon pump (IABP) counterpulsation and other ventricular assist devices can be used. However, none of our patients required any of these extracorporeal therapies . The effAccording to the literature, the incidence of kidney failure in LCOS is 20 to 30%, which is consistent with our results.The drug used for treating LCOS was an independent factor of kidney failure. In our study, the incidence of kidney failure at 48 h after treatment completion was lower in the patients who were administered the calcium sensitizer for LCOS, as compared to those who received beta-agonists. Similar results have been obtained in previous comparative studies of levosimendan and beta-agonists or placebo. Levin et al. performed a study in 252 patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass who developed LCOS. Preoperative levosimendan was compared with placebo, and the incidence of kidney failure was found to be lower with levosimendan . Baysal Differences were also observed in the incidence of kidney failure –not significant but with a clear tendency– based on the timing of levosimendan administration. Early administration and the agent selected were found to be determinant. Differences may have not reached significance because our sample size was not calculated for this endpoint.Balzer et al. conducted a retrospective study in 46 patients who underwent coronary artery bypass grafting with creatinine < 2 mg/dl and a left ventricular systolic function < 35% and/or LOCS. The incidence of acute kidney failure was significantly lower in patients who received early levosimendan therapy vs. those who received late-start levosimendan therapy . TreskatAlthough our results are consistent with those obtained by other authors such as Fedele et al., who documented the benefits of levosimendan on renal function , conflicThe possibilities of a relationship between the effect on potassium channels, as well as the possible properties related to pharmacological post-conditioning, in addition to the improvement of renal perfusion through the treatment of low cardiac output, should be the starting point again clinical trials that have the ability to confirm our findings.The main limitation of this study was that patients were not randomized to treatment groups. The reason is that we preferred that physicians treated their patients with the medications they were more familiar with. This may have caused bias in the interpretation of results, as physicians will probably favor the conventional therapy. A triple-blinded study was not possible due to the type of study. However, the team conducting statistical analysis was blinded to the group analyzed. The use of certain biochemical parameters with greater sensitivity and specificity (N-GAL or Cystatin C), would also be useful to evaluate their action.The incidence of kidney failure decreased with the postoperative administration of levosimendan to cardiac surgery patients with LCOS, as compared to beta-agonists.