Based on the aortic pressure waveform, a specially designed computational fluid dynamic (CFD) method was proposed to determine coronary angiography-derived diastolic pressure ratio (caDPR) without using invasive pressure wire. The aim of the study is to retrospectively assess diagnostic performance of the caDPR in the catheterization laboratory, based on a previous multicenter trial for online assessment of coronary angiography-derived FFR (caFFR).Patients with diagnosis of stable or unstable angina pectoris were enrolled in six centers. Wire-derived FFR was measured in coronary arteries with 30–90% diameter stenosis. Offline caDPR was assessed in blinded fashion against wire-derived FFR at an independent core laboratory. A total of 330 patients who met the inclusion/exclusion criteria were enrolled from June 26 to December 18, 2018. Offline computed caDPR and wire-derived FFR were compared in 328 interrogated vessels. The caDPR with a cutoff value of 0.89 shows diagnostic accuracy of 87.7%, sensitivity of 89.5%, specificity of 86.8%, and AUC of 0.940 against the wire-derived FFR with a cutoff value of 0.80.Using wired-based FFR as the standard reference, there is good diagnostic performance of the novel-CFD-design caDPR. Hence, caDPR could enhance the hemodynamic assessment of coronary lesions. Fractional flow reserve (FFR):aP is the mean aortic pressure and dP is the mean pressure distal to the stenosis (2 cm downstream from the stenosis) averaged over the entire cardiac period at the maximal hyperemia.Instantaneous wave–free ratio (iFR):aP)WTP is the mean aortic pressure and (dP)WTP is the mean pressure distal to the stenosis (2 cm downstream from the stenosis) averaged over the wave-free period (WFP) of diastole at baseline.Diastolic pressure ratio (dPR):aP)diastole is the mean aortic pressure and (dP)diastole is the mean pressure distal to the stenosis (2 cm downstream from the stenosis) averaged over the entire diastolic period at baseline.Since fractional flow reserve (FFR) was first proposed by Angiography-derived FFR without using pressure wire and hyperemic stimulus has shown high diagnostic accuracy by using wire-derived FFR as the reference standard . HoweverIn a previous multicenter trial (FLASH FFR), the FlashAngio system was used to determine the coronary angiography-derived FFR (caFFR) without using pressure wire and hyperemic stimulus, which showed high diagnostic accuracy by using wire-derived FFR as the reference standard . The wirA novel coronary angiography-derived resting physiological parameters, caDPR, was proposed as follows:aP)diastole is the mean aortic pressure and (dP)diastole is the mean pressure distal to the stenosis (2 cm downstream from the stenosis) averaged over the entire diastolic period, as shown in where (2); had known severe coagulopathy or bleeding disorders; were allergic to iodine contrast agents, adenosine or ATP or participated in or were participating in another clinical trial in the past month. Angiographic exclusion criteria included if the interrogated stenosis was caused by a myocardial bridge; ostial lesions ≤3 mm from the aorta; poor contrast opacification, severe vascular overlap or distortion of the interrogated vessel or poor angiographic image quality precluding contour detection required by the FLASH software  . Patientsoftware .This study retrospectively assessed diagnostic performance  of the caDPR in those patients, by using wired-based FFR as the reference standard. The retrospective clinical trial was approved by the Institutional Review Board (IRB) in six hospitals, which conforms the declaration of Helsinki and Good Clinical Practice Guidelines of the China Food and Drug Administration. Written consent was waived owing to the minimal patient risk in accordance with the relevant guidelines and regulations of the IRB from those centers.Briefly, a Certus pressure wire  was inserted to the most distal position by interventional cardiologists . HyperemCoronary angiographic images were recorded at 15 frames/s in routine fashion in patients with suspected coronary artery diseases . IntravaaP)diastole) averaged over the third to eighth cycles following angiography. Digital Imaging and Communications in Medicine (DICOM) images corresponding to the recorded pressure waves were exported to the FlashAngio console. The diastolic flow velocity (Vdiastole) was determined automatically by the FlashAngio software. Briefly, based on the movement of the tip of the guiding catheter  in angiograms, we can determine systolic and diastolic periods, where the shorter time interval refers to the systolic period and the longer time interval represents the diastolic period as the tip of guiding catheter moves in or out. We compute the diastolic flow velocity by the Thrombolysis in Myocardial Infarction (TIMI) Frame Count Method diastole, along meshed coronary arteries from the inlet to the most distal position. Furthermore, we computed that(dP)diastole = (aP)diastole−(ΔP)diastole, where (aP)diastole is determined from the aortic pressure waves. The caDPR was computed in Eq. 1 in an independent core lab blinded to the FFR measurement.We have developed a specially designed computational fluid dynamic (CFD) model to carry out the steady-state laminar flow simulation across the stenotic blood vessel , which iBaseline demographic and vessel characteristics of all patients were recorded as mean ± standard deviation (SD) or percentage with counts. Diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the caDPR were calculated with the FFR as the reference standard. Two-sided 95% confidence intervals (CIs) were added to these parameters using the Clopper-Pearson exact method. Correlations were summarized by linear regression models and the coefficient of determination. Systematic differences were assessed by the Bland–Altman analysis. Statistical analysis was performed by the Proc Genmod with the repeated statement and the adjusted center effect. Receiver-operating curve of the caDPR with a cutoff value of 0.89, with wire-derived FFR  as the gold standard, was estimated by a logistic regression model .Three hundred thirty patients with one or more intermediate coronary lesions  were enrolled in six centers from June 26 to December 18, 2018. Angiography and wire-derived FFR were successfully demonstrated in 328 patients (328 vessels) at the age of 63.2 ± 9.4 years  including 26.8% prior PCI with stent, 0.9% prior CABG, and 7.9% prior myocardial infarction. Offline caDPR computation was carried out in these patients at an independent laboratory in blinded fashion. N = 328 in full analysis set) are 87.7% (95% CI: 83.7 to 91.1%), 89.5% (95% CI: 82.3 to 94.4%), 86.8% (95% CI: 81.5 to 91.0%), 78.5% (95% CI: 72.0 to 83.8%), and 93.9% (95% CI: 90.0 to 96.3%), respectively. There are good correlations between caDPR and FFR , as shown in We performed further sensitivity analyses to evaluate the diagnostic utility of caDPR with FFR in the “gray zone.” In 119 lesions with FFR between 0.75 and 0.85, diagnostic accuracy, sensitivity, specificity, PPV and NPV of the caDPR are 73.1% (95% CI: 64.2 to 80.8%), 83.0% (95% CI: 70.2 to 91.9%), 65.2% (95% CI: 52.4 to 76.5%), 65.7% (95% CI: 57.4 to 73.1%) and 82.7% (95% CI: 72.0 to 89.9%), respectively.This study assessed a coronary angiography-derived resting physiological parameter, caDPR, against the wire-derived FFR. The key finding of the study was reported as: the caDPR  showed good correlations with the FFR .Adenosine-free indexes of coronary physiology have recently been introduced to quantify coronary artery disease severity, e.g., iFR, dPR, resting full-cycle ratio (RFR), diastolic hyperemia-free ratio (DFR), and so on . Adenosiangio  in the gray zone (FFR between 0.75 and 0.85). Hence, a hybrid iFR-FFR decision-making strategy for revascularization was suggested to increase adoption of physiology-guided PCI  before tTo our knowledge, this is the first study to show diagnostic performance of the caDPR compared with the wire-derived FFR in a clinical trial at multiple centers. In comparison with the wire-derived iFR or dPR , the caDSince this study is a sub-study from the prospective and multicenter trial that was designed for online assessment of caFFR , we onlyThe high accuracy, sensitivity and specificity show good correlation and agreement between caDPR and wire-derived FFR. The caDPR can be determined from the measured aortic pressure wave and TIMI frame-determined resting blood flow without any assumptions. Hence, the caDPR can be a fast, accurate and stable approach in hemodynamic assessment of coronary lesions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This is a sub-study of a previous multicenter trial, which was demonstrated to assess diagnostic performance  of the angiography-derived FFR in the Flash caFFR system . The clinical trial was approved by the Institutional Review Board (IRB) in six hospitals, which conforms the Declaration of Helsinki and Good Clinical Practice Guidelines of the China Food and Drug Administration. Written consent was waived owing to the minimal patient risk in accordance with the relevant guidelines and regulations of the IRB from those centers. The patients/participants provided their written informed consent to participate in this study.TY, FY, YL, LZ, BZ, TH, ZL, and JL performed the experiments. YF and YG performed the theoretical analysis. YuH drafted the manuscript. YuH, YG, JL, and YoH reviewed the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that this study received funding from Rainmed Ltd., Suzhou, China. The funder had the following involvement with the study: providing the device for caDPR analysis. YH holds stocks of Rainmed Ltd., Suzhou, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In meta-analyses, it has been reported that myopia is a risk factor for glaucoma and there is increasing evidence that autonomic dysfunction causing vascular dysregulation or perfusion dysfunction is considered an important factor in the progression of glaucoma. There have been experimental studies to find out the association between autonomic nervous system and ocular growth, but no clinical study yet has evaluated the relationship between them. Therefore, we enrolled 208 open angle glaucoma patients and measured heart-rate-variability(HRV). We used the standard deviation value of the qualified normal to normal intervals (SDNN) parameter of HRV, which is considered an autonomic influence index and characterized the total effect of the regulation of autonomic blood circulation. Patients were classified into the two groups according to SDNN: those with low possibility of autonomic dysfunction (LoAD group) and those with high possibility of autonomic dysfunction (HiAD group). We evaluated myopic features employing a ‘posterior scleral profile’ identified by the disc tilt ratio, disc torsion, fovea-BMO center (FoBMO) angle and peripapapillary area(PPA) to disc ratio. HiAD group showed higher values than LoAD group in posterior scleral deformation profile such like axial length, disc tilt, torsion degree. We suggest the possibility of association between myopic deformation and autonomic dysfunction. While elevated intraocular pressure and age are considered main risk factors for the development and progression of the disease, the pathogenesis of glaucoma is still unclear. There is increasing evidence that vascular dysfunction and perfusion insufficiency need to be considered as important factors in the progression of glaucoma4. Autonomic dysfunction may contribute to unstable or fluctuating blood pressure which can cause dysfunction of autoregulation and lead to glaucoma progression5. A previous study revealed that there is the sympathovagal inbalance of autonomic nervous system(ANS) in patients with NTG8. Sympathovagal inbalance may be responsible for the faster rate of central visual field(VF) progression in NTG9.Glaucoma is a progressive optic neuropathy characterized by the optic nerve damage and loss of retinal ganglion cells10. The Tajimi Study reported that age, intraocular pressure (IOP) and myopia were significant risk factors for primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG)11. In parallel with the increased prevalence of myopia, glaucoma also increases. Posterior pole profile variables like disc tilt, FoBMO angle, disc torsion, PPA to disc ratio are related to myopic optic nerve change13. These structural changes in the ONH may affect the higher susceptibility to glaucomatous optic disc damage15. Brazitikos et al.16 reported that tilted disc may cause visual field defects. Park et al.17 reported that optic disc torsion was related to the location of the visual field defect.Meanwhile, myopia has been reported as a risk factor for glaucoma in meta-analyses of epidemiological studies20. They reported that dysfunction or abnormality of autonomic nervous system result in ultradian rhythms in axial length and choroidal thickness that are associated with an increased rate of ocular growth underlying myopia development18. But no study yet has evaluated the linkage of myopic ocular change and autonomic inbalance in glaucoma patients, which are known to be associated with glaucomatous optic nerve damage.Several experimental studies have documented that there is relationship between the autonomic nervous system and ocular growthThe purpose of the present investigation was to evaluate whether the various indices including the posterior scleral profile have differences in according to presence of autonomic dysfunction.The mean value of the SDNN in 208 NTG patients was 33.71 and the standard deviation was 18.16. So LoAD group had a SDNN values between 15.55(33.71 –(minus) 18.16) and 51.87(33.71 + (plus)18.16) and HiAD group had a SDNN value less than 15.55 or greater than 51.87. Among 208 NTG patients, 164(78.8%) were LoAD group (15.55–51.87) and 44(21.2%) were HiAD group (<15.55 or >51.87). Analysis of several factors, including the posterior scleral pole profile for both groups is shown in Table To the best of our knowledge, this is the first study that has revealed a relation with myopic ocular change and autonomic nervous system in patients with glaucoma. The association of these two factors with glaucoma has already been well investigated, respectively.21. There have been many studies to explain the correlation between glaucoma and myopia22. In myopia, structures of optic nerve, including lamina, may be more vulnerable to glaucomatous damage. The shearing force caused by scleral deformation of myopia affects the lamina cribrosa27. This may be the main mechanism of glaucomatous damage in myopia27. There are also studies about myopia-related optic disc and retinal change such like the axis of tilt and tilt ratio and PPA28. Chameen et al.29 reported that beta-PPA was predominantly located in the temporal direction in eyes with disc tilt as myopic patients are predominantly temporally tilted. Tilted disc may exacerbate visual field defects16. Park et al.17 reported that the torsion direction of the optic disc may predict the location of VF damage. So, the indicators of myopic optic disc change are associated with glaucomatous damage.An association between open-angle glaucoma and myopia has been reported for decades32. Glaucoma patients with vascular dysregulation have impaired autoregulatory function, so they cannot respond appropriately to low perfusion pressure34. The pathogenesis of vascular dysregulation is not clearly known, but it is assumed to be due to dysfunction of ANS and endothelial vascular layer35. Systemic sympathetic or parasympathetic neuropathy has been reported in patients with POAG and NTG patients38. In particular, NTG patients have been reported to have abnormal autonomic nervous system, it would have affected ocular blood flow and structural damage8.There are many studies that hemodynamic instability can contribute to the onset and exacerbation of glaucomaet al.39 tried to explain the relationship between myopia and autonomic nervous system by several experiments in chicks. They found abnormal ocular rhythms in chick having procedures like parasympathetic resection, which causes autonomic dysfunction18. They also reported that abnormal ocular rhythm results in abnormal ocular growth stimulation18.In our study, we described the correlation between myopic change parameter, namely the posterior scleral profile, and an autonomic dysfunction parameter, namely HRV. Nickla 40. HRV is defined as ‘the amount of fluctuations from the mean heart rate’41. It is mainly controlled by the continuous interaction of the ANS41. The HRV test has many indicators. Among them, the SDNN is considered the best indicator of the ANS42. It reflects all the cyclic components that affect variability, therefore it represents total variability and balance of SNS and PNS43. Autonomic nervous system dysfunction which can cause blood pressure problems may relate to hypertension, orthostatic intolerance, cardiac disease, and other disease states44. So it can cause fluctuation of blood pressure. When blood pressure is decreased and renal blood flow is decreased, juxtaglomerular cells convert the precursor prorenin into renin in the kidneys45. Renin breaks down angiotensinogen synthesized in the liver to make angiotensin I46. Angiotension I is converted to angiotensin II46. This angiotensin II has multiple effects in various organs including constricting blood vessels and producing aldosterone in the adrenal cortex46.We used Heart rate variability (HRV) to evaluate autonomic dysfunction. HRV is a non-invasive tool, which is widely used to evaluate the autonomic nervous system (ANS). HRV provides information about the functions of the sympathetic and parasympathetic nervous system47. So activated renin-angiotension system(RAS) affects the ECMs in many organs, then what about eyeballs? Sclera is composed of approximately 50% collagens and ECM such as proteoglygan, glycoproteins and matrix metalloproteinase. Therefore, We hypothesize that the renin angiotension system may have a effect on sclera. Especially events that occur in scleral extracellular matrix during childhood and young adulthood may be very important because it is the time when the eyeball is growing. The composition of extracellular matrix plays a very important role in determining the properties of the sclera, which affects the eyeball elongation48. Deformity of scleral canal  and thinning of sclera, especially posterior pole, is usually happens with elongation of the eyeball during childhood and young adulthood. We carefully suggest that people who have abnormality of HRV are more affected by activated renin-angiotensin system than normal people during childhood and young adulthood. So that may explain our result that posterior scleral deformity such as tilt ratio, FoBMO angle, axial length is associated with abnormality of HRV.Meanwhile, it has been reported that ECM synthesis is regulated by sympathetic nervous system or angiotensin II49. The pathophysiology of myopia that we are interested in is not just myopia (myopic refraction), but axial myopia. Because only axial myopia is associated with posterior scleral deformity and glaucomatous optic nerve damage.In our results, there was no statistical difference in refraction  between the two groups. The amount of refraction is determined by axial length, curvature and refractive index. Curvature myopia refers to a type of refractive error that develops when the cornea is curved too much. By contrast, index myopia is caused by change in the refractive index of the media such as cataracts or hydration of lens We found a difference for axial length, tilt ratio and torsion degree of the optic disc in Chi-Square, independent t-test and logistical regression analysis, with only torsion degree being statistically significant for a multivariate(multiple) logistic regression analysis. It does not mean that the axial length, tilt ratio are not associated with HRV. Since all three factors: axial length, tilt and torsion, have similar mechanism in development, the association wound have been reduced in multivariate analysis, which adjust for confounding.Figure In summary, We found that patients with abnormality of HRV had more association with posterior scleral deformity such as disc tilt, FoBMO angle, axial length. And further studies are needed to explore this finding and mechanism.This study included 208 OAG patients who visited the Seoul St. Mary’s Hospital between September 2018 and October 2018. It was approved by Institutional review and Ethics Board of Seoul St. Mary’s Hospital and performed according to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all the subjects.50. Exclusion criteria included any other neurologic disorder and the taking of any drugs known to affect ANS or the cardiovascular system.All patients enrolled underwent comprehensive ophthalmologic examination consisting of best-corrected visual acuity, intraocular pressure by Goldmann applanation tonometry. Anterior chamber angle evaluated by gonioscopy. Central corneal thickness were measured using ultrasound pachymetry , and axial length was measured by biometry . Optic disc was examined with red-free fundus photography . RNFL thickness was measured using the Cirrus OCT. Global RNFL thickness was automatically calculated. VF was examined using the Swedish Interactive Threshold Algorithm standard 24-2 perimetry . History of disc hemorrhage (DH) was investigated through medical records. NTG was defined as the presence of an open anterior chamber angle, glaucomatous optic disc cupping by funduscopic examination and compatible repeatable VF damage, and IOP never exceeded 21 mmHg by a Goldmann applanation tonometer in repeated measurement on different days. Glaucomatous optic disc is increased cupping or loss of neuroretinal rim. Glaucomatous VF was defined as a cluster of 3 or more non-edge points on pattern deviation map with a probability <5% of the healthy population, including at least one of these points with the probability of <1% of the healthy population; or VF is outside the normal limits on the glaucoma hemifield test for a pattern standard deviation (PSD) outside 95% normal limits, reliable test . Refractive errors  were usually corrected with a trial lens when performing VF tests. Mild myopia not exceeding −3 diopters was not corrected, astigmatism less than 1 diopter was corrected with spherical equivalent and astigmatism over −1.25 diopters was corrected with the corrective lens. And in myopia over −6 diopters, contact lenses were used when VF examination was performed43. A reduction of SDNN is correlated with left ventricular dysfunction indicating a high tone of heart sympathetic activity and has been found to be predictive of increased risk of sudden cardiac death55. Reduced SDNN mainly reflects sympathetic overactivity, and increased SDNN reflect parasympathetic overactivity56.The participants were asked to avoid activities that could affect blood pressure at least 2 hours before the test. The testing was performed over 5 minutes in controlled conditions. The echocardiography was monitored for 5 minutes by an experienced technician. The echocardiography signal was transferred to a Medicore Heart rate Analyzer, Model SA-3000P . The SDNN index is the mean of the standard of all the normal RR ECG wav intervals of the standard deviations of all the normal RR intervals. The parameter is primarily a measure of the autonomic effect on heart rate variability and characterize the total effect of autonomic blood circulation regulationPatients were divided into 2 groups, according to their SDNN. LoAD group consisted of patients within the one standard deviation from the average of the SDNN measurements. And HiAD group consisted of patients outside one standard deviation from the average of the SDNN measurements, indicating that they had too higher or too lower SDNN of HRV. So HiAD group having deviated value was thought to have abnormality in HRV. it can cause fluctuation of blood pressure.http://rsb.info.nih.gov/ij/index.html; developed by Wayne Rasband, National Institutes of Health, Bethesda, MD).Optic disc tilt, torsion, and PPA to disc ratio were measured from photographs by a two independent examiners(DYS and H-YLP) using the National Institutes of Health image-analysis software Figure .FoBMO angle determined as the angle between and the line connecting the fovea and BMO center and the horizontal meridian passing through the Bruch’s membrane opening (BMO) center. It was measured by spectral domain-OCT scans performed with the Heidelberg spectralis OCT.Sample size calculations were performed using the G*Power 3.1. The sample size calculation showed a power of 80 and alpha error of 0.05, for sample size of 160 in the LoAD group versus 40 in the HiAD group. The independent t-test and chi-square test for independent samples were used to assess the differences between groups. Binary logistic regression analyses were used to identify posterior scleral factors associated with autonomic dysfunction. A value of P < 0.2 in the simple binary logistic regression model was included in multiple model. A value of P < 0.05 indicated statistical significance. The independent variables were age, axial length, MD of the VF, PSD of the VF, PPA to disc ratio, FoBMO angle from spectral domain-OCT, tilt ratio, torsion degree. All statistical analysis were performed with SPSS for windows statistical software.


Sodium glucose co-transporter-2 inhibitors (SGLT 2 inhibitors) are newer anti-hyperglycemic agents, which improve glycemic control independent of insulin secretion with a low risk of hypoglycemia. This study aimed to assess the efficacy of SGLT 2 inhibitors in terms of glycemic control, weight reduction and safety profile in our patients with type 2 Diabetes (T2D).This is a prospective analysis, conducted at Medicell Institute of Diabetes, Endocrinology and Metabolism (MIDEM), Karachi Pakistan from January 2018 till July 2019. This study included patients with T2D, who were treated with SGLT 2 inhibitors add on to other anti-diabetic drugs. Baseline and follow up weight, BMI, HbA1c, blood pressure (BP), renal function and side effect profile was assessed.Study included 140 patients; 53% females and 47% males. Mean Age was 55.6 ± 10.3 years. Mean weight at baseline was 81.5 ±16.5 kg. Mean duration of T2D was 10.3 ± 6.75 years, with a mean HbA1C at baseline of 9.1± 1.6%. Follow up data was available for 90 patients at the time of analysis. HbA1C improved considerably to 7.6± 0.9 (P< 0.001) and mean weight reduced to 78.5 ± 16.1 kg (P≤0.003), at first follow-up.Dapagliflozin and Empagliflozin offer a significant additional drug in improving glycemic control with the additional advantage of weight loss and hypoglycemia safety. T2D is a major global public health concern. Just fewer than half a billion people are living with diabetes worldwide and the number is projected to increase by 25% in 2030 and 51% in 2045.12SGLT 2 inhibitors are newer anti-hyperglycemic agents, which improve glycemic control independent of insulin secretion with a low risk of hypoglycemia.This is a prospective analysis conducted at Medicell Institute of Diabetes, Endocrinology and Metabolism (MIDEM), Karachi Pakistan from January 2018 till July 2019. This study was approved by the ethical committee of MIDEM (IRB – 004/MHS/19).Patients with T2D, who need escalation of treatment for failing to achieve HbA1c target on usual anti-diabetic drugs or a change of anti-diabetic medication required for purpose of cardiovascular and renal protective benefits of this class of drugs. All patients were counseled about the side effects and the need to report immediately if there were symptoms related to urinary, vulvo-vaginal or perineal infections.Patients with T2D, who needed escalation of treatment for failing to achieve HbA1c target on standard anti-diabetic medication, including insulin (HbA1c > 6.5).Drug naive patients who meet ADA/EASD guideline specified criteria for using SGLT 2inhibitors, i-e cardiovascular disease (CVD), chronic kidney disease (CKD) and ObesityPatients on other anti-diabetic medications with existing CVD or mild CKD (eGFR < 90 and > 30 mL/min/1.73m2) for beneficial effects of SGLT 2inhibitors.Patients with CKD, if eGFR < 30 mL/min/1.73m.Baseline weight, BMI, HbA1c, fasting and random blood sugar, blood pressure, renal function and duration of diabetes were assessed.The preexisting anti diabetic medication included Metformin, Sulphonylurea, DPP4 Inhibitors, Thiazolidinediones, GLP 1 Analogues or Insulin. The patients on insulin were either continued with the pre-existing dose of insulin or dose was reduced if there was risk of hypoglycemia. Likewise, dose of sulphonylurea was also reduced and was stopped in a few patients with hypoglycemia risk. Patients were advised to check blood glucose at-least twice per week and if they were unwell or had symptoms suggestive of hypoglycemia occurs. Hypoglycemia is defined as a blood sugar level below 70 mg/dl with or without symptoms. Diet and lifestyle were intensified.The commercially available SGLT 2 inhibitors in Pakistan at the time of this study were Dapagliflozin 5- 10 mg and Empagliflozin 10-25 mg, and either of them were prescribed once daily in the morning, in addition to other anti-diabetic drugs. The duration of follow up was 3-6 months. Changes in weight, HbA1c, FBS, blood pressure, Cholesterol levels and Creatinine along with side effect profile were analyzed on follow up.Frequency and percentages were presented for categorical variables that include gender, treatment assigned and adverse reactions reported during follow up visits. Mean and standard deviation was illustrated for age, weight, BP, T2D Duration, HbA1C and other numerical variables. Mean difference of HbA1c, SBP, DBP, weight, FBS from baseline to follow-up (3-6 months) was analyzed by applying paired sample T-test through SPSS v.21, considering p-value <0.001 as statistically highly significant.2. Mean systolic blood pressure at baseline was 144.1± 19.5 mmHg and diastolic blood pressure was 83.9± 10.5 mmHg. Mean duration of T2D was 10.3 ± 6.75 years, with a mean HbA1C at baseline of 9.1± 1.6%. Baseline creatinine of our study group was 0.9 mg/dl and eGFR was 127.92 mL/min/1.73m2. In our study group, 58 (41.4%) patients were overweight/obese, 18 (12.8%) had Ischemic Heart Disease (IHD) and 27 (19.2%) patients had CKD. The patients were on different anti-diabetic medications: 87.1% on Metformin, 75.7% on DPP-4 inhibitors, 31.4% on Sulphonylureas, 26.4% on Insulin, 7.9% on Pioglitazone and 6.5% were on GLP-1 agonist. Patients received two types of SGLT 2 inhibitors; 54.3% were given Dapagliflozin in the dose of 5-10mg per day, while 45.7% were given Empagliflozin in the dose of 10-25mg per day.Our Study included a total of 140 patients; 53% were females and 47% were males. Baseline characteristics are given in Follow up data was available for 90 patients at the time of analysis. Fifty Patients were lost to follow, approximately 40 % of these patients, were still taking the drug but could not come and get the test done due to financial constraints or other issues. HbA1C improved considerably to 7.6± 0.9 (P≤ 0.001), at first follow-up between three to six months. Mean weight reduced to 78.5 ±16.1 (P≤ 0.003). There was significant reduction in systolic and diastolic blood pressures  Graph.1Graph.1; With the increasing prevalence of T2D and associated risk of CVD and CKD, SGLT 2 inhibitors represent a key therapeutic addition for clinicians in the management of patients with diabetes. Our study demonstrates that when SGLT 2 inhibitors were added at any stage of the disease in the real world scenario, in patients with uncontrolled T2D, there is a clinical and statistically significant improvement in glycemic control, weight loss and reduction in blood pressure in our patients, as has been demonstrated in the landmark studies with SGLT 2 inhibitors.19There is a paucity of data from South Asian countries specially Pakistan. This study aims to evaluate the effects and tolerability of this class of drugs in our population. In an Indian study, the mean HbA1c reduction and weight reduction observed was 1.02±0.24% and 2.64±1.27 kg respectively.SGLT 2i have additional advantage of blood pressure reduction. This effect is multifactorial mainly attributable to volume contraction by natriuretic and diuretic effects, weight loss, and better arterial compliance (elasticity index of large arteries).SGLT 2 inhibitors are often associated with a risk of genital mycotic and lower UTI due to increased urinary excretion of glucose; these side effects being observed more often in women than in men.26Clinical studies have demonstrated that SGLT 2 inhibitors often induce an initial decrease in eGFR in patients with T2D; subsequently eGFR remains stable over time and returns toward baseline during continuous SGLT 2 inhibition.Limitation of our study is its small sample size and inability to report on the follow up of all patients prescribed SGLT 2 inhibitors in this cohort. We did not compare the effect of SGLT 2 inhibitors with other anti-diabetic drugs in a controlled manner. Since this was a short study, we did not assess the effect of SGLT 2 inhibitors on long term cardiovascular and renal outcomes.Mean reduction of HbA1c (-1.34%) showed that Dapagliflozin and Empagliflozin offer a significant additional drug for improving glycemic control with the additional advantage of hypoglycemia safety and cardiovascular and renal benefit without any significant side effects in our population.ES: Contributed to conception and design of the study, Data acquisition, analysis and interpretation, Drafting the article and Final approval of the version to be published and responsible and accountable for this study.TA: Accuracy and Integrity of the work, Contribution to conception and design of the study, Patient management, Critical analysis of the article and Final approval of the version to be publishedSG: Contributed to conception and design of the study, Data acquisition and collection and Revision of article.WA: Conception and design of study and Data acquisition and collection.


Chronic kidney disease (CKD) is a growing problem among aging population, and the number of individuals at risk of end stage renal disease is rising. Part of the reason lies in incomplete understanding of the pathways underlying renal aging and kidney disease, as well as insufficient delivery of evidence-based treatment to elderly patients with CKD. This review aims to address these unsolved issues by delineating updated mechanisms of renal senescence and summarizing recent findings on key clinical aspects of CKD in the elderly. Challenges and obstacles in caring for older people with CKD are discussed, with an emphasis on modification of risk factors, prevention of acute kidney injury, stabilization of progression and decision on dialysis initiation. Chronic kidney disease (CKD) is increasingly being recognized among the elderly population, which pose significant challenges for clinicians around the world -3. Many As people age, renal mass declines by about 10% per decade from aged 30 to 80 years old . The numStudies of healthy living kidney transplant donors have provided appropriate information on both structural and functional changes that occur with normal aging. Because kidney donors undergo a sequential of clinical evaluations, including renal function and image study to confirm health before donation. Pre-implantational biopsy of the renal allograft may provide renal tissues for structural evaluation. For example, in an observational study involving 1203 adult living kidney donors, Rule et al. observed a rising prevalence of nephrosclerosis with aging, from 2.7% for ages 18-29 years to 73% for ages 70-77 years, as determined by core needle biopsy of the graft kidney. They found a strong association between age and nephrosclerosis even after adjustment for kidney function and risk factor covariates such as diabetes and hypertension .2 does not increase mortality risk among patients ≧65 years compared to patients with eGFR of more than 60 mL/min/1.73 m2 , 7776, 7Several studies have reported predictors of renal progression to ESRD in the elderly. Nicola et al. identified high proteinuria level as a strong prognostic factor of ESRD development in older patients with incipient CKD . Obi et https://pop-proj.ndc.gov.tw/main_en/ June 12, 2020). The prevalence of elderly CKD is expected to increase further if the current preventive measures against CKD remains unchanged. It has been suggested that age-specific care considerations should be incorporated into the scope of management for elderly patients with CKD [2, based on mortality outcomes stratified by levels of GFR in the general population [Taiwan will become a super-aged society by 2026 when at least 20 percent of the population are 65 years or older (National Development Council. Population projections for Taiwan, assessed at with CKD , 93. To pulation . The prepulation .There are few evidence-based guidelines available for preventing CKD progression in the elderly. More studies in this regard are warranted. The following are some selected topics which merit special attention for the medical professionals.For older people with or without CKD, modifiable risk factors or controllable comorbidities should be identified and managed appropriately, irrespective of diabetic status . The AmeAKI, even if followed by renal recovery, is emerging as a prominent risk factor for the future development of CKD and ESRD , 80. A cNovel drug development for kidney diseases has been limited over the last few decades. Current practice guidelines recommend blood pressure control with RAS blockade as the gold standard therapy for patients with proteinuric CKD. However, blocking the RAS by either ACE inhibitors or ARBs slows but does not stop the progression of kidney disease , 109-1112 for asymptomatic patients, i.e., deferring the initiation of long-term dialysis until absolutely indicated [2associated with a higher median life expectancy of 26, 25, and 19 months for patients aged 65, 75, and 85 years, respectively [Elderly patients with advanced CKD have to face with the difficult decision-making about dialysis initiation as renal function declines toward ESRD. The choices have become even tougher in the wake of escalating financial burden imposed by the long-term nature of treatment. Most guidelines advocate to postpone dialysis initiation until the eGFR has reached 5-10 or ≤6 ml/min/1.73 mndicated . This pandicated , and a sectively . Conversectively . Other sectively , 130. Thectively . In contThe aged kidney undergoes structural and functional changes which are indistinguishable from that of incipient kidney diseases. Differentiating these two conditions is crucial in implementing available strategies to prevent the development of kidney disease. Apart from mechanistic research need on kidney senescence, there exist knowledge gaps in caring for older patients with CKD. First, most clinical trials for renal progression have excluded older patients, leading to competing therapeutic priorities, and the resultant clinical guidelines might not be generalizable to all persons involved. Second, elderly people are vulnerable to superimposed AKI, yet effective measures or treatment tackling AKI to CKD transition or AKI on CKD progression have not been explored to the fullest extent possible. Last but not least, it remains a challenge for clinicians when it comes to the decision-making of dialysis initiation. Studies addressing the risk of mortality, quality of life and functional capacity in geriatric patients are desperately required so that those who are robust can opt for dialysis whereas those complicated by existing functional or cognitive impairments may consider conservative management.


Hypertension (HTN) can be present in up to two-thirds of patients living with diabetes mellitus (DM). It is a risk factor for the development of diabetes as well as complications like coronary artery disease (CAD), nephropathy, retinopathy, and neuropathy. Hypertension is treatable, and the degree to which it is controlled determines the risk of development of cardiovascular diseases and other complications in a given individual patient. Even though antihypertensive drugs are available and issued to hypertensive diabetic patients, the rate of control of HTN is often inadequate. The aim of this study was to assess the prevalence of suboptimal blood pressure (BP) control, its associated factors, and the choice of antihypertensive drugs among type 2 DM patients at Kilimanjaro Christian Medical Centre (KCMC). p value of <0.05 was considered to be statistically significant.  A hospital-based cross-sectional study was conducted at the KCMC diabetes clinic from October 2018 to March 2019 among type 2 DM patients with HTN based on the inclusion criteria. Data were collected using structured questionnaires, and written informed consent was obtained. Suboptimal BP was defined as BP levels ≥ 140/90 mmHg according to the American Diabetes Association guideline published in 2018. Data analysis was done using the Statistical Package for the Social Sciences (SPSS) version 25. Chi-square analysis was done to identify the independent predictors of BP control, and a  The data of 161 participants was analysed; the mean age was 63.9 ± 20.2 years, with the majority being females (67.1%). Despite all participants being on different classes of antihypertensives, 57.8% had suboptimal BP control. Among the participants with good BP control, 52.7% were on angiotensin-converting enzyme inhibitors (ACE-I). Poor diabetes control was observed in 50.1% participants as indicated by elevated glycated haemoglobin.  This study demonstrated that BP control in type 2 DM patients was suboptimal in more than half of the participants. The study showed that the use of ACE-I or angiotensin II receptor blockers (ARBs) in the majority of DM patients has a good impact in the control of blood pressure. The early initiation of ACE-I or ARBs among the diabetic patients will improve the optimal BP control. Diabetes mellitus (DM), more simply called diabetes, is a group of metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both.According to the International Diabetes Federation (IDF) report published in 2017, DM is estimated to affect over 425 million people or 8.8% of adults aged 20-79 years worldwide and expected to rise to 629 million by the year 2045. Africa is estimated to have 16 million people living with DM, which is predicted to increase to 41 million people by the year 2045. Approximately 87% to 91% of all people with DM have type 2 DM especially in the high-income countries. [Hypertension (HTN) in patients living with DM is contributed by insulin resistance, obesity, and inactivity . StudiesThe growing burden of DM and HTN globally is considered to be a major medical and public health problem associated with increased morbidity and mortality. Nonoptimal BP control is the leading cause of deaths globally responsible for 7 million deaths annually of which most are from low- and middle-income countries (LMIC) .HTN is a major modifiable risk factor for cardiovascular diseases (CVDs) including heart failure and myocardial infarction, estimated to cause 65% deaths globally . There iThe Appropriate BP Control in DM (ABCD) study, the United Kingdom Prospective Diabetes Study (UKPDS), and the Hypertension Optimal Treatment (HOT) trial showed a consistent benefit on cardiovascular events or mortality when BP is reduced. The number of patients with diabetes in Tanzania is increasing. Prevalence of HTN among patients with diabetes is equally high . FurtherThe degree of control of HTN in both rural and urban areas of Tanzania is not well established; therefore, effective BP control in DM patients is an important goal that demands special attention. The American Diabetes Association (ADA) guidelines published in 2018 recommends blood pressure targets of <140/90 mmHg in patients with diabetes [A hospital-based cross-sectional analytical study was conducted at the Kilimanjaro Christian Medical Centre (KCMC) diabetes clinic from October 2018 to March 2019 among type 2 DM patients with HTN. KCMC is a consultant referral hospital in north-eastern Tanzania. It caters to a wide population estimated to be over 15 million in the northern part of the country. The diabetes clinic is run once a week with an average of 100 patients on each clinic day.Patients with type 2 DM above 18 years old with established clinical diagnosis of hypertension and on regular medications were considered eligible and enrolled consecutively until the desired sample size of 161 was attained. The diagnosis of HTN was defined as BP ≥ 140/90 mmHg based on the ADA guideline published in 2018 [2). Random blood glucose (RBG) was measured using a standardized Gluco Plus machine (Glucometer Type 25 KB JPG) capillary finger prick method, and further venous blood samples were drawn for serum creatinine, serum urea and fasting total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) and for glycated haemoglobin (HBA1C), and lastly midstream urine for protein was taken.A face-to-face interview was conducted, after obtaining written informed consent. A structured questionnaire was used to collect the patients' sociodemographic characteristics and the duration of HTN and DM. The history of drug compliance and regular clinic attendance was obtained from the patients' files, and the attendance of three months consecutively was regarded as regular. Physical activity was assessed using the International Physical Activity Questionnaires (IPAQ). This is the validated tool for self-reported measure of physical activity. After 5 minutes of rest, the BP was measured using the Spengler sphygmomanometer; then, a second reading was taken after 5 minutes of the first reading, and the third BP reading was obtained from the patients' last medical visit records, and thus, the overall average BP was obtained. The drug medications were self-reported using the single item past 7 days by . SuboptiData analysis was done using the Statistical Package for the Social Sciences (SPSS) version 25.p value of <0.05 was considered to be statistically significant. We categorised BP as normal when it was <140/90 mmHg, stage 1 HTN when it was 140/90 mmHg to 159/99mmHg, and stage 2 HTN when it was ≥160/100 mmHg.Categorical variables were expressed as proportions and percentages while continuous variables were expressed as means ± standard deviation. Comparison between categorical variables was done by the use of the chi-square test, while that of numerical variables was done by the use of analysis of variance; multivariates were used to assess the strength of association between the independent and dependent variables in the study, and a The data of 161 participants were analysed in this study. The majority of the study participants were females 108 (67.1%), and the mean age of the participants was 63.9 ± 20.4 years; the majority of them 124 (77%) were aged between 50 and 75 years. The highest level of education attained by most of the participants was primary level which accounted for 59.6%, and 76 (47.2%) of the respondents were either peasants or small-scale farmers; the majority of them were either current drinkers or those who used to take alcohol, accounting for 67.8%, and cigarette smoking was observed in 14 (8.7%) of the respondents. Among the respondents, 67.7% had taken initiative measures of reducing salt intake in their meals. Two-thirds of the participants were covered by the National Health Insurance Fund (NHIF) in Tanzania. Other subscribers from different insurance companies were not considered because they were temporarily suspended by the hospital management during the time of the study see .In the medical and laboratory characteristics shown in p ≤ 0.482), and retired participants had 70.8% (p ≤ 0.079) suboptimal BP control. Cigarette smoking was another factor which was associated with suboptimal BP control   and diastolic BP (DBP) was seen in 137 (85.1%) and in 98 (60.9%), respectively. Thus, the overall suboptimal SBP/DBP was 93 (57.8%) as shown in p ≤ 0.020). Duration since the diagnosis of HTN or DM was another factor which contributed to suboptimal BP control as those who had HTN for 11 years and those who had above 5 years since DM diagnosis were 65.8% and 60%, respectively. Overweight and obesity were also associated with suboptimal BP control . Suboptimal BP control was reported in 90.0% of the participants who were physically inactive, and in those who were having few days of physical activities (1-5 days per week), suboptimal BP control accounted for 59.1%. The total serum cholesterol was normal in 63.2%. Positive urine for protein was found in 21% with uncontrolled BP. Elevated serum creatinine was reported in 45.5% of the participants with suboptimal BP control whereas uncontrolled blood sugar as indicated by high HbA1C levels was recorded in 64.9% (p ≤ 0.078) of the participants. Drug adherence was another predictor of suboptimal BP control as was reported in 81.8% (p ≤ 0.004) of the participants   or angiotensin II receptor blockers (ARBs) or ACE-I/ARBs in combination with other drugs, were the most frequently prescribed antihypertensive drugs; 72.1% of the participants were on those regimens.p ≤ 0.001).Significant BP control was seen in participants who were receiving ACE-I alone (63.2%); even in the multivariate logistic regression, there were no changes. The poor control of HTN was observed in patients who were on calcium channel blockers alone (88.2%)  see .The following independent variables age, sex, level of education, salt reduction, family history of HTN, and type of antihypertensive drugs showing a significant association with the dependent variable in the univariate analysis therefore were used in the multivariate analysis as shown in In this hospital-based cross-sectional analytical study, we explored the extent of suboptimal BP control as defined by the ADA 2018 guideline to be BP ≥ 140/90 mmHg [The overall suboptimal BP control was 57.8%, whereby the prevalence of suboptimal systolic and diastolic BP control was 85% and 60.9%, respectively. This high prevalence is contributed by poor drug adherence and financial constraints for those paying out of their pockets, taking into consideration that in Tanzania, we have less than 15% of insured population. Suboptimal BP control has been reported in other many studies worldwide; to mention few, in India, uncontrolled BP was found to be 62.3% ; in the The highest prevalence of suboptimal BP was observed in a study done in Singapore with 86.6% . This isSuboptimal BP control was more prevalent in the elderly . These findings have been similar to those of other studies done in South Africa  and EthiAn increased body mass index as indicated by overweight and obesity was another important finding which was associated with suboptimal BP control where the prevalence was 56.6% and 63.2%, respectively. This was similar to the findings in Jordan where the prevalence of overweight and obesity was 52.5% and 28.8%, respectively .p ≤ 0.02), it was different from the study done in Ethiopia which found the prevalence of 17.56% [Duration since the diagnosis of HTN in this study was also associated with suboptimal BP control, where 65.8% of the participants with the duration of more than 11 years were compared to those who had less duration. This was also observed in the study done in Ethiopia where the prevalence was 46.6% for participants who had duration of more than 5 years . The diff 17.56% .Uncontrolled blood sugar as shown by HBA1C was 68.2% which can be explained by poor adherence to medication. Elevated cholesterol was found in 50.3%; these findings are almost the same with that of the study done in Jordan (HBA1C (52.5%) and cholesterol (54.9%)) . InactivAlcohol intake was another factor which contributed to suboptimal BP control among the study participants (56.9%); this is because most of the participants in our study were drinking local brew together with medication thinking that local brew was not alcohol. 87% was found in the study done in South Africa .ACE inhibitors were found to be superior (53.57%) in the control of BP in diabetic patients to other antihypertensives; this has been observed in many studies including the study done in Germany which showed superiority of RAS blockade, particularly ACE inhibitors  and the In this study, only 42.2% of hypertensive diabetic patients met the recommended BP control values in DM (<140/90 mmHg). More effort should be addressed to control the risk factors associated with poor BP control in diabetic patients. Physicians should put more emphasis on the early initiation and proper selection of antihypertensive especially the use of ACE inhibitors because they have shown better effect. It should be borne in mind that ACE-I and ARBs should not be taken concurrently.Most of the participants who attend the clinic every 2 to 3 months tend to refill their antihypertensive in other peripheral health facilities where there are limited drug options so compliance to one class or a course of antihypertensive cannot be guaranteed.It was difficult to ascertain the contribution of dietary salt intake in the study population because we did not measure urine sodium excretion. Poor adherence to medication contributed by high cost of people who are not covered by health insurance was difficult to control.


Background: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular morbidity and mortality, and it has a detrimental effect on renal function. Obesity is the major risk factor for OSAS, and represents a risk factor for chronic kidney disease. Continuous positive airway pressure (CPAP) is the suggested therapy for moderate-to-severe OSAS. We designed this study to evaluate the effect of CPAP on estimated glomerular filtration rate (e-GFR) in a cohort of obese patients with moderate-to-severe OSAS and normal renal function.Methods: We enrolled 198 obese subjects, divided into two groups (OSAS+ and OSAS–), on the basis of cardiorespiratory monitoring; mild OSAS patients (n = 33) were excluded from the study, thus the analyses were conducted on 165 patients. Comparisons between groups were made by Student t-test or χ2 test as appropriate. Linear regression analyses were used to assess the relationship between baseline e-GFR and different covariates and, in the OSAS+ group, between Δe-GFR and different covariates. A multivariate regression analysis was performed to determinate the independent predictor of the Δe-GFR.Results: OSAS+ subjects showed significantly increased values of systolic blood pressure, HOMA, pulse wave velocity, high-sensitivity C reactive protein and uric acid compared with OSAS– group. OSAS+ group showed significantly lower values of e-GFR and increased values of microalbuminuria. At linear regression analysis e-GFR resulted significantly and inversely related to AHI in the whole study population and in the two groups. After 6 months of CPAP therapy, OSAS+ subjects showed an improvement in respiratory parameters, as well as a significant increase in e-GFR values . At multiple regression analysis, Δ apnea/hypopnea index (AHIa) resulted the main independent predictor of Δe-GFR explaining 22% of its variation.Conclusions: Obese OSAS patients show significantly lower values of e-GFR, even if in the normal range, compared with obese non-OSAS subjects. After 6 months of CPAP, e-GFR significantly improved (+20 ml/min/1.73 m2) and ΔAHIa resulted the most important independent predictor of Δe-GFR. In the last years obstructive sleep apnea syndrome (OSAS) has been considered as an independent risk factor for cardiovascular (CV) morbidity and mortality, similarly to other classical risk factors such as obesity, diabetes mellitus (DM), and hypertension . Even ifRenal function decline, evaluated by estimated glomerular filtration rate (e-GFR), is associated with increased CV morbidity and mortality in the general population as well as in various settings of patients –9, and mHowever, the relationship between OSAS and renal function decline needs to be further elucidated; it is well-known that OSAS is highly prevalent among individuals with end-stage renal disease (ESRD)  and thatOn the other hand, several data showed that obesity, the main risk factor for OSAS, is also associated with dysregulation of renal function, such as glomerular hyperfiltration and increased albuminuria, thus representing a risk factor for CKD and its progression to kidney failure –18.Currently, the gold-standard treatment of moderate-severe OSAS is continuous positive airway pressure (CPAP), regardless of body weight . This th2).Previous studies investigating the effect of CPAP treatment on renal function were conducted in patients with CKD  or in no2; 110 males and 55 females; mean age 55.3 ± 11.0 years) referred to the Sleep Breathing Disorders Clinic of the University Hospital of Catanzaro, who underwent cardiorespiratory monitoring (CRM) during sleep for reported daytime sleepiness and persistent (>6 months) snoring. None of the patients had history or clinical evidence of angina, myocardial infarction, valvular heart disease, arrhythmias, peripheral vascular disease, arterial hypertension, DM, coagulopathy or any disease predisposing to vasculitis or Raynaud's phenomenon, liver and respiratory disease, lung failure, CKD  or urinary tract infections. At the time of the first evaluation, we collected medical history and performed physical examination evaluating body weight, height and BMI, waist and neck circumference (NC), determination of arterial stiffness, routine blood tests, and 75-g oral glucose tolerance test (OGTT) after 12 h fasting, 0 and 120 min of sampling for plasma glucose and insulin determination. According with clinical guidelines for OSAS management  approved the protocol  and informed written consent was obtained from all participants. All the investigations were performed in accordance with the principles of the Declaration of Helsinki.We recruited 198 obese Caucasian outpatients . Triglyceride and total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol concentrations were measured by enzymatic methods . Plasma concentrations of insulin were determined by chemiluminescence test (Roche Diagnostics). Insulin resistance was determined by homeostasis model assessment (HOMA) index, calculated according with the following equation:2) were calculated with the equation proposed by investigators in the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration  concentrations were determined by chemiluminescent immunoassay . High sensitivity C-reactive protein (hs-CRP) levels were measured by an automated instrument .that is strongly related to the euglycemic clamp, which represents the gold standard test for measuring insulin sensitivity. Creatinine measurements and uric acid (UA) were performed at baseline by use of the Jaffe methodology and the uricase peroxidase  method implemented in an autoanalyzer. Values of e-GFR , with continuous non-invasive recordings of respiratory pressure and flow, thoracic-abdominal motion, oxygen saturation, ECG and body position. Results from the sleep studies were analyzed by a trained technician using the recommendations of the American Academy of Sleep Medicine (AASM) . The sevBlood pressure (BP) measurements readings of clinic BP were obtained in the non-dominant arm of the seated patient, after 5 min of quiet rest, with a mercury sphygmomanometer. Systolic and diastolic BP was recorded at the first appearance (phase I) and disappearance (phase V) of Korotkoff sounds. Baseline BP values were the average of the last two of the three consecutive measurements obtained at intervals of 3 min .TM; AtCor Medical, Sydney, Australia) that employs high-fidelity applanation tonometry (Millar) and appropriate computer software for the analysis of pressure wave (SphygmocorTM). Aortic pulse wave velocity (PWV) was determined from carotid and femoral pressure wave forms. Carotid to femoral transit time (DT) was computed from the foot-to-foot time difference between carotid and femoral waveforms. The distance between the surface markings of the sternal notch and femoral artery was used to estimate the path length between the carotid and femoral arteries (L), and PWV computed as L/DT.These measurements were obtained by a validated system (Sphygmocort-test or χ2 test as appropriate. Patients were divided in two groups: OSAS + (AHI>15) and OSAS– (AHI < 5). Linear regression analysis was used to assess the relationship between baseline e-GFR and different covariates in all population and in the groups separately. Thus, the same analysis was performed in the OSAS+ to evaluate the major determinant of the e-GFR variation (Δe-GFR), before and after 6 months of CPAP, considering the variation (Δ) of the examined covariates. After this, a multivariate regression analysis was performed to determinate the independent predictor of the Δe-GFR. A value of P < 0.05 was considered statistically significant. All calculations were made with a standard statistical package (SPSS for Windows version 16.0).The analysis was performed on 165 subjects, and results were expressed as mean ± SD or as percent frequency. Comparisons between groups were made by paired or unpaired Student n = 100, and OSAS+ n = 65) on the basis of CRM results. Baseline anthropometric, clinical, and humoral characteristics of the whole study population and of the two groups separately are listed in 2, P < 0.0001) compared with OSAS– group ; baseline anthropometric, clinical and humoral characteristics of these patients are described in the S– group .r = −0.667, P < 0.0001), ODI , TC90 , microalbuminuria , SBP , UA , hs-CRP , triglycerides , while it was directly associated with HDL-cholesterol  and IGF-1  in the whole study population. In OSAS– group e-GFR was significantly related to hs-CRP  and DBP , while it was inversely related to AHI . In OSAS+ patients, e-GFR was significantly and inversely related only with AHI  .At linear regression analysis  e-GFR wa= 0.005)  and micr2, P < 0.0001) after 6 months of CPAP therapy (2) at the end of the follow-up period, to be intended as a hyperfiltration due to a weight gain >5% from the basal value. Subsequently, in the same group, a linear regression analysis was performed between Δe-GFR, as dependent variable, Δ of different covariates and baseline e-GFR. As shown in r = −0.482, P < 0.0001) and e-GFR at baseline . Then, we performed a multiple regression analysis ( therapy ; in two analysis  includin2. Clinically relevant, ΔAHI resulted the most important independent predictor of Δe-GFR, allowing to affirm that the improvement of nocturnal respiratory function is the main determinant of e-GFR increase in this particular setting of patients. In fact, ΔAHI -or the resolution of apneas during CPAP-, and ΔTC90 -or the improvement of oxyhemoglobin saturation during sleep-, represent the main predictors of Δe-GFR, independently from metabolic, hormonal, and inflammatory status. These findings are consistent with other published literature, which identifies the resolution of chronic intermittent hypoxic episodes during sleep as the major pathophysiological mechanism of the improvement of endothelial glomerular function (The most important finding obtained in this study, conducted in a population of obese patients with normal renal function, is that those with moderate-to-severe OSAS showed lower—even if in the normal range—baseline e-GFR values compared to subjects without OSAS; moreover, 6 months treatment with CPAP was effective in improve e-GFR by 20 ml/min/1.73 mfunction , 27, 28.function ; mineralfunction . In our function , 31 throfunction . Other sfunction . With thfunction , 35; in The novelty of our study is that, differently from other Authors, we considered a group of obese subjects with preserved renal function. Many studies describe a major prevalence of breathing sleep disorders in subjects affected by ESRD in comparison with those with normal renal function , 37. On In conclusion, even if this study has several limitations such as the single-center non-blinded design and the small sample size, our data confirm previously published literature about the detrimental effect of OSAS on renal function also in subjects free from kidney disease; this detrimental effect may be reverted, at least in part, by CPAP therapy.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comitato Etico Calabria Centro. The patients/participants provided their written informed consent to participate in this study.MP, FP, and RM: Conceptualization; PS and AS: methodology; RM and PS: software; MP, GS, and FP: validation; RM: formal analysis; PS, BC, LM, MV, and ES: investigation; MP, RM, and PS: writing—original draft preparation; MP and FP: writing—review and editing; MP, AS, and FP: supervision. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The prevalence of chronic kidney disease (CKD) in Malaysia was 9.07% in 2011. We aim to determine the current CKD prevalence in Malaysia and its associated risk factors.2 or the presence of persistent albuminuria if eGFR ≥60 ml/min/1.73m2.A population-based study was conducted on a total of 890 respondents who were representative of the adult population in Malaysia, i.e., aged ≥18 years old. Respondents were randomly selected using a stratified cluster method. The estimated glomerular filtration rate (eGFR) was estimated from calibrated serum creatinine using the CKD-EPI equation. CKD was defined as eGFR < 60 ml/min/1.73mOur study shows that the prevalence of CKD in Malaysia was 15.48%  in 2018, an increase compared to the year 2011 when the prevalence of CKD was 9.07%. An estimated 3.85% had stage 1 CKD, 4.82% had stage 2 CKD, and 6.48% had stage 3 CKD, while 0.33% had stage 4–5 CKD. Hypertension (aOR 3.72), diabetes mellitus (aOR 3.32), increasing BMI (aOR 1.06), and increasing age (aOR 1.06) were significantly associated with CKD.Our study has shown that CKD has become one of the leading public health issues in Malaysia. Thus, there is an urgent need to screen for CKD and prevent its progression, associated morbidity, and mortality at the national level. Chronic kidney disease (CKD) affects about 1 in 10 adults and accounts for millions of premature deaths worldwide . CKD repIt is, therefore, necessary to determine the current prevalence of CKD to assist healthcare planning, resource allocation, and to guide healthcare policy in prevention, early detection, and treatment of CKD. KDIGO’s 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease supports early detection of CKD in asymptomatic individuals at increased risk . ScreeniThis is a cross-sectional study; conducted from September 2017 to June 2018. The target population was residents in non-institutional living quarters (LQ) aged 18 years and above in Malaysia. The Department of Statistics Malaysia provided the latest available sampling frame that is representative of Malaysia, divided into enumeration blocks (EBs) and stratified by the state as well as locality . In 2017, Malaysia had about 83,000 EBs.A multi-stage cluster sampling design was used in our study. Respondents were sampled throughout Malaysia Fig. . GeograpA complex design study formula was used to calculate the sample size to estimate population prevalence, which includes expected CKD prevalence of 9%, a margin of error of 0.03, and a confidence interval of 95%. Although estimation of CKD prevalence in Malaysia requires an optimal sample size of 700, we targeted 1440 respondents, taking into account a possible high non-response rate due to the biological samples that were needed (venous blood and urine samples).The inclusion criteria were Malaysians 18 years of age and above who gave written consent for participation in the study. The exclusion criteria were women who were pregnant or menstruating during the data collection. Trained staff conducted face-to-face interviews using tablets with all the respondents to complete the data collection. Measures were taken to minimise the dropout rate and maximise the response rate. Field staff not only worked in the evenings but also on weekends to cater to the working individuals; this even involved visits to the workplace of the respondents.A sociodemographic questionnaire was used to collect demographics, disease history, and medication use. It was developed by a panel of experts, pre-tested, and validated before the study .Clinical measurements were taken, which included blood pressure (BP), waist circumference, body weight, and height. Blood pressure was measured with a calibrated digital automatic BP monitor (Omron HEM-7221) at chest level with an appropriate-sized cuff. Three BP measurements were taken at 1 to 2-min intervals with the respondent at rest and seated; only the mean of the last two readings was used for analysis. This was done because the first reading of BP in a series is usually the highest , and it Urine albumin-to-creatinine ratio (uACR) was measured using a single urine sample. Urine samples were transported in insulated boxes with ice packs to an accredited central laboratory. Blood for serum creatinine and random blood sugar was taken from respondents at their home by qualified staff from a nearby Ministry of Health (MOH) haemodialysis unit.2 were contacted to repeat uACR within 4 months. Only respondents with albuminuria in repeat sampling were classified as having persistent albuminuria  with the Abbott Architect ci8200 machine and Abbott/Creatinine reagent. The creatinine assay has calibration traceable to an isotope dilution mass spectroscopy (IDMS). Random blood glucose was measured with the Abbott Architect ci8200 using Abbott/Glucose reagent. Microalbumin in urine was measured using an immunoturbidimetric method.Completed questionnaires and biochemistry results were sent to the Survey Creation System server centralised in the Institute for Public Health. Datasets were continuously monitored for quality control by the data manager.The CKD-EPI equation , 20 was where SCr is serum creatinine (in mg/dl), k is 0.7 for female and 0.9 for male,α is - 0.329 for female and - 0.411 for male,min is the minimum of SCr/k or 1, and max is the maximum of SCr/k or 1.CKD stages were defined as below:2 and persistent albuminuria;Stage 1 as eGFR > 90 ml/min per 1.73m2 and persistent albuminuria;Stage 2 as eGFR 60–89 ml/min per 1.73m2;Stage 3 as eGFR 30–59 ml/min per 1.73m2 and,Stage 4 as eGFR 15–29 ml/min per 1.73m2.Stage 5 as eGFR < 15 ml/min per 1.73mKidney Disease Improving Global Outcomes (KDIGO) guideline for CKD [Kidney damage was assessed using uACR, which provides a sensitive measure for the detection of kidney damage. Based on the  for CKD , albuminMicroalbuminuria as urine ACR 30 mg/g – 300 mg/g;Macroalbuminuria as urine ACR of > 300 mg/g and,Persistent albuminuria as two episodes of albuminuria at least 1 month apart.2 was classified as underweight, 18.5 to 24.9 kg/m2 as normal weight, 25 to 29.9 kg/m2 as overweight and BMI ≥30 kg/m2 as obese. A waist circumference of more than 90 cm in male and more than 80 cm in female were considered as abdominal obesity [Hypertension, diabetes mellitus, and hypercholesterolemia were defined as self-reported diseases previously diagnosed by medical personnel. Also, blood pressure and random blood sugar levels were tested to detect undiagnosed hypertension and diabetes in those respondents who did not have any previous diagnoses of these two diseases. These respondents were categorised to have hypertension if mean systolic BP was ≥140, diastolic BP was ≥90 mmHg or both , and to  obesity . The IntData were analysed using SPSS version 22. Identified outliers were rechecked and verified. The calculated sample weight was according to the Malaysian population aged 18 years and above. The national prevalence of CKD was estimated using complex design analysis. The sampling procedure and the population weight were adjusted for sex and locality  during the analysis .p-value of less than 0.05 was considered significant.Data were reported as a mean for continuous variables and proportion for categorical variables. Prevalence estimates were performed. Multiple logistic regression was employed to identify factors associated with CKD. The multivariable model was obtained based on the backward stepwise variable selection method. All possible two factors interaction terms were each checked together with the main effects. The fit of the logistic model against the actual outcomes was assessed using the goodness of fit statistics. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated. A n = 1047) consented to participate. Serum creatinine was measured in 977 respondents. Further breakdown of the analysis numbers is shown in Fig. n = 1047) and the final analysis set.A total of 1398 individuals were approached for this study, and 75% of them (n = 890). Around two-thirds (64.9%) were low-income earners. Nearly half (47.9%) of the respondents had a maximum education level at the secondary school level. Respondents with self-reported hypercholesterolemia were 32.6%, while about half of the respondents (51.0%) had hypertension. More than half (55%) admitted to using pain killers, while 12.6% admitted to using traditional medicines. A total of 31.8% of respondents had ever smoked.Table 2) and 6.8% had moderate to severe renal failure (eGFR < 60 ml/min/1.73m2) , and increasing age were significantly associated with increased risk for CKD . In Malaysia, the distribution of urban to rural population was 75.5 and 24.5% in 2017 . In the Our study shows that awareness of CKD diagnosis was still low at 5%, which is similar to the previous study in Malaysia (4%). Awareness of CKD was found to be 12.5% in China , 7.9% inThis study also found that respondents with diabetes had a three times higher incidence of albuminuria compared to non-diabetics (37.3% versus 11.4%). The incidence of new dialysis patients with diabetes mellitus in Malaysia has risen from 44% in 2000 to 65% in 2016 . In lighStudies on CKD prevalence in other countries found that CKD was closely associated with diabetes mellitus, increasing age, obesity, hypertension –38, use The strengths of this study include the use of an accredited central laboratory, the use of standardised equipment, trained workforce and questionnaires that were validated by the previous NHMS studies . The resOn the other hand, this study also has several limitations. First, an actual cause and effect relationship could not be established in this study due to its cross-sectional design. Secondly, we did not include very rural areas in this study, especially in East Malaysia, due to logistic reasons. Thirdly, kidney damage was only assessed using a single parameter, which was albuminuria. If other signs of kidney damage  were included in this study, the prevalence of CKD might have been higher. Although we managed to repeat uACR testing to confirm persistent albuminuria, the same could not be done for serum creatinine after 3 months due to logistic limitations. Thus, some subjects with acute kidney injury could have been included in this study.Our study has shown that CKD has become one of the leading public health issues in Malaysia with increased prevalence and low awareness. Our results support the need to emphasise on improving the education and early detection of CKD in the community. The findings of this study have helped to convince policymakers of the need to stem the rising tide of CKD in the country. In April 2018, the National Strategic Action Plan  adopted


In the first group, there was a decrease of both brachial AIx and PWV in the second and third trimester, followed by a post-partum increase; better outcomes were noticed in physically active women. Conclusions. Arterial function modifies during pregnancy and these alterations differ according to the trimester of gestation. Further research is needed to establish the cut-off values for this category. Pregnant women can have better outcomes through physical activity.Introduction. Maternal age for the first pregnancy is increasing and so, the prevalence of cardiovascular risk factors in pregnancy is also increasing. Heart disease is the main reason for maternal death during pregnancy in developed countries. Arterial stiffness is an independent risk factor for atherosclerosis and a predictor of cardiovascular morbidity and mortality. The most widespread parameters for detecting subclinical atherosclerosis are augmentation index (AIx) and pulse wave velocity (PWV). The objective of this prospective study was to assess the differences between arterial function in pregnant vs. non-pregnant women of the same age, and its changes throughout the gestation period. Materials and Methods. Between 2010–2019, 887 patients were enrolled into 2 groups: pregnant (N1 = 471) and non-pregnant (N2 = 416). Data about their anthropometric characteristics, arterial function , smoking status and physical activity were collected. Results. There were statistically significant differences ( Cardiovascular disease is associated with increased arterial stiffness and central aortic systolic blood pressure (SBPao) . The firArterial stiffness describes properties of the arterial vascular system such as distensibility, compliance, and elastic modulus . It can Physiological pregnancy has a shifting effect on the cardiovascular system, which is maintained into the post-partum period . At arouSystemic vasodilation and physiologic anaemia lead to tachycardia (heart rate increases by 15–30% in the first trimester of pregnancy) and contribute to a further cardiac output augmentation . Blood pThere are proofs regarding the contribution of maternal arterial dysfunction in pregnancy-specific conditions such as preeclampsia and intrauterine growth restriction . ArteriaThe predictive value of PWV for cardiovascular diseases (CVD) has been studied and reported in the general population and in patients with different clinical conditions . The infIn the general population, arterial stiffness is an early marker of cardiovascular disease and a predictor for mortality. During pregnancy, the entire cardiovascular system suffers modifications, including the arterial stiffness and compliance parameters. These alterations are more extensive and prolonged in preeclampsia patients. Arterial stiffness enhancement precedes the onset of pregnancy-related hypertensive disorders. Its parameters can be used as early risk detectors in normotensive, low-risk women who will develop preeclampsia. The current study aimed to compare arterial stiffness in pregnant and non-pregnant women and assess the differences. There are no reference values for gestational period and previous research was based on numbers for the general population. In all pregnant patients with pregnancy-related diseases, chronic conditions prior to gestation, or risk factors, or even healthy women, it is necessary to assess their arterial stiffness parameters as predictors for possible future events. It is mandatory to thoroughly study the arterial stiffness before, during and after gestation on large groups of subjects and to establish the exact cut-off values for this population.This prospective study was performed in patients admitted to the Obstetrics and Gynaecology Department of “Pius Brînzeu” Emergency Clinical County Hospital of Timisoara, Romania, during a 10-year period (between 2010–2019). The study was performed with the approval of the Ethics Committee of the hospital mentioned above (decision no. 54/20 April 2017) and it was conducted according to the established principles of the Declaration of Helsinki .First, 1000 patients were included in the study. Patients with high blood pressure, cardiac arrhythmias, diabetes, obesity, hypercholesterolemia, chronic kidney disease, and systemic vasculitis, were excluded from the study. The final group consisted of 887 pregnant and non-pregnant healthy women, aged between 20–45 years, after they signed the informed consent.The patients were divided into two different groups: group 1—healthy primiparous pregnant patients , without comorbidities or risk factors and group 2—control, healthy non-pregnant patients . Personal data about lifestyle, smoking status, exercise, medical history (including family history), anthropometric features ) and results of arterial function assessments were collected. In group 1 , data about arterial functions were collected during four separate visits, in the first, second and third trimester of pregnancy, and 6 weeks post-delivery. In addition, data about the gestational period, the foetus weight and gender and delivery type  were added.The pulse wave was analysed through an easy, non-invasive method and an accredited medical device: Arteriograph . Each patient was prepared 24 h prior to the test, and the procedure was explained (according to the “patient info” document). For PWV determination, the protocol from the technical book  of the dThe room/doctor’s office offered a proper environment ; the consultation bed was a horizontally fitted mattress with easy access to both arms. Patients who smoked, ate, drank energy drinks/coffee within <3 h prior to the assessment were rescheduled. The patient was laid down to rest for approximatively 10–20 min before the investigation. After the patient was set in the supine position, tight clothing was removed from forearms and arms. The circumference of both arms and the distance between the pubic symphysis and the sternum fork were measured. Personal information, anthropometric characteristics and anamnesis data were registered. The cuff recommended by the software  was placed in the middle of the arm and the measurements were performed. The patient was not allowed to speak, sleep or move throughout the investigation, and remained in the supine position. If the investigation values appeared erroneous, or the patient was emotional or had tachycardia, the assessment was repeated 4 times  on the same arm. The cuff was shifted to the contralateral arm (observing the size of the cuff according to the software recommendation) if the expected results were not obtained. If no results were obtained on the contralateral arm as well, manual measurements were performed, as allowed by the software. In the case of arrhythmias, the investigation was postponed until sinus rhythm was established and performed only in hemodynamic stability, with properly controlled values (according to the European Society of Cardiology guidelines) . PatientAccording to the data from the literature, the reference value of PWV in adult women is 7.4 m/s . ReferenThe complex arterial function assessment included parameters such as systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), aortic SBP (SBPao), aortic pulse wave velocity (PWVao), and augmentation index (AIx). All measurements were performed with the same device, TensioMed Arteriograph, mentioned before.t Student test, Mann–Whitney test, ANOVA unifactorial test and Friedman test were used. For the entire study, α = 0.05 was considered as the confidence level. For descriptive statistics, the central tendency and dispersion indicators were calculated, and the main results were plotted. The statistical analysis was performed using the SPSSv17 and the Microsoft Excel programs.The database was created using the Microsoft Excel program. For testing the data distribution, the Kolmogorov–Smirnov normality test was applied. To see if the observed differences were statistically significant, the most suitable statistical tests for our variables, the For the qualitative dichotomous variables, frequency tables were used. The mean values for basic characteristics and hemodynamic parameters in both groups are presented in p < 0.05); thus, parametrical tests were valid. For double-checking, one parametrical test (the Student t unpaired test) and a nonparametric test (the Mann–Whitney test) for age, body mass index (BMI), brachial AIx, PWVao, SBP, DBP, PP (which is the difference between systolic and diastolic blood pressure), SBPao and HR values were combined. Statistically significant differences (p < 0.05) were obtained for BMI, brachial AIx, PWVao, DBP, PP and SBPao values. All the results are presented in To determine if there are any significant differences between both groups and between subjects who performed physical activity and who did not, several statistical tests were used. The Kolmogorov–Smirnov normality test was applied to see the data distribution for the numerical variables, and a normal distribution for all data was found . PWVAo started to decline in the second trimester and continued to decline in the third trimester; in post-partum, it was increased compared to the first trimester  .p < 0.001) between the brachial AIx (%) and PWVao values during the study period. Brachial AIx % decreased until the third trimester, when it started to increase again until the post-partum stage , APGAR score (9.22 ± SD) and foetus weight (3468.97 g ± SD) are presented in t unpaired test and Mann–Whitney test were applied, for each group separately. Significant differences were obtained (p < 0.05) for BMI, brachial AIx, PWVao, SBP, DBP, PP, SBPao and HR values. In group 1, women who regularly exercised (33.97%) were compared to women who did not exercise (66.03%). We also compared them in all 4-time moments: first, second, third trimester, and in post-partum. Patients who are physically active had statistically significant better outcomes (p < 0.05) for delivery, anthropometric features, hemodynamic status and arterial functions.To see if physical activity can modify the outcomes, both the Student PWV is an independent predictor of future CVD in women with high blood pressure , stroke Lynch et al. highlighted the critical role of communication between physicians and pharmacists for the best outcomes of pregnancy . The intNumerous studies have demonstrated the prognostic significance of PWVao measurement as an indicator of subclinical organ damage, both in the general population and patients with increased cardiovascular risk, especially patients with hypertension, diabetes, or chronic renal failure. Evidence suggests that aortic stiffness may precede and contribute initially to the development of hypertension .In a healthy pregnancy, there is a significant increase in uterine blood flow, remodelling of the spiral arteries , more niConsidering the literature data, we hypothesised that pregnant women would have a different pattern of arterial function compared to non-pregnant women. This field is yet to be explored. Some studies concluded that in physiological pregnancy, there is a significant decrease in unadjusted aortic PWV from pre-conception to the second trimester . In the Fujime et al. observed that central aortic SBP (cSBP) and AIx significantly declined during pregnancy, reaching lowest values in mid-pregnancy and rising towards term, especially the heart rate-corrected AIx (AIx-75). cSBP and AIx-75 were significantly increased in healthy pregnant women older than 35 years.p < 0.05) in terms of delivery, anthropometric features, hemodynamic status and arterial functions. Beck et al. demonstrated that resistance and endurance exercise alone effectively reduce peripheral arterial stiffness, central blood pressure, AIx, and myocardial oxygen demand in young pre-hypertensive subjects . FurtherNumerous pharmacological ,49 and nThis study offers insights regarding PWV analysis and additional information about arterial stiffness in pregnant women versus conventional brachial blood pressure measurements . In addiThe results obtained in this study proved that arterial function is modified during pregnancy and these alterations differ according to the trimester of gestation; there was a decrease of both Aix brachial and PWV in the second and third trimester, followed by a post-partum increase. In addition, women who regularly exercised had ameliorated anthropometric features, hemodynamic status and delivery outcomes. Due to these specific changes that occur in normal healthy pregnancies, further studies are necessary to establish cut-off values for this category of patients, in order to detect early changes in arterial stiffness parameters. Arterial stiffness assessment represents a useful tool in the early diagnosis of pregnancies at risk and can lead to better routine care and better outcomes for these patients, through early detection and physical activity.


Pulmonary transit time (PTT) measures the time that blood travels through the pulmonary vasculature. PTT correlates well with pulmonary vascular resistance. It is prolonged in patients with pulmonary hypertension and congestive heart failure. Similar to systemic and coronary vasculature, the pulmonary arteries dilate in response to purine nucleoside adenosine which has a direct endothelium independent effect on the A2b receptor in vascular smooth muscle. Despite the detrimental effect of cigarette smoking on endothelium dependent systemic vascular function, little is known of its effect on endothelium independent function of the pulmonary vasculature.The objective of this study is to develop a non-invasive strategy using first pass perfusion MRI to measure PTT and to test the hypothesis that cigarette smoking inhibits endothelium independent pulmonary vasodilation.The study included 63 prospectively recruited subjects (65% women) without significant pulmonary disease. All subjects underwent first pass perfusion cardiac MRI in a 1.5 Tesla Siemens scanner. Three long axis planes were acquired per heartbeat over 50 heartbeats using a partial Fourier saturation-recovery steady state free precession sequence during a breath hold. Dynamic perfusion imaging was first performed during adenosine infusion at 140 μg/kg/min with gadolinium concentration at 0.05 mmol/kg. Following a 20 minute washout period dynamic imaging was repeated without adenosine using the same parameters. Images were analyzed in commercial software . PTT was measured between the times when signal intensity reached a peak in main pulmonary artery and in the left atrium.The mean age of the study cohort was 55.9 ± 13.1 years. The prevalence of never, past and current smoking was 42.4%, 49.2% and 8.5%, respectively. Compared to rest PTT (5.98 ± 1.33 s) there was a 25.4% reduction (p < 0.001) in PTT during adenosine infusion (4.46 ± 0.94 s). When the analysis was stratified by smoking status significant PTT reduction was seen in never smokers  and in past smokers  but not in the current smokers . However, there was significant correlation between R-R interval and PTT with Spearman correlation coefficient 0.640 (p < 0.001) for rest PTT and 0.551, (p < 0.001) for stress PTT. In view of a 27.5% heart rate increase (p < 0.001) the analysis was repeated using PTT values normalized to RR interval. In contrast to absolute PTT measurements the normalized values demonstrated minimal change between rest and stress PTT in never smokers  and in past smokers . In contrast, there was an 18.7% increase (p = 0.029) in normalized stress PTT among current smokers.Adenosine infusion was associated with significant PTT shortening in never and past smokers. Shortened PTT likely represented reduced pulmonary resistance in response to the endothelium independent vasodilatory effect of adenosine. However this response appeared to be blocked by active cigarette smoking. In the absence of active cigarette smoking PTT normalized to R-R interval remained constant at rest and during stress, suggesting an intact vasoreactivity to accommodate increased cardiac output during adenosine infusion. Conversely this value was significantly prolonged during adenosine infusion among current smokers, implying impaired vasoreactivity likely due to the detrimental effect of cigarette smoking, which resulted in delay of pulmonary blood transit in the presence of increased blood volume. Our findings suggest that CMR adenosine stress testing may be an important modality to evaluate pulmonary arterial function.