Individuals with a family history of systemic arterial hypertension (FHSAH)and / or prehypertension have a higher risk of developing thispathology.To evaluate the autonomic and vascular functions of prehypertensive patientswith FHSAH.Twenty-five young volunteers with FHSAH, 14 normotensive and 11prehypertensive subjects were submitted to vascular function evaluation byforearm vascular conductance(VC) during resting and reactive hyperemia(Hokanson®) and cardiac and peripheral autonomic modulation,quantified, respectively, by spectral analysis of heart rate (ECG) andsystolic blood pressure (SBP) (FinometerPRO®). The transfer functionanalysis was used to measure the gain and response time of baroreflex. Thestatistical significance adopted was p ≤ 0.05.2; p < 0.01) and higher spectral components of verylow  and lowfrequencies  ofSBP. Additionally, we observed a lower gain of baroreflex control inprehypertensive patients compared to normotensive patients , but similar delay time.Pre-hypertensive individuals, in relation to normotensive individuals, havehigher VC both at rest  and peak reactive hyperemia . The indices of cardiac autonomic modulation weresimilar between the groups. However, in the peripheral autonomic modulation,greater variability was observed in prehypertensive patients compared tonormotensive individuals (9.4 [4.9-12.7] vs. 18.3 [14.8-26.7]mmHgPrehypertensive patients with FHSAH have autonomic dysfunction and increasedvascular conductance when compared to normotensive patients with the samerisk factor. Among them, individuals with afamily history of SAH (FHSAH)4 reduction of heart rate variability4 and reduction of baroreflexsensitivity5 are among thechanges that may contribute to the onset of hypertension in normotensive children ofhypertensive individuals. In addition, vascular abnormalities have also beenconsidered as potential candidates for the onset of hypertension in thispopulation.7The reason for the increased susceptibility of hypertensive offspring to developinghypertension is not completely elucidated. However, studies indicate that autonomicabnormalities, such as increased sympathetic modulation,9 and autonomic and vascular10 have also been pointed out as the main etiological factorsof pressure elevation.In prehypertensive patients, similar to those with FHSAH, dysfunctions12 the pathophysiological mechanisms responsible for pressureelevation in individuals with both risk factors, namely prehypertension and FHSAH,are not yet known. Therefore, this study aimed to evaluate the autonomic andvascular functions of prehypertensive individuals with FHSAH.Although prehypertension has a strong genetic predisposition,2 between the means of the normotensiveand prehypertensive groups,13standard deviation of 0.21 ms2, alpha errors of 5% and beta of 20%, 7individuals in each group would be needed. The sample consisted of 25volunteers, subdivided according to blood pressure levels in the normotensivegroups  and prehypertensive.14 All volunteershad FHSAH defined as father, mother, or both with a diagnosis of SAH, which wasevaluated by means of a questionnaire.From the sample calculation performed based on the difference in sympatheticcardiac modulation of 0.31 msInclusion criteria adopted were age between 18 and 40 years, SBP lower than 140mmHg, DBP lower than 90 mmHg and not involved in systematized physical exercisesfor at least six months prior to the research. In addition, only volunteers whohad blood test results within 30 days prior to the start of the study in theirmedical records were included. Individuals with cardiometabolic diseases,smoking or drug treatment that could interfere with the cardiovascular systemwere not included.This study was approved in the Committee of Ethics in Human Research of the HU /UFJF under the opinion nº 720/370. All volunteers signed the Free and InformedConsent Form.2).15 Waist circumference wasmeasured using an inextensible metric tape (Cescorf®), with anaccuracy of 0.1 cm. All of these variables were measured according to thecriteria established by the American College of Sports Medicine.16For body mass and height measurements, we used, respectively, a scale with aprecision of 0.1 kg and a stadiometer with a precision of 0.5 cm coupled toit (Líder®). The body mass index was calculated by dividingthe body mass by the squared height , heartrate and respiratory rate were monitored simultaneously for 15 minutes.Beat-to-beat BP was monitored by digital infrared photoplethysmography(FinometerPRO®) on the volunteer's dominant arm. Cardiac andrespiratory rates were recorded continuously (Biopac®) usingelectrocardiogram in lead II and thoracic piezoelectric tape,respectively.All acquired signals were reconstructed, digitized and recorded in amicrocomputer with a sampling frequency of 1 kHz and 16-bit resolution forfurther analysis.Forearm muscle blood flow was evaluated using venous occlusionplethysmography (Hokanson® Plethysmograph). The volunteer was placedin dorsal decubitus position and the non-dominant forearm was raised abovethe level of the heart to ensure adequate venous drainage.A silicon tube filled with mercury, connected to the low-pressure transducerand the plethysmograph, was placed around the volunteer's forearm, fivecentimeters away from the humeral-radial joint. One cuff was placed aroundthe wrist and another at the top of the volunteer's arm. The wrist cuff wasinflated at supra-systolic pressure level (200 mmHg) one minute before themeasurements started and was kept inflated throughout the procedure. At15-second intervals, the cuff placed on the arm was inflated at supra venouspressure (60 mmHg) for seven to eight seconds, then was deflated rapidly andmaintained for the same period. This procedure totaled four cycles perminute.Non Invasive Vascular Program 3.The increase in tension in the silicone tube reflected the increase inforearm volume and, consequently, in an indirect way, increased forearmmuscle blood flow, reported in ml/min/100 ml. The signal of the forearmmuscle blood flow wave was acquired in real time in a computer through the17The evaluation of peripheral vascular conductance was performed by dividingthe peripheral vascular blood flow by the mean BP (mmHg), multiplied by 100and expressed in "units".18 It was considered peak flow, the value ofthe first wave flow after the onset of reactive hyperemia.After measuring the forearm blood flow at rest for three minutes, theocclusion cuff positioned on the arm was inflated to 200 mmHg for fiveminutes. One minute before its deflation, the cuff placed on the wrist wasalso inflated to 200 mmHg remaining thus until the measurement wascompleted. After five minutes of occlusion, the arm cuff was rapidlydeflated to induce reactive hyperemia and blood flow was recorded for thenext three minutes, maintaining the cycle protocol, inflating to 60 mmHg for10 seconds followed by 10 seconds of deflation.19During the evaluation of the blood flow of the forearm at rest and theprotocol of reactive hyperemia, BP was measured beat-to-beat(FinometerPRO®). Additionally, during the rest period, cardiacoutput, left ventricular contractility (dP/dT maximum) and total peripheralresistance were also measured by the same equipment. In order to calculatethe cardiac index, the cardiac output was corrected by the body surfacearea.The variabilities of the iRR, SBP and respiratory activity were evaluated inthe frequency domain by autorregressive spectral analysis.20 This procedure allowed the automatic quantificationof the central frequency and power of each relevant component of thespectrum. The spectral components of the frequency band between 0 and 0.04Hz were considered very low frequency (VLF), the frequency band between 0.04and 0.15 Hz was considered low frequency (LF) and the frequency band between0.15 and 0.40 Hz, synchronized with respiration, considered high frequency(HF). Due to the short registration period, the VLF component of iRRvariability does not present well-established physiologicalexplanation.21While the VLF of SBP variability seems to be related to myogenic vascularfunction.22 The LFcomponent of iRR variability reflects, predominantly, cardiac sympatheticmodulation and the HF component, synchronized with respiration, cardiacparasympathetic modulation.21 In the variability of SBP, the LF component quantifiesthe vasomotor sympathetic modulation, whereas the HF reflects the mechanicaleffect of respiration in the heart and vessels and does not represent anautonomic index.23In stationary segments of 250 to 300 points, the time series of the iRR,respiration and SBP were decomposed into their frequency components by theautoregressive method using the Levinson-Durbin feature and the Akaikecriterion for the choice of model order.21 The ratio between the LFand HF components of the iRR was calculated to quantify the cardiacsympathovagal balance.The spectral power of each component of the variability of iRR and SBP wascalculated in absolute terms and in normalized units.24 This procedure allowed thequantification of coherence, phase shift and gain among the time series ofthe iRR  and the SBP  as described by Freitaset al.24The gain and the time delay of response of the baroreflex control of theheart rate were measured by the analysis of the transfer function analysisusing the bivariate autoregressive identification procedure.In this study, the gain was calculated whenever the coherence between thesignals was greater than 0.5 and the phase shift negative in the LF band,which indicates that the changes in the SBP preceded the changes in the iRR.In addition, it should be noted that the coherence, phase shift, gain andtime delay of baroreflex control of heart rate were quantified at thecentral frequency corresponding to the maximum coherence within the LFband.The evaluations were performed at the University Hospital of the FederalUniversity of Juiz de Fora (HU-CAS), always in the morning. The volunteerswere instructed not to ingest alcohol and / or caffeine and not to undertakevigorous physical activities within 24 hours prior to the evaluations aswell as not eating fatty foods on the day of data collection.The volunteers responded to the anamnesis that included the clinical data ofthe patients and their parents and were submitted to anthropometricevaluation. After the volunteers remained in the supine position for 10minutes, simultaneous recording of heart rate, respiratory rate and BP wasstarted for 15 minutes at rest. Then, the muscular blood flow of the forearmwas measured during three minutes of rest and three minutes of reactivehyperemia.Data were presented as mean ± standard deviation of the mean or as medianand interquartile range. To verify the normality of the distribution of allvariables analyzed, the Shapiro-Wilk test was used. In addition, the assumptionof homogeneity of variance was also verified by the Lèvene test. Thedistribution of the sexes between the groups was presented in absolute andpercentage values. Fisher's exact test was used to verify the possibledifference between the proportions of the sexes and of volunteers with bothhypertensive parents in the groups.Studentt test for the data that presented normal distribution andMann-Whitney U for the variables that violated this assumption. Two-way analysisof variance for repeated measures was used to test for possible differencesbetween groups in vascular conductance during resting and reactive hyperemia.The main and interaction effects were analyzed with Bonferroni confidenceinterval adjustment.The possible differences related to the demographic, clinical and autonomiccharacteristics of the groups were verified through the unpaired All statistical analyzes were performed using SPSS® software version 20.The statistical significance was p ≤ 0.05.Of the 25 volunteers analyzed, one normotensive volunteer did not meet theacceptability criteria for the analysis of the cardiac and peripheral autonomicmodulation, and one normotensive volunteer and two prehypertensive patients did notattend to the analysis of arterial baroreflex function.Indices of cardiac autonomic modulation were similar between the groups . HoweverThe main finding of this study is that peripheral autonomic dysfunction precedes thepossible vascular dysfunction in prehypertensive individuals with FHSAH.12 who also observed elevation of cardiac index andcardiac contractility, but similar peripheral resistance, in young prehypertensiveindividuals when compared to normotensive ones. Thus, although the typicalhemodynamic finding of hypertension is elevation of peripheral resistance, elevationof cardiac output appears to be responsible for pressure elevation in the earlystages of disease development.25As expected, the prehypertensive group had higher SBP and DBP. Since blood pressurevalues are determined by cardiac output and peripheral vascular resistance, in thisstudy, increased cardiac output by increasing systolic volume, possibly modulated byincreased cardiac contractility, appears to be related to blood pressure elevation,since both heart rate and peripheral vascular resistance were similar between thegroups. Similar results were obtained by Davis et al.,10 reduction of the plasma concentration of vasodilatorysubstances, such as nitric oxide26and elevation of vasoconstrictors such as endothelin-1.26 However,in this study, we observed greater forearm vascular conductance in both the rest andthe peak of reactive hyperemia in the prehypertensive patients when compared to thenormotensive ones. Other studies, also using the venous occlusion plethysmographytechnique, obtained controversial results regarding the vascular function ofprehypertensive patients. For example, Schwartz et al.27 evaluated the resting forearm vascular conductanceof normotensive and prehypertensive young men and did not observe differencesbetween groups. Beck et al.28evaluated youngsters of both sexes and observed lower vascular conductance inprehypertensive patients in relation to the normotensive ones.In addition, studies have shown impairment in the vascular function ofprehypertensive patients such as reduction of endothelium-dependent vasodilation,assessed by the infusion of acetylcholine,26 and Beck et al.,28 in contrast to the results of thisstudy, observed a lower peak flow in prehypertensive patients using, respectively,venous occlusion plethysmography and high-resolution ultrasound. The differencesbetween the results of this study and the others may be related to thecharacteristics of the population studied, such as the presence of FHSAH in bothgroups, since individuals with this risk factor have demonstrated vasculardysfunction in several studies.7 In addition to FHSAH,pre-hypertensive volunteers in this study had higher cardiac and contractilityrates, which may have triggered a local vasodilatory homeostatic response in anattempt to alleviate pressure elevation,12 although this mechanism failed systematically in view ofthe fact that no difference was observed between groups in peripheral vascularresistance. No studies were found that investigated the association between cardiacand contractility indices and vascular conductance in prehypertensive patients. Inhypertensive patients with hyperkinetic circulation, characterized by elevation ofcardiac index and mean arterial pressure, Stevo et al.29 observed greater forearm muscle blood flowcompared to normotensive individuals. However, in this study the calculation ofvascular conductance was not performed. Thus, future studies should investigate theassociation between these variables in pre-hypertensive individuals with a familyhistory of arterial hypertension.Already during the maneuver of reactive hyperemia, Beck et al.12 BPelevation in prehypertension results from hereditary disorders that present a set ofgenetic determinants and pathogenic traits that act on hemodynamic and autonomicevents in series and trigger the SAH. In this scenario, autonomic alterations appearto be the first changes observed in prehypertensive patients.12 However, although changes in thespectral indices of cardiac autonomic modulation in prehypertensive patients havebeen demonstrated in other studies,30 in this one, theywere not observed. Lin et al.,13who also observed LF and HF components in normalized units, as well as the LF/HFratio of heart rate variability, similar among normotensive and prehypertensiveyoungsters, reported results similar to ours. A possible explanation for thesecontradictory results is the population studied. In this study, we evaluatednormotensive and pre-hypertensive individuals with FHSAH, while the other studiesdid not control the distribution of this risk factor in the analyzed groups. Thus,since alterations in cardiac autonomic modulation have been demonstrated innormotensive individuals with hypertensive father and / or mother,5 further studies are needed to elucidate these alterations inindividuals who have both risk factors, prehypertension and FHSAH.According to Davis et al.,23 Similar results were reported by Hering et al.31 and Seravalle et al.9 who evaluated individuals withnormal-high pressure and also observed greater peripheral sympathetic modulation,assessed by the microneurography technique, in these individuals when compared tonormotensive individuals.Regarding the autonomic peripheral modulation, in this study we verified dysfunctionsin this system in the prehypertensive individuals. We observed a higher LF componentof SBP variability in prehypertensive patients compared to normotensive patients,which shows a greater performance of vascular tone sympathetic modulation as well asmyogenic vascular function in this population.32 In this study, pre-hypertensive individualspresented greater variance of SBP in relation to normotensive individuals,corroborating the results of Duprez et al.33 However, these authors did not report the FHSAH of studyparticipants.The variability of SBP, as well as elevation of pressure levels, has been recognizedas an important risk factor for target organ damage.23 Thus, theelevations of the LF and VLF components observed in this study may be related to theincrease in SBP variability through changes in myogenic vascular function.23 The HF component, which appears tobe related to endothelial nitric oxide23, was similar between the groups and did not appear to beinvolved in increased pressure variability.BP fluctuations are triggered by multiple systems including the renin-angiotensinsystem, baroreflex, myogenic vascular response, and release of nitricoxide.34The results of this study corroborate the findings of previous studies13 that alsoobserved reduction of baroreflex sensitivity in prehypertensive patients. However,this is the first to demonstrate autonomic changes in prehypertensive patients withFHSAH in relation to normotensive individuals with the same risk factor.In addition, this study demonstrated a reduction in the baroreflex control of heartrate in prehypertensive individuals when compared to normotensive individuals, afactor that may also be related to the increased pressure variability and peripheralsympathetic modulation observed.35In this study, we verified the baroreflex response time preserved in prehypertensivepatients. This characteristic of the baroreflex is mainly affected by changes incardiac parasympathetic nervous modulation,36 a change that was not observed in the prehypertensivepatients evaluated in this study. Therefore, it is possible that the response timeof the baroreflex could be affected later in the course of pressure rise anddevelopment of hypertension and that in the prehypertension phase only the reductionof the gain contributes to the reduction of the efficiency of this reflex. Inaddition, the fact that the volunteers in this study have FHSAH may be related tothe observed results. No studies were found to investigate this time delay of thebaroreflex effector response in prehypertensive individuals, as well as in childrenwith hypertensive parents, which made difficult to compare our results.In addition to sensitivity, the response time of the baroreflex can also determinethe efficiency of this reflex.37 Inaddition, the benefits of regular aerobic physical exercise in the attenuation ofautonomic dysfunction have already been demonstrated both in prehypertensivepatients37 and in thedescendants of hypertensive parents,38 which leads us to believe that individuals with both riskfactors may also benefit from the effects of this practice.This study demonstrated that prehypertensive youngsters with FHSAH present autonomicdysfunction and vascular function similar to normotensive with the same risk factor.Thus, the results of this study emphasize the importance of preventive interventionwith measures aimed at attenuating this dysfunction and, consequently, acting on theprevention of hypertension in this population. In this sense, physical exercise hasbeen considered effective since it acts in a beneficial way in multiplephysiological systems.39 future research should include detailed medicalevaluation of the parents. The presence of renal diseases was not an exclusioncriterion in this study, since all the necessary tests to exclude safely thischaracteristic were not performed. In spite of this, all the volunteers declaredthat they did not have a diagnosis of renal diseases and those who did thecreatinine and uric acid tests presented normal values for these variables.Additionally, the women in this study were not evaluated during the same periodof the menstrual cycle, a fact that may also be a limitation of this work.However, Jarvis et al.40 andCarter et al.41 observed noinfluence of the ovarian cycle phase on sympathetic modulation, heart rate andBP during rest in young women. Despite the limitations pointed out, the greatstrength of this study is the fact that we evaluated young adults, withoutmedication and with similar glycemic and lipid profile.The diagnosis of SAH of the parents of the volunteers of this study wasself-reported. Although self-report has been used in many studies,We conclude that prehypertensive patients with FHSAH have autonomic dysfunction,characterized by increased peripheral sympathetic modulation and reduced baroreflexcontrol of heart rate, and increased vascular conductance when compared tonormotensive patients with the same risk factor.


Patients with atrial septal defects (ASD) are often misdiagnosed as asthma patients and accordingly receive erroneous bronchodilator treatment. In order to characterise their symptoms of dyspnoea to explain this clinical observation, we investigated the prevalence of asthma-like symptoms in patients with secundum ASD who then underwent successful percutaneous closure.A total of 80 ASD patients  retrospectively completed dyspnoea questionnaires determining the presence and extent of cough, wheezing, chest tightness, effort dyspnoea and bronchodilator use on a 7-point scale  before and after ASD closure. The Mini Asthma Quality of Life (Mini-AQLQ) and Asthma Control Questionnaire with bronchodilator use (ACQ6) were administered.p < 0.001). The number of patients using bronchodilators decreased from 16 (20 %) to 8 (10 %) patients after ASD closure (p = 0.039) with less frequent use of bronchodilators (p = 0.015).A total of 48 (60 %) patients reported cough, 27 (34 %) wheezing, 26 (33 %) chest tightness and 62 (78 %) effort dyspnoea. Symptom resolution or reduction was found in 64 (80 %) patients after ASD closure. Asthma symptom scores decreased significantly on the Mini-AQLQ and ACQ6 (both A high prevalence of asthma-like symptoms and bronchodilator use is present in ASD patients, which exceeds the low prevalence of bronchial asthma in this study population. Future prospective research is required to confirm this phenomenon. The presence of an ASD should be considered in the differential diagnosis of patients with asthma-like symptoms, after which significant symptom relief can be achieved by ASD closure. The ostium secundum atrial septal defect (ASD) is one of the most commonly diagnosed congenital heart diseases among adults. Patients with ASD usually present with symptoms of dyspnoea, which may develop with increasing age. Due to the epidemiologically more prevalent asthma in the general population, we observed that dyspnoeic ASD patients are often erroneously diagnosed with asthma and receive lengthy bronchodilator treatment. Delay in the correct diagnosis and treatment of ASD leads to complications of long-standing right ventricular volume and eventually pressure overload such as atrial arrhythmias, paradoxical embolism, pulmonary hypertension and right ventricular failure , 2.Percutaneous ASD closure is the treatment of choice in haemodynamically significant left-to-right shunts with suitable anatomy . PreviouThe purpose of this study was to examine the prevalence of asthma-like symptoms in patients with ASD, and investigate whether percutaneous closure of the left-to-right shunt affects asthma-like symptoms both in diagnosed asthma patients and in non-asthmatics.n = 80). This study was conducted in accordance with all human research regulatory guidelines and the need to obtain informed consent was waived by the institutional ethics committee.Between 2005 and 2013 a total of 105 consecutive adult patients underwent percutaneous closure of an ASD in our centre using the Amplatzer Septal Occluder device . Of the 89 patients with successful percutaneous closure of their ASD (16 converted to surgery), 80 patients were available for follow-up and were therefore included in this study. Follow-up was fully obtained . Aspirin (100 mg daily) and clopidogrel (600 mg loading dose and 75 mg daily) were prescribed for six months along with standard endocarditis prophylaxis. Patients were followed clinically and TTE was performed at least one day and six months after device implantation.Primary outcomes were the prevalence of asthma-like symptoms, defined as wheeze, chest tightness, cough, effort dyspnoea and bronchodilator use, before and after successful percutaneous ASD closure. Secondary outcome measures were the Mini Asthma Quality of Life Questionnaire symptom and environmental score  and asthma control level  –10. The The primary and secondary outcomes are defined in the overall group, as well as in the subgroups of asthmatics and non-asthmatics. Asthmatics are defined as patients with a physician’s diagnosis of bronchial asthma by presence of variable expiratory airflow obstruction. Conveniently, symptoms of wheezing, chest tightness, cough and effort dyspnoea are referred to as asthma-like symptoms, even if reported by patients with bronchial asthma.th–75th percentile). A p value <0.05 was considered statistically significant. All statistical analyses were made using IBM SPSS Statistics for Windows, Version 21 .The Mini-AQLQ score was inverted for data analyses to be consistent with a lower score indicating less severity. Dichotomous variables were analysed using the McNemar test and are expressed as frequency (percentage). The continuous, non-parametric variables were analysed using the Wilcoxon signed-rank test (baseline vs. follow-up) and the Mann-Whitney-U test (asthmatics vs. non-asthmatics) and are expressed as median (25Baseline characteristics of the 80 patients with successful percutaneous closure are shown in Table p < 0.001) at a median follow-up of 3.0 (2.0–5.0) years.Of all 80 patients with unrepaired ASD, 48 reported cough (60 %), 27 wheezing (34 %), 26 chest tightness (33 %) and 62 effort dyspnoea (78 %). After successful percutaneous closure, 64 (80 %) reported either complete resolution or symptom reduction (Table p = 0.039). The prevalence and frequency of use is shown inFig. Of all 80 patients, 16 patients 20 %) reported current bronchodilator use, which decreased to eight patients(10 %) after closure (0 % reporp < 0.001), both in non-asthmatics and asthmatics alike.The results of our observational study show a high prevalence of asthma-like symptoms in yet unrepaired ASD patients: 70 of 80 patients (88 %) reported cough, wheezing, chest tightness and/or effort dyspnoea. This cannot be accounted for by the low prevalence of either the number of diagnosed asthma patients in this study population (8 %) or the prevalence of bronchial hyperreactivity in the general Dutch population (maximum 25 % including asymptomatic patients) . PercutaBronchial asthma is characterised by variable airflow limitation and by airway hyperreactivity, which represents an exaggerated contractile response of the airway smooth muscle to various stimuli . Atopy iAlternatively, the left-to-right shunt in ASD patients might contribute to any of the inflammatory, physiological, and structural factors in the pathogenesis of asthma or in the initiation of bronchial hyperreactivity. Several experimental studies have suggested an association between bronchial hyperreactivity and impaired left ventricular function, chronic elevation in left atrial pressure, and precapillary pulmonary hypertension due to aorto-caval shunts –20. In cWhichever pathophysiological mechanism is responsible, asthma-like symptoms in ASD patients decrease significantly after closure of the defect. The possibility exists of wrongly diagnosing asthma in such patients while they should be recognised as potential ASD patients; however, as of yet we cannot differentiate between bronchial asthma and ASD patients with asthma-like symptoms. Currently the only way to obviate asthma misdiagnosis is to optimise awareness that ASD is included in the differential diagnosis of bronchial asthma, especially when bronchodilation appears insufficient. More insight into the pathophysiology of these asthma-like symptoms is required to provide an attainable tool for distinguishing ASD patients from the large pool of asthmatics. Also, further studies are needed to objectify these asthma-like symptoms, e. g. by bronchoprovocation testing.Several limitations must be noted. This study had a retrospective design, therefore the questionnaire results relied on patients’ recollection of symptoms. Although paired testing was performed to provide for per-patient changes, as of now the Mini-AQLQ and ACQ6 questionnaires are validated in asthmatics only. Questions on dyspnoea and wheezing are acceptably sensitive and specific for detecting bronchial hyperreactivity in the general population, but patient-reported outcomes remain subjective. Statistical analysis of group differences between non-asthmatics and asthmatics could not be performed due to the small number of asthmatics in this patient cohort; therefore, only frequency comparisons were made.p < 0.001). The prevalence and pathophysiology of asthma-like symptoms in this patient population remains to be further investigated in prospective studies.A high prevalence of patient-reported cough, wheezing, chest tightness and effort dyspnoea is present in patients with unrepaired ASD. Percutaneous ASD closure leads to significant symptom resolution or reduction in the majority of these patients (80 %,


Acute Kidney Injury (AKI), a common complication of acute coronary syndromes (ACS), is associated with higher mortality and longer hospital stays. The role of cytokines and other mediators is unknown in AKI induced by an ACS (ACS-AKI), leading to several unanswered questions. The worsening of renal function is usually seen as a dichotomous phenomenon instead of a dynamic change, so evaluating changes of the renal function in time may provide valuable information in the ACS-AKI setting. The aim of this study was to explore inflammatory factors associated to de novo kidney injury induced by de novo cardiac injury secondary to ACS.+, K+, blood urea nitrogen (BUN), total cholesterol, HDL, LDL, triglycerides, creatinine (Cr), endothelin-1 (ET-1), leukotriene-B4, matrix metalloproteinase-2 and -9, tissue inhibitor of metalloproteinases-1, resolvin-D1 (RvD1), lipoxin-A4 (LXA4), interleukin-1β, −6, −8, and −10 were measured. We finally enrolled 78 patients, and subsequently we identified 15 patients with ACS-AKI. Correlations were obtained by a Spearman rank test. Low-rank regression, splines regressions, and also protein–protein/chemical interactions and pathways analyses networks were performed.One hundred four consecutive patients with ACS were initially included on the time of admission to the Coronary Unit of the Instituto Nacional de Cardiología in Mexico City, from February to May 2016, before any invasive procedure, imaging study, diuretic or anti-platelet therapy. White blood count, hemoglobin, NT-ProBNP, troponin I, C-reactive protein, albumin, glucose, Na+, K+, WBC, age, body mass index, GRACE, SBP, mean-BP and Hb.Positive correlations of ΔCr were found with BUN, admission Cr, GRACE score, IL-1β, IL-6, NT-ProBNP and age, and negative correlations with systolic blood pressure, mean-BP, diastolic-BP and LxA4. In the regression analyses IL-10 and RvD1 had positive non-linear associations with ΔCr. ET-1 had also a positive association. Significant non-linear associations were seen with NT-proBNP, admission Cr, BUN, Nade novo cardiac injury leading to de novo kidney injury”.Inflammation and its components play an important role in the worsening of renal function in ACS. IL-10, ET-1, IL-1β, TnI, RvD1 and LxA4 represent mediators that might be associated with ACS-AKI. IL-6, ET-1, NT-ProBNP might represent crossroads for several physiopathological pathways involved in “The online version of this article (doi:10.1186/s12872-017-0640-0) contains supplementary material, which is available to authorized users. Acute Kidney Injury (AKI) is a common complication of acute coronary syndromes, and its ultimate expression is the cardiorenal syndrome (CRS) type 1, defined “as an acute worsening of heart function leading to AKI or dysfunction” that is a complication of “acute heart failure (AHF) and/or acute coronary syndrome (ACS)”, associated with a high risk mortality and longer hospital stay .The heart-kidney axis is complex and usually ill-defined . ComplexThe role of various inflammatory mediators has not been fully studied in ACS-AKI –8. A cleHence, the role of cytokines and mediators is unknown in AKI specifically in the context of ACS, leading to several unanswered questions. Furthermore the worsening renal function is usually seen as a dichotomous phenomenon instead of a dynamic change in the target organ, the kidney, and evaluating the declining kidney’s function may provide more valuable information in the ACS-AKI setting .The aim of this study was to explore inflammatory factors associated to de novo kidney injury in patients with de novo cardiac injury secondary to ACS.One hundred four consecutive patients were initially included at the time of arrival to the coronary unit of the Instituto Nacional de Cardiología Ignacio Chavez, in Mexico City with ST-elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NSTE-ACS), ≥18 years of age and <24 h of the initial symptom, from February to May 2016. All patients’ records were thoroughly examined and reviewed until the patient discharge or dismissal. We enrolled 78 patients, and subsequently we identified 15 patients with ACS-AKI. Seventeen healthy volunteers were included as controls for the serum lipid mediators’ analysis  were also excluded. We eliminated patients that were diagnosed during the study with any of the exclusion criteria, or loss of information occurred at any time of the study.Patients with known pregnancy or in postpartum period, infectious, autoimmune, hepatic, or neoplastic diseases were excluded; as well as patients with current or previous dialysis, transplant, episodes of AHF or chronic heart failure, and previous ACS. Furthermore, patients with a baseline clearance <55 ml/kg/minThe study protocol was approved both by the Research Committee and the Ethics in Research Committee of the Instituto Nacional de Cardiología Ignacio Chavez (#16–971). All patients or their legally authorized representatives provided written informed consent. All procedures were conducted based on the Declaration of Helsinki and local regulations.Samples were collected on the time of admission before any invasive procedure, imaging study, diuretic or anti-platelet therapy. We obtained between 10 and 20 ml of blood. The serum was centrifuged at 3000 rpm for 25 min, recollected in 500 μL vials and stored at −76 °C until the serum readings were performed.+), potassium (K+), blood urea nitrogen (BUN), high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TChol), triglycerides (TG) and creatinine (Cr) levels were performed by the hospital clinical laboratory.White blood count (WBC), hemoglobin (Hb), NT-Pro B-Type-Natriuretic-Peptide (NT-ProBNP), troponin-I (TnI), high-sensitive C-reactive protein (hs-CRP), albumin, glucose, sodium , matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitor of metalloproteinases (TIMP)-1 , RvD1 , LXA4  were determined by enzyme-linked immunosorbent assays using commercial kits per instructions provided by the manufacturer.And for interleukin (IL)-1β, IL-6, IL-8, IL-10, multiplex magnetic bead-based antibody detection kits were used per the manufacturer’s protocols  and read in Luminex®MAGPIX  with software v4.2 (Luminex-xPonent-MAGPIX®).2 test was used to compare clinical characteristics. Mann-Whitney-U test for group comparisons and Kruskal-Wallis test for multiple group comparison were performed. Also, both correlation and regression analysis were performed. Correlations were obtained by a Spearman rank test    had 2 sharp positive slopes at the extremes of its concentrations, the first one under 90 pg/mL (log 4.5) and the second one over 2980 pg/mL (log 8)  = 3.815, and the slope was steeper in values >54.6 mg/L (log 4)  Fig. . NT-proB 8) Fig. . Additio 4) Fig. .Table 3Gdf = 3.096)  but overall it behaved with a positive slope up to 40 mg/dL, being steeper beyond 30 mg/dL, and becoming negative after 40 mg/dL , tended to be L-shaped, with a negative relation below 135 mmol/L , greater beyond 4.5 mmol/L, however, a slight negative slope was seen in concentrations greater than 5.5 mmol/L levels  mainly in levels under 12.5 g/dL , with the positive slope between 10 and 15 × 109/L  which describes a steep positive slope in values >1 ng/mL (log 0)  had an additive log-shaped behavior in the model (96) Fig. ; BUN had/dL Fig. . Electrol/L Fig. . K+ had els Fig. . In the /dL Fig. , and whi9/L Fig. . TnI had 0) Fig. .Fig. 3Gedf = 1.349) to ΔCr , and in patients with >35 kg/m2 a sharp positive curve was seen  and despite the complexity of their behavior, had an overall negative association to ΔCr. GRACE score likewise had a non-linear positive relationship to ΔCr (df = 2.496), especially noticeable in scores >150 points , ET-1 (edn-1), CRP, LxA4, RvD1, Na+, K+, Cr, BUN (lotion)]. We propose a pathway of predicted protein-protein interactions, based on text-mining, experiments, databases, co-expression, neighborhood, gene fusion, co-occurrence and predictions (STITCHv4.0). Using the STITCHv4.0 database we added 10 protein interactors for the final network, these were obtained by initially adding 20 interactors and further removing receptors and chemical components, leaving only non-receptor proteins . The network analysis showed that the current input data had a strong association with the suppressor of cytokine signaling (SOCS)-3, signal transducer and activator of transcription (STAT)-3, STAT-1, JUN, janus kinase (JAK)-2, FOS, IL-18, IL-17A, renin (REN) and caspase (CASP)-1. Furthermore, we used the Enrichment option included in Chemical Disease Interference System [Protein and chemical interactions are common in vivo; therefore, we performed a network analysis of the significant variables obtained in this study [IL-1β, IL-6, IL-10, NT-ProBNP . As far as we could acknowledge, no study had previously reported human serum levels of these lipid mediators in ACS or AKI. Both have its biological action by halting the damage and clearing apoptotic neutrophils . In our  and LxA4Hs-CRP and WBC are no foreigners to the cardio-renal interactions, our results agree with previous studies that show that raised levels of hs-CRP are independent predictors of AKI by impairing tubular epithelium cell regeneration and altering macrophage polarization . MeanwhiNT-proBNP and ET-1 are part of the so-called hormonal pathway. In the current study, both had a positive relationship to ΔCr, with the highest values having a steeper slope Figs.  and 2c. In our data Hb had a negative correlation to ΔCr in which a steeper slope was seen in the values <12.5 g/dL. Anemia can be part of a dreadful combination in the so call cardio-renal-anemia syndrome since it carries a poorer prognosis, and its prevalence can reach just over 20% in patients with chronic HF . In addi2. The so called “obesity paradox” has been a point of controversy in ACS [BMI had a significant relation with ΔCr in our study, mainly after 30 kg/my in ACS , but in y in ACS .Our study is not exempt of limitations. Previous studies suggest that sampling timing might influence the measurements , 52, andde novo cardiac injury leading to de novo kidney injury”.In conclusion, our data suggest that inflammation and its components play an important role in ACS-AKI and the worsening of renal function in the ACS setting. IL-10, ET-1, IL-1β, TnI, RvD1 and LxA4 represent mediators that might be associated with cardiorenal crosstalk. Furthermore, IL-6, ET-1, NT-ProBNP possibly represent crossroads for several physiopathological pathways involved in “Additional file 1: Table S1.Results containing the contrast in serum lipid mediator’s levels against controls. (DOCX 63 kb)Additional file 2: Table S2.Spearman’s rank correlations between all studied variables and Δ Cr. (DOCX 79 kb)


In the meta‐analysis of blood pressure reduction, thiazide‐like diuretics seemed to further reduce systolic BP  and diastolic BP . Meanwhile, in the analysis of side effects, the incidence of hypokalemia , hyponatremia , change of blood glucose  and total cholesterol  showed that there is no statistical significant differences between the two groups of drugs. In conclusion, using thiazide‐like diuretics is superior to thiazide‐type diuretics in reducing blood pressure without increasing the incidence of hypokalemia, hyponatraemia and any change of blood glucose and serum total cholesterol.Thiazide diuretics are widely used for the management of hypertension. In recent years, it has been actively debated that there is interchangeability of thiazide‐type diuretics hydrochlorothiazide and thiazide‐like diuretics including indapamide and chlorthalidone for the treatment of hypertension. With the purpose of seeking out the best thiazide diuretic for clinicians, we summarized the existing evidence on the two types of drugs and conducted a meta‐analysis on their efficacy in lowering blood pressure and effects on blood electrolyte, glucose and total cholesterol. Twelve trials were identified: five based on the comparison of indapamide  Thiazide diuretics were once the first effective oral antihypertensive agents with an acceptable side‐effect profile. For more than a half‐century, thiazide diuretics have been used for the management of hypertension Recently, the interchangeability of hydrochlorothiazide and chlorthalidone has been a matter of intense debate Indapamide, a member of thiazide‐like agents, presents some differences with others. In fact, besides its diuretic properties, indapamide presents some protective effects on vascular or organ damage in animal and human investigations. In some clinical trials, it was effective in reducing left‐ventricular mass index in hypertensive patients and remarkably improving the renal function versus chlorthalidone or HCTZ versus indapamide as the independent comparative arms.To examine whether thiazide‐like diuretics were superior over the thiazide‐type diuretics in lowering blood pressure without affecting the biochemical properties, we undertook a meta‐analysis of clinical trials with either HCTZ In our meta‐analysis, we adhered to the PRISMA guideline strictly. The search strategy was designed by the first author and reviewed by another two authors. We searched for evidence in PubMed (1948–2017/Jan) and Embase (1980–2017/Jan), Google Scholar, the ScienceDirect, the metaRegister of Controlled Trials and the Cochrane Central Register of Controlled Trials using the following terms:  AND (hydrochlorothiazide) AND(systolic blood pressure OR diastolic blood pressure)AND . Moreover, references about the relevant reviews were also sought.via ambulatory blood pressure monitoring, if not, where resting BP measurements were available for >1 time during a 24‐hr period, the trough measurement, defined as 22–26 hr after dose, was used. When BP was recorded in multiple positions, sitting BP was used, unless variance data were only given for another position, in which case that position was used.Trial inclusion criteria met the following criteria: (1) randomized clinical trial or double‐blind controlled trial of thiazide‐like or thiazide‐type therapy in people with hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg); (2) patients were allocated to 2 monotherapy thiazide or combined with other kind of antihypertensive drugs in fixed‐dose arms; (3) duration of follow‐up ≥4 weeks; (4) baseline washout and run‐in phase of medication ≥1 week; (5) measurements of ≥1 of the following, systolic BP, diastolic BP, serum potassium, uric acid, serum cholesterol, glucose or heart rate. There were not yet enough trials including thiazide‐like or thiazide‐type diuretics for meta‐analysis with the exception of hydrochlorothiazide, chlorthalidone and indapamide, so only trials including the comparison between hydrochlorothiazide and chlorthalidone or hydrochlorothiazide and indapamide were included. We excluded trials where subjects were predefined as responders or non‐responders before the trial. If the study used the titration method in step‐up protocols, we just extract the data using the initial doses. Studies using potassium supplementation were included, but step‐down and drug withdrawal protocols were ineligible. Trials were also ineligible if participants were <18 years old or had cirrhosis with ascites, type 1 or 2 diabetes, nephrotic syndrome, renal insufficiency, documented serum creatinine level >1.5 times normal, history of ischaemic stroke, unstable angina or myocardial infarction within the past 6 months, cardiac failure, secondary hypertension, dementia or other cognitive impairment, pregnancy or lactating women. If the study condition permits, we used the blood pressure records The characteristics of studies The primary end‐point for our analysis was the systolic and/or diastolic BP reduction, the incidence of hypokalemia, hyponatremia and the change of serum total cholesterol and glucose throughout the different drug therapy. The changes of blood pressure, serum TG and glucose were computed as the difference in the BP values at the final follow‐up (or specific time‐point if multiple time‐points were provided) compared to the baseline or initial measurement. However, we analyse the incidence of hypokalemia using the dichotomous method. All data extracted from the 12 studies were recorded in Microsoft Excel before transfer to Review Manager version 5.0 program for analysis. Continuous variables were conveyed in the form of the mean and standard deviation (SD). Research results data whose means and SDs were unavailable were kicked out of the meta‐analysis. Heterogeneity was calculated using the I‐square statistic A total of 2485 records were found after searching in PubMed, Embase, Google Scholar and other databases. As some literatures did not provide free full texts, or the inappropriate comparative methods, only 45 full‐text articles were reviewed after the first selection process Fig. . In the P = 0.35); I² = 10%) than thiazide‐type diuretics (hydrochlorothiazide).In all of the included studies, 1307 patients from 10 trials provided data of systolic BP change from the baseline to the end‐point of treatment period. Figure A meta‐analysis of diastolic BP reductions between the thiazide‐like and thiazide‐type diuretics also showed a statistically meaningful result. As shown in Figure P = 0.16; Heterogeneity: Tau² = 0.13; Chi² = 4.10, df = 3 (P = 0.25); I² = 27%).Four trials provided data of incidence of hypokalemia happened during or after the treatment period among 1050 subjects. It is shown in Figure P = 0.54; Heterogeneity: Chi² = 0.13, df = 1 (P = 0.71); I² = 0%).As shown in Figure P = 0.11; Heterogeneity: Tau² = 0.00; Chi² = 0.64, df = 3 (P = 0.89); I² = 0%). In the meta‐analysis of change of serum glucose, we scanned seven trials included 804 subjects and the results also show no significant differences between thiazide‐like and thiazide‐type diuretics ; I² = 69%). The heterogeneity exists.Four trials included data from 550 subjects; as shown in Figure 2 is <30% of the variability in point estimates. However, in the meta‐analysis of diastolic blood pressure reduction and the change of serum glucose, a notable heterogeneity is observed as I2 is more than 50% We can believe that there is no heterogeneity exists in the analysis of systolic blood pressure reduction, incidence of potassium and total cholesterol because mild heterogeneity might account for IFor meta‐analysis, we searched for published thiazide diuretic‐related studies that are three decades old. We extracted useful data from 12 included clinical trials. We reanalysed them and made a series of outcomes. The potent of thiazide‐type and thiazide‐like diuretics differed quite remarkably. We found out that thiazide‐like diuretics, indapamide and chlorthalidone, have an advantage in lowering both systolic and diastolic blood pressure without significantly increasing the risks of hypokalemia and hyponatremia, or making a significant change of blood glucose and serum total cholesterol compared to the most prescribed thiazide‐type diuretics such as hydrochlorothiazide.Thiazide diuretics are the second most common type of antihypertensive drug. Therefore, it continues to be widely used in the treatment of hypertension. Whereas in the past half‐century, there was few studies which compared the thiazide‐type and thiazide‐like diuretics directly in random trials. To provide more powerful evidence for clinical therapy, it is essential to make a comprehensive comparison between the most common prescribed antihypertensive agents. In consideration of the side effects of thiazide diuretics, the major concern might be electrolyte disturbance, serum glucose and total cholesterol. Due to the longer half‐life of thiazide‐like diuretics, risks of adverse events would be expected to increase, particularly the sodium and potassium homoeostasis disorders. Our analysis made a comprehensive comparison of thiazide‐type and thiazide‐like diuretics to indicate that to achieve the same level of BP reduction, thiazide‐like diuretics were not worse than thiazide‐type diuretics in increasing risks of electrolyte disturbance.Antihypertensive drugs are not only able to lower blood pressure, but there are many extra benefits in the cardiovascular system, such as anti‐inflammatory, anti‐atherosclerosis, improve cardiac function and target organ protection. Several clinical studies had shown that low‐dose diuretics could exert target organ protection effect when compared to other antihypertensive Our findings of this study should be set in context of previous meta‐analyses. In a dose‐stratified meta‐analysis and metaregression of 26 studies, Peterzan et al. vs. HCTZ 25 mg/day and CTDN 25 mg/day vs. HCTZ 50 mg/day). The dose‐titrate of CTDN and HCTZ was mentioned in Berkris et al. study Electrolyte disturbance might be a major concern for prescribing thiazide diuretic. Jan C. performed a case–control study Several limitations exist in our meta‐analysis. First, in two of the included studies, the original design is a crossover study, but to insure statistical robustness of the data in the presence of a possible carryover effect, we decided that only the data from those who complete the first active treatment period would be analysed. Secondly, we combined the indapamide and chlorthalidone together as one of the comparison arm without considering the variance between these two agents. On the other hand, we did not do the dose–response of the three drugs separately. This therefore means that we cannot neglect the error from different doses in the same group. Thirdly, some of our included studies were published long ago with the differences in inclusion and exclusion criteria, BP measurement techniques and drug formulation. Although the score of these trials (as assessed by Jadad criteria) is more than 3, the data from these studies will contribute to heterogeneity between studies. As there is lack of head‐to‐head comparative trials between chlorthalidone and HCTZ, we used the data from a combination of them with beta‐blocker, ACEI or calcium channel blocker. The combination trials might make it hard to access the effects on blood pressure reduction efficacy, the risk of incidence of hypokalemia and hyponatremia and the change of blood glucose and total cholesterol of thiazide diuretics, which would make the results of the meta‐analysis less compelling.In summary, we performed a meta‐analysis for the controversial clinical decision that whether thiazide‐type or thiazide‐like diuretics should be more prescribed as the initial antihypertensive therapy. Our analysis obtained the different efficacy of BP reduction and biochemical outcomes when used the two kinds of drugs. It is recommended that further randomized controlled trials should be done to compare these two types of drugs. The available conclusion from our analysis suggests that thiazide‐type diuretic should be replaced by the thiazide‐like diuretic, which possess higher BP reduction efficacy and no more risk of electrolyte disturbance and metabolic disorders.No potential conflict of interests were disclosed.W.J.L designed and conducted the analysis and wrote the manuscript. H.M and L.X.C collected and evaluated the data. J.J.Y and W.J.Y contribute to the design, analysis and revised the manuscript. J.J.Y is the guarantor of the work and takes the responsibility and accuracy for the integrity of the results.


Blood pressure control with renin-angiotensin system (RAS) blockade has remained the gold standard for treating patients with proteinuric chronic kidney disease (CKD) up to date. Nevertheless, RAS blockade slows but does not halt the progression of kidney disease, thus highlighting the need to search for additional therapeutic approaches. The nonselective phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) is an old drug that exhibits prominent anti-inflammatory, anti-proliferative and anti-fibrotic activities both in vitro and in vivo. Studies in human subjects have shown that PTX monotherapy decreases urinary protein excretion, and add-on therapy of PTX to background RAS blockade additively reduces proteinuria in patients with CKD of various etiology. More recent studies find that PTX combined with RAS blockade delays the decline of glomerular filtration rate in diabetic patients with mild to moderate CKD, and reduces the risk of end-stage renal disease in diabetic and non-diabetic patients in late stage of CKD with high proteinuria levels. In this review, we update the clinical trial results of PTX as monotherapy, or in conjunction or in comparison with RAS blockade on patients with proteinuria and CKD, and propose a mechanistic scheme explaining the renoprotective activities of this drug. Current practice guidelines recommend blood pressure control with inhibitors of the renin-angiotensin system (RAS) as the gold standard therapy for patients with proteinuric chronic kidney disease (CKD) –3. Block2. No differences were found between crossover periods in C-reactive protein (CRP), α1-microglobulin, and urinary N-acetyl-beta-d-glucosaminidase. More recently, in a double-blind, placebo-controlled trial, Badri et al. [Table i et al.  observedIn addition to native kidney disease, PTX also works in the setting of transplant kidneys. An early randomized double-blind trial found that PTX at a dose of 800–1200 mg daily ameliorated the consequences of rejection on graft survival comparing to placebo during the first 6 months after transplantation . SubsequDiabetic kidney disease (DKD) or diabetic nephropathy has become the single most important primary etiology of end-stage renal disease (ESRD) worldwide , and the2. Clearly, this study comprised patients with relatively normal renal function. They were not under uniform RAS blockade, yet receiving dietary protein restriction. These discrepancies in baseline characteristics and study designs might be linked to the lack of anti-proteinuric effects by PTX treatment.Later investigators consistently found that add-on PTX on top of RAS blockade led to a greater reduction of proteinuria in patients with type 2 DKD across CKD stages 1 to 3, and the benefit of which was independent of metabolic or blood pressure control , 44. Of Systematic reviews and meta-analyses have been employed to quantitatively evaluate PTX’s anti-proteinuric effects in diabetic patients with microalbuminuria or overt proteinuria. The first work was by McCormick et al.  which inThe renoprotective potential of PTX has been eagerly reviewed , 54–56 oLin et al.  first reThen, Navarro-González et al.  reportedMost prior studies had been conducted in patients with CKD across stages 1 to 4 and used proteinuria or eGFR decline rate as surrogate outcomes. Whether PTX may exhibit efficacy on hard renal endpoints such as ESRD or death in more advanced CKD remains relatively unexplored. Recently, Chen et al.  analyzedNot all studies have shown concomitant anti-proteinuric and renoprotective effects by adding PTX to RAS blockade. In a double-blind, randomized, placebo-controlled design, Perkins et al.  examinedModulation of intracellular cyclic nucleotides by targeting PDE activity can be a novel therapeutic strategy for fibrotic kidney disease –70. Curr. These seemingly non-specific actions of PTX may turn out to be an advantage and form the basis of developing new drugs with pleiotropic activities beyond RAS blockade. Recently, a novel small molecule drug, CTP-499, which mimics the primary metabolites of PTX has demonstrated its safety and tolerability in a phase 1b randomized, double-blind, placebo controlled clinical trial in patients with CKD [It has been reported that TNF-α downregulate nephrin expression and cAMP-elevating agents enhance nephrin level in cultured podocytes . More rewith CKD .2A-dependent cascade [Apart from blocking the PDE activity, PTX can modulate other effectors or signaling pathways depending on the experimental settings. In vitro, PTX suppresses TNF-α production via PKA-independent pathway in endotoxin-activated mononuclear cells , and inh cascade , and ame cascade . WhetherThe most common adverse effects of PTX are gastrointestinal symptoms and dizziness , 52, 94.There exists concern that PTX might exert a negative impact on glycemic control in patients with diabetes. Previous studies have shown that PDE3,4 inhibitors enhance both glycogenolysis and gluconeogenesis in hepatocytes isolated from fasted rats , and thePTX is a nonselective PDE inhibitor that exhibits anti-inflammatory, anti-proliferative and anti-fibrotic actions both in vitro and in vivo. Current evidence suggests that PTX, used either alone or in combination with RAS blockade, may have an adjunct role of renoprotection for CKD. Nevertheless, most published literatures were limited by small sample size, short observation period and imperfect methodology using surrogate outcomes . There is need for more well-designed studies with longer duration of follow-up aiming at hard renal endpoints . Because PTX is an old drug that lacks financial sponsorship, future researches examining the efficacy PTX on a background of RAS blockade would better be conducted on patients with more severe CKD, e.g., stage 3B or higher, so that hard outcomes can be evaluated using a minimum number of subjects within an acceptable period of time.


The annual European Society of Cardiology (ESC) meeting was held at the Nuova Fiera di Roma with over 32 000 delegates from 126 countries in attendance.The meeting commenced with an outstanding address on the heart and art by a British cardiac surgeon, who demonstrated the amazing discoveries in cardiac anatomy and function made by Leonardo da Vinci over 500 years ago, and the awarding of the ESC gold medal to Dr Bernard Gersh of the Mayo Clinic, whose foundational training in cardiology took place at Groote Schuur Hospital.https://www.escardio.org/ Guidelines/Clinical-Practice-Guidelines.Four new ESC guidelines addressing atrial fibrillation (AF), heart failure, cardiovascular (CV) disease prevention and dyslipidaemia, as well as a position paper on cardiooncology, were released during the meeting. The full texts ofthese documents are available to all at The meeting planners placed particular emphasis on the ‘heart team’ approach and included a large number of ‘heart hub’ presentations. The latter were delivered ‘in the round’ and provided a more informal, more easily accessible presentation format, which improved interaction between presenters and the audience.The following are my impressions of the presentations I attended over the five days of the meeting.The 2016 dyslipidaemia guideline has been harmonised with the CV disease prevention guideline, which appeared simultaneously. The ESC has maintained the SCORE risk factor charts as well as a chart estimating relative risk in younger people. The risk categories have likewise been maintained. However, whereas the presence of significant plaque on carotid ultrasound classifies the patient as very high risk, increased carotid intima–media thickness does not. Treatment targets have been maintained. Very high-risk patients have a low-density lipoprotein cholesterol (LDL-C) target of < 1.8 mmol/l, high-risk subjects < 2.6 mmol/l and moderate- to low-risk individuals < 3.0 mmol/l. In patients with diabetes an HbA1c < 7% is recommended in addition. In very high- and high-risk patients, treatment should achieve a > 50% reduction in LDL-C. High-density lipoprotein cholesterol (HDL-C), apoB/apoA1 and non-HDL-C/HDL-C ratios are not recommended as treatment targets. Statins remain first-line treatment, given up to the highest recommended dose or highest tolerable dose to achieve the treatment goal. Statin treatment should be given for the same indications and using the same targets in women and the elderly.A small Japanese study from the Heart Institute of Japan involving 1 734 patients with dyslipidaemia followed for 3.9 years after acute coronary syndrome (ACS) found no benefit from the addition of ezetimibe to pitivastatin vs pitivastatin alone. LDL-C was 1.7 mmol/l in the combination group vs 2.2 mmol/l in the statin-only group.Patients with heterozygous familial hypercholesterolaemia (FH) respond inadequately to statin therapy and frequently require plasma apheresis to lower their LDL-C. Apheresis is both expensive and inconvenient for the patient. A study evaluating the PCSK9 inhibitor, alirocumab, demonstrated a 75% reduction in the need for apheresis.A session on hypertension dealt with the problems of masked and white-coat hypertension (WCH). Masked hypertension is defined as a normal office blood pressure, but elevated home blood pressure or 24-hour ambulatory blood pressure readings. Home monitoring  and ambulatory blood pressure (recorded over 24 hours) measure different aspects of the blood pressure profile. Masked-hypertension patients are, by definition, untreated. Masked uncontrolled hypertension (MUCH) is seen in treated hypertensives. The blood pressure typically fluctuates and elevations may occur either during waking hours or at night . Masked hypertension is present in 10–20% of the population and doubles the risk of a CV event.There is currently no guidance from clinical trials as to the correct treatment of masked hypertension. The MASTERS trial commenced recently to explore what the correct treatment should be. At present the recommendation is to establish strict risk factor control and, though ‘logically’ incorrect, not to institute antihypertensive therapy.WCH affects 30–40% of the hypertensive population. Patients with WCH have a metabolic profile similar to that of hypertensive patients. Their baseline blood pressure is marginally higher than that of the normotensive population. The WCH group has a higher incidence of increased pulse pressure and left ventricular hypertrophy and a higher 10-year risk of developing established hypertension and diabetes. The prognosis of WCH is intermediate between normotensive and hypertensive patients with a higher incidence of CV events. There are no therapeutic strategies proven to be effective in WCH.https://sentry.phc.ox.ac.uk/proof-bp)  .Kario from Japan pointed out that central aortic pressure is a further component to be considered in blood pressure control. It is best controlled with an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) and not with beta-blockade. Diurnal variation in blood pressure and aortic stiffness are other aspects receiving attention. He commented that when combined with an ARB (olmesartan), hydrochlorothiazide is superior to calcium channel blockade for the control of nocturnal hypertension.+ polystyrene sulphonate . Patiromer+ zirconium cyclosilicateA lunchtime symposium was devoted to the underuse of mineralocorticoid antagonists (MRAs), namely spironolactone and eplerenone, in both hypertension and heart failure. Both have proven benefits in improving blood pressure control in resistant hypertensionThe CLARIFY study analysed data from 22 672 patients with stable coronary artery disease (CAD) and treated hypertension. It found an increase in cardiovascular events in those with systolic blood pressure > 140 mmHg and diastolic blood pressure > 80 mmHg. However systolic blood pressure < 120 mmHg and diastolic blood pressure < 70 mmHg were also associated with an increase in cardiovascular events, except for stroke. This finding supports the presence of a J-shaped curve in relation to outcomes and the blood pressure achieved on treatment.62, blood pressure < 140/90 mmHg, LDL-C according to the guideline on dyslipidaemia  and, in patients with diabetes, an HbA1c level < 7%. Aside from the general recommendations, the guidelines contain specific recommendations for the management of patients with hypertension, CAD, chronic heart failure, cerebrovascular disease and peripheral vascular disease.The 2016 guidelines on the prevention of CV disease target smoking, diet, physical activity, body weight, blood pressure, serum lipids and diabetes. Management should be individualised after assessment of personal risk using the SCORE tables. No additional predictive accuracy derives from the measurement of biomarkers. In apparently healthy individuals, risk assessment should be carried out from the age of 40 years in men and 50 years in women or when they are post-menopausal. Risk assessment may be repeated at five-year intervals in those with no identifiable risk factors and more often in those with risk close to threshold. Broadly speaking, management targets are avoidance of any exposure to smoking, a diet low in saturated fat, activity for at least 150 minutes each week, a body mass index (BMI) of 20–25 kg/mA ‘naturally randomised’ study evaluated outcomes dependent on whether the study population’s LDL-C and blood pressure lay above or below the median, therefore evaluating lifelong exposure to these recognised risk factors. The differences between the lower and higher groups were LDL-C 0.31 mmol/l and blood pressure 5 mmHg. Outcomes were better in those with a lower LDL-C or blood pressure with a multiplicative effect observed when both were below the median.Population data have been collected in Finland since 1972. At the outset, the regions in the east of the country had the world’s highest incidence of CAD. A programme to encourage behavioural change was launched, including, smoking cessation and a reduction in dairy product intake. Since then there has been a continuous decline in CV disease of 4.4% per annum, thus achieving a cumulative reduction of 80% since the start of the project. Two-thirds of the decline is ascribed to risk factor management and one-third to medication and intervention.7The Europe-wide survey EURO-ASPIRE IV demonstrates persistent overweight and obesity in the population. Eightyeight per cent of respondents were found to be overweight with two-thirds exhibiting central obesity. Women were more frequently affected than men.A study from the Netherlands examined medication compliance in 59 000 patients after either ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI). It showed that only 34% of patients took all five of the recommended therapies. STEMI patients were more likely to adhere (43%) than those with NSTEMI (28%). The latter group was more likely not to be taking statins and antiplatelet therapy. A Korean study showed that medication adherence can be improved by simplifying the timing of daily administration.The PALM registry found that underdosing of secondary preventative therapies was prevalent and that untreated and underdosed patients exhibited a higher LDL-C value.The OPTICARE study involved an educational and interventional programme in patients after ACS, comparing standard care versus a face-to-face physical training programme combined with counselling, versus a programme of telephone contact. More than 80% of patients completed the programme. A high percentage received optimal medical therapy (OMT). The study found no benefit to patients from more intensive management.Depression and anxiety are frequent concomitants in patients with CAD (25%) or stroke (33%). Its occurrence is more frequent with advancing age, elevated blood pressure and alcohol use. In the study reported at the meeting, effective secondary preventative treatment did not influence the rate of depression or anxiety. Very few patients had received treatment for their depression/anxiety.Bisphosphonates may reduce arterial calcification and so influence the progression of atherosclerotic disease. A retrospective analysis showed that the cardiovascular mortality rate was reduced by 19% and all-cause mortality by 10%.An international randomised study in 2 717 patients with prior CAD or stroke, who had obstructive sleep apnoea, showed that the use of continuous positive airway pressure (CPAP) over four years failed to improve cardiovascular outcomes. Quality of life was improved. The apparatus was used on average only for around 3.5 hours each night. Fewer stroke events were noted in those who used CPAP for more than four hours per night.8Several reports were predicated on concerns about the high incidence of normal coronary angiograms in patients investigated for suspected stable CAD. Most quoted an incidence of 60–70% without obstructive disease. The CONSERVE trial over 12 months used coronary computed tomography angiography (CCTA) first, to assess whether invasive angiography was required. This approach reduced the assessed need for invasive angiography by 78%, revascularisation from 17 to 10% and the cost by 50%. In the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 trial (CE-MARC 2), the NICE guidelines were compared to cardiac magnetic resonance (CMR) and to myocardial perfusion imaging. This reduced the ‘unnecessary’ angiography rates to 28, 7 and 7%, respectively. In both studies, the MACE rates were not impacted on by avoidance of angiography.9The PACIFIC study carried out a head-to-head comparison of CCTA, myocardial perfusion single-photon emission computed tomography (SPECT), positron emission tomography (PET) and hybrid imaging in the diagnosis of ischaemic heart disease. The finding was that PET scanning was superior to both CCTA and SPECT.Plasma apheresis was used in patients with uncontrolled angina receiving maximally tolerated medical therapy. Apheresis improved myocardial perfusion and increased exercise tolerance, as assessed by the six-minute walk test.The 15-year follow up of the FRISC-II study was reported; it had compared an early invasive strategy in NSTEMI to an initial non-invasive strategy.A Japanese trial, which had compared ad hoc to deferred PCI in patients with stable CAD, reported its five-year outcomes. There were no differences in incidence of death or MI. Deferred cases fared better when heart failure was present, but the deferred group also had a higher incidence of stroke.Widimsky presented a small trial (1 230 patients) from the Czech Republic that looked at one-month outcomes in STEMI patients who received either prasugrel or ticagrelor (PRAGUE-18 study). No differences were discernible at seven and 30 days. Due to financial constraints, many patients had to switch to clopidogrel after discharge, frustrating the assessment of effect at a later time point.11NORSTENT included 9 013 patients receiving their first coronary stent [either bare-metal (BMS) or newer drug-eluting stents (DES)] between 2008 and 2011.Median follow up was for five years. There were no differences in outcome between the two types of stent. Repeat revascularisation was 3.3% less with DES. Stent thrombosis occurred in 0.8% with DES and 1.2% in BMS patients. Quality of life was no different between the two groups.In the LEADERS FREE trial, patients over 75 years of age at high risk of bleeding received either a BioFreedom® polymerfree drug-coated stent or Gazelle® BMS and DAPT for only one month. Their average age was 81 years, 63% had multi-vessel disease and one-third had atrial fibrillation (AF). Sixty per cent of procedures were performed via the radial artery. At one year the event rate was 14 versus 11% in favour of the BioFreedom® stent, the difference being driven by the incidence of MI. There was a 49% reduction in target-vessel revascularisation and no increase in rate of bleeding.13A 10-year follow up of the SIRTAX trial showed an increase in non-CV mortality rate between five and 10 years and a constant rate of MI, but a fall-off in the incidence of target lesion revascularisation and stent thrombosis with no difference between paclitaxel- and sirolimus-eluting stents. The use of DAPT, aspirin and statin treatment was observed to be declining.14A five-year follow up of the trial comparing Biolimus® (biodegradable polymer) to sirolimus-eluting stents showed some crossover of benefit in favour of Biolimus® with regard to rates of death, MI, stent thrombosis and target-vessel revascularisation.15A two-year follow up of the ABSORB® stent (bio-absorbable vascular scaffold) study found four instances of very late stent thrombosis. Optical coherence tomography showed that undersizing of the stent and discontinuities in stent structure might have been the cause.16The DOCTORS study compared optical coherence tomographyguided to angiography-guided intervention in localised single-vessel disease. Fractional flow reserve (FFR) results were moderately improved when using optical coherence tomography.The BBK II trial compared TAP stenting with Culotte stenting in bifurcation lesions, demonstrating that the Culotte technique yielded better results in the side branch. Commentators cautioned against use of the Culotte technique by those who are not experts.17Jang, from Harvard Medical School, reported on an optical coherence tomography-guided study in Chinese patients with ACS, which identified plaque erosion as the underlying cause in 30%. These patients were treated with aspirin and ticagrelor without stenting. He showed that thrombus volume was diminished at one month.18A sub-study of the DAPT trial evaluated whether OMT  influenced the outcome of prolonging DAPT. The benefit of DAPT was shown to be consistent, whether or not patients were receiving OMT.19The ITALIC trial two-year result showed no difference between six months and 24 months of DAPT (predominantly using clopidogrel). However, there was a trend towards increased events in patients with prior MI who received only six months of DAPT.A study of an ‘as-treated’ subgroup of the FREEDOM trial compared coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) in patients with diabetes and multi-vessel CAD, both with and without chronic kidney disease. CABG was associated with a lower incidence of death and MI but with an increase in the risk of stroke.20The STITCH trial evaluated the benefit of CABG in patients with left ventricular systolic dysfunction (LVSD). CABG benefited patients in all age groups. CV mortality was the most frequent cause of death at all ages. Non-cardiac causes of death were more frequent in the elderly.BASKET-SAVAGE compared BMS to DES in saphenous vein graft stenting with the option of using a filter wire and/ or GPIIb/IIIa inhibitors. DES were associated with an 80% reduction in MACE (12 vs 30%) driven by non-fatal MI and target-vessel revascularisation. There was no difference in mortality rate. The contribution of the filter wire and GPIIb/IIIa inhibition used in 67% of cases could not be determined.The 2016 heart failure guideline discusses means to prevent or delay the onset of symptomatic heart failure. Predominant among these are treatment of hypertension, statins for those with CAD or at high risk thereof, smoking cessation, avoidance of excess alcohol intake, an ACE-I for patients with asymptomatic LVSD, and beta-blockade for those with LVSD after MI.Heart failure is defined as appropriate symptoms, possibly accompanied by physical signs of congestion, with evidence of structural heart disease on echocardiography. The guideline includes a new category of heart failure with mid-range ejection fraction (HFmrEF) of 40–49% in the range between heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Treatment of HFmrEF is yet to be clearly defined.ProBNP is more important in ruling out heart failure than in proving the diagnosis. Novel additions to the guidelines are the use in appropriately selected patients of an angiotensin receptor neprilysin inhibitor (ARNI)  to replace ACE-I, cardiac resynchronisation therapy (CRT), and ivabradine should they remain symptomatic on ACE-I/ARB, beta-blockade and MRA treatment. HFpEF and HFmrEF should be treated symptomatically, using diuretics to relieve congestive symptoms. The guideline discusses at length various co-morbidities and their management in the setting of heart failure.A ‘hotline’ session was devoted to device interventions in heart failure. The DANISH study evaluated the use of implantable cardioverter defibrillators (ICDs) in non-ischaemic heart failure in patients with NYHA class II to III symptoms and an ejection fraction < 35% .21 The sAnother two studies on cell therapy in heart failure could not demonstrate any benefit.This is an emerging area of concern for cardiologists and oncologists alike, given the increasing numbers of patients who may now survive for years after cancer treatment. The heart and blood vessels may be affected in a variety of ways by either chemotherapy or radiation. Myocardial dysfunction and heart failure, CAD, valvular heart disease, pericardial involvement, arrhythmias, hypertension, pulmonary thromboembolism, stroke, peripheral vascular disease or pulmonary hypertension may occur, not only acutely but also after a delay of months or years.The patient’s presentation is influenced by the agent used, the dose and duration of treatment, age, kidney function and pre-existing CV disease. Myocardial toxicity is of particular concern and its early detection, as evidenced by deteriorating LVSD on echocardiography in comparison to baseline values and/or by elevation in hs-troponin T, is important. Baseline echocardiography with follow up at the completion of treatment and then at three and six months is recommended. ACE-I or ARB, beta-blocker and MRA therapies are cardioprotective as well as effective in managing overt heart failure. Not all patients recover normal left ventricular function after the cessation of treatment. In those who do, it may be possible to discontinue the cardioprotective treatment.22Apart from death and stroke, the ESC 2016 guideline includes recognition of hospitalisations, left ventricular dysfunction and heart failure, cognitive decline and vascular dementia, and impaired quality of life as consequences of AF. An algorithm is provided for the detection of AF in patients with an implanted device presenting after detection of a high atrial rate episode lasting longer than five to six seconds or a rate > 180 beats/min.For the assessment of stroke risk and the need for anticoagulation, the CHADS-VaSC score remains unchanged but the stroke risk has been reclassified for women. Anticoagulation is indicated in men with a score of 2 or more; for women it’s a score of 3 or more. Anticoagulation is not mandated but may be considered in men and women with respective scores of 1 or 2.Bleeding risk scores should be considered to determine the presence of modifiable risk factors for major bleeding in patients taking anticoagulant therapy. A non-vitamin K antagonist (VKA)/novel oral anticoagulant is preferred to warfarin. Occlusion of the left atrial appendage may be considered in patients who have a long-term contra-indication to anticoagulation. The guideline provides recommendations for the initiation of anticoagulation after transient ischaemic attack or stroke and the re-initiation of anticoagulation after intracranial bleeding.The integrated management of AF includes symptom control, maintenance of haemodynamic stability and the preservation of LV function, stroke prevention and the management of CV risk factors. Recommendations for ventricular rate control include consideration of digoxin as a second-line therapy.ENSURE-AFConnolly reported on the ongoing trial of the antidote, andexanet alfa, in patients treated with a factor Xa inhibitor presenting with critical bleeding. Haemostasis was achieved in 79% of patients. However, thrombotic events have been observed after reversal. The 30-day mortality rate was 15%.24The channelopathies include long-QT syndrome , short-QT syndrome , Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, early repolarisation syndrome, progressive conduction system disease and idiopathic ventricular fibrillation. Although genetic testing is helpful in a variety of these conditions, it cannot rule out the presence of a particular condition. However once a genetic marker has been identified in a patient, there is a class I indication for testing family members. ‘Overlap’ syndromes may occur.Depending on the specific diagnosis, the management armamentarium includes lifestyle changes, reduction in the risk of exposure to triggers  betablockade (possibly nadolol to be preferred), late sodium channel blockers , quinidine, ablation of an ectopic focus and consideration of an ICD or pacemaker. Fever and alcohol exposure should be avoided in Brugada syndrome.Priori presented her basic science research on gene therapy in mice using adeno-associated virus (AAV) infection to either add an active gene or silence a mutant. Problems may be posed by the high incidence of antibodies to this virus.25In a session on mitral valve repair, Obadia illustrated several surgical approaches to the mitral valve. Alifieri discussed the problems associated with mitral valve repair. He emphasised the importance of recognising that ‘everything is closer than you think’: the commissure between the left and non-coronary aortic valve leaflets, the circumflex coronary artery, the artery to the atrioventricular node, the atrioventricular node itself and the coronary sinus all lie in close proximity to the mitral annulus and risk being injured during repair. It is challenging to remove calcification from the mitral annulus. As a result, mitral leaks in the region of the posterior annulus are seen more frequently in the elderly. Mitraclip®, discussed by Latib, may be complicated by inadequate grasping of the leaflet or leaflet perforation. Occasionally systolic anterior motion of the mitral anterior leaflet may result in intermittent mitral regurgitation during exercise only; this may require provocation with isoprenaline to demonstrate its presence.It is important to recognise that in patients with aortic regurgitation, only 50% have primary aortic valve disease; the primary pathology is in the aorta in the other half. Sinotubular dilatation, aortic dissection and occasionally aortic dissection flap prolapse may be at fault. Three-dimensional echocardiography is to be preferred over two-dimensional to quantify the degree of aortic regurgitation. A left ventricular end-systolic diameter > 50 mm or left ventricular end-diastolic diameter > 70 mm predicts the need for surgery. However, earlier referral for surgery is recommended in symptomatic patients and those with LVSD. TEE is strongly recommended prior to referral for surgery as well as intra-operatively.The feasibility of aortic valve repair depends upon the pliability of the leaflets and their freedom from calcification. Repair of a bicuspid aortic valve is less successful, especially when decalcification and cusp repair with a pericardial patch is required. There are many smaller studies reporting successful aortic root repair with freedom from re-operation and absence of residual regurgitation.Computed tomographic pulmonary angiography (CTPA) is frequently used in suspected acute pulmonary embolism (PE). The majority of these costly investigations yield a negative result. The YEARS project devised a simplified algorithm for diagnosing acute PE. The first step is to obtain a D-dimer test and score 1 point for each of the following: clinical assessment for signs of deep venous thrombosis (DVT), haemoptysis and whether PE is the most likely diagnosis. If the YEARS score is 1 or more or if the D-dimer value is < 1 000 ng/ml, order CTPA. If not, PE can be ruled out and CTPA is unnecessary. This method has been shown to be safe and will reduce the frequency of CTPA by 14% overall and to a greater degree in younger patients.In DVT-PE the outcome is not influenced by whether treatment is initiated with rivaroxaban or with enoxaparin with later bridging to rivaroxaban.2, and O: older than 65 years of age.Following treatment for venous thromboembolism (VTE), it is problematic to decide whether anticoagulant therapy may be safely withdrawn owing to the potential for recurrent events. Rodger presented a validation of the ‘men continue and HERDOO2 rule’ which identifies those at low risk of recurrence in whom anticoagulation can be withdrawn. The rule states that all males and certain females scoring 2 or more using the HERDOO rule must continue anticoagulation long term after unprovoked or minor provoked VTE. The HERDOO factors are HER: hyperpigmentation, oedema or redness in either leg, D: level of D:dimer assessed through blood testing, O: obesity defined as BMI ≥ 30 km/m


PCR (polymerase chain reaction) was used to detect the ACE gene I/D polymorphism in T2DM patients. Metabolic measurements including blood glucose, lipid profile, and blood pressure were obtained. Frequencies of the ACE genotypes  were not significant among the 4 groups of BMI-defined patients (P = 0.679) while ACE II carriers showed higher systolic blood pressure (SBP) and pulse pressure (PP) . Hyperglycemia, hypertension, and dyslipidemia in these T2DM patients were found to be significantly associated with BMI. In conclusion, the relationship of ACE gene I/D polymorphism with obesity is insignificant in Chinese patients with T2DM. SBP and PP might be higher in the ACE II carriers than in the DD and ID carriers.Association between ACE gene I/D polymorphism and the risk of overweight/obesity remains controversial. We investigated the possible relationship between ACE gene I/D polymorphism and obesity in Chinese type 2 diabetes mellitus (T2DM) patients. In this study, obesity was defined as a body mass index (BMI) value ≥ 25 kg/m Angiotensin converting enzyme (ACE), a key enzyme in the renin angiotensin system (RAS), can convert angiotensin I (Ang I) into vasoconstrictor molecule angiotensin II (Ang II) . Body faAll the subjects were newly diagnosed T2DM patients between January 2012 and June 2015 from the teaching hospitals of Guilin Medical University. A study's power calculation using the ratio of obesity and hypertension was done separately at the beginning of our work. By applying the sample estimate formula, we found that a sample size between 90 and 140 indicates a proper evaluation of the validity of the findings; thus, our participants  were validated. And none of the patients recruited in the study were under antidiabetes and antihypertensive medications. The patients signed informed consent and an ethical approval was obtained from the institutional clinical research review committee. The diagnosis of T2DM was based upon the American Diabetes Association (ADA) criteria .1c)), lipid profile , triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)), and blood pressure (systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP)).The metabolic variables included the definition of obesity (BMI and waist-to-hip ratio (WHR)), blood glucose (fasting plasma glucose (FPG) and glycated hemoglobin  were obtained by laboratory tests. Clinical and biochemical data were acquired as described previously , frequency, or percentage, as appropriate. Hardy-Weinberg equilibrium was calculated using the gene-counting method and difference was assessed by Chi square (A total of 1,574 patients were enrolled in this research. Of these newly diagnosed patients, 40.53% were male, 35.13% were hypertensive, and 27.06% were obese. Frequencies of ACE gene I/D polymorphism were in Hardy-Weinberg equilibrium, indicating a homogeneous and representative sample population. Frequencies of I and D alleles were 67.25% and 32.75%, respectively. The genotype frequencies were 11.18% for ID, 43.14% for II, and 45.68% for DD accordingly.An association between hypertension and BMI was identified in our study . The patThe relationships between ACE genotypes and hypertension and between ACE gene alleles and hypertension were demonstrated in Tables 1c, TC, TG, LDL-C, SBP, DBP, and MAP values, but lower HDL-C level. Interestingly, ACE gene II carriers showed higher SBP and PP compared to DD and ID carriers in these Chinese T2DM subjects.Tables To the best of our knowledge, this is the first large-scale epidemiological study to explore the relationship of ACE gene I/D polymorphism with obesity in Chinese patients with T2DM. Additionally, associations between the ACE gene I/D polymorphism and hypertension were analyzed. We found that there was no statistical significance in the relationship of ACE gene I/D polymorphism with BMI-based obesity, whereas ACE II carriers showed higher SBP and PP than those of DD and ID carriers.It is increasingly recognized that obesity has been identified as a key risk factor for hypertension , dyslipiIn addition, our results indicated that the ACE II carriers had higher SBP and PP than those of DD and ID carriers; this was a novel finding which was not reported in adults. In accordance with our results, one prior research reported that children carrying the II genotype were demonstrated to have higher BP and greater early growth acceleration compared to those with the other ACE genotypes . ConversStudy Limitations. One limitation in our research was that we mainly focused on a polymorphism point. It is well known that obesity and T2DM are polygenic disorders and have a multifactorial influence, as evidenced by the various disease outcomes modulated by the gene-gene and gene-environment interactions, and thus a combination of other gene polymorphisms was considerable. It is also worth pointing out that our analysis was a transversal and monocenter research in the study design. Further longitudinal studies need to be performed to strengthen our result.In conclusion, SBP and PP might be higher in the ACE II carriers than those in DD and ID carriers. The relationship of ACE gene I/D polymorphism with obesity was insignificant in Chinese patients with T2DM.


P < 0.00001) and plasma brain natriuretic peptide level . However, NPPV did not reduce all-cause mortality  or re-hospitalization rate  as compared with conventional therapy. Despite no benefits on hard endpoints, NPPV may improve cardiac function of CHF patients. These data highlight the important role of NPPV in the therapy of CHF.Chronic heart failure (CHF) has been shown to be associated with an increased incidence of sleep-disordered breathing. Whether treatment with noninvasivepositive-pressure ventilation (NPPV), including continuous positive airway pressure, bi-level positive airway pressure and adaptive servo-ventilation, improves clinical outcomes of CHF patients is still debated. 2,832 CHF patients were enrolled in our analysis. NPPV was significantly associated with improvement in left ventricular ejection fraction (39.39% vs. 34.24%; WMD, 5.06; 95% CI, 3.30-6.81;  Sleep-disordered breathing (SDB), including Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) and obstructive sleep apnea (OSA), is highly prevalent in patients with chronic heart failure (CHF). Large scale studies revealed that the prevalence of SDB in CHF patients is about 69% ~76% . CHF patDrug therapy, mainly including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and β-blockers, has substantially improved the prognosis of patients with mild to moderate CHF, but the prognosis of patients with severe CHF remains poor. Hence, novel nonpharmacotherapy such as NPPV that might extend life expectancy and improve quality of life of CHF patients is required. However, studies focusing on effects of NPPV on CHF prognosis were limited by small sample size and inconclusive. Thus, we used powerful pooled-analysis methodology to investigate the impact of NPPV on all-cause mortality, re-hospitality and cardiac function in CHF patients, regardless of breathing status during sleeping.We identified 8,869 potentially eligible literature citations, of which 56 were reviewed as full articles. Only 23 reports of studies with suitable data were eligible for inclusion, all of which were full articles published in English from 1997 to 2015 –31. A toThe sample sizes ranged from 14 to 1,325 participants. The mean ages of the study participants ranged from 56.9 to 72.8 years and the mean follow-up from 1 to 24 months. The methodological quality of the included studies was in general poor, with only 9 of 23 reports describing two or more of the four quality criteria. Loss to follow-up was reported as < 10% in only 16 reports.vs. 0.24%; pooled odds ratio [OR], 1.13; 95% confidence interval [CI], 0.93-1.37; P = 0.22) or re-hospitality , it significantly reduced left ventricular ejection fraction (LVEF) (39.39% vs. 34.24%) with a pooled weighted mean difference (WMD) of 5.06  and plasma brain natriuretic peptide (BNP) level (268.23 pg/ml vs. 455.55 pg/ml) with a WMD of −105.66  as compared with conventional therapy in CHF patients.Cardiovascular events as well as cardiac function were evaluated for all 23 studies Table . AlthougFor the sensitivity analysis, removal of the largest study  produced2I = 48%) and plasma BNP level (2I = 34%). However, high heterogeneity existed in the analyses of LVEF (2I = 82%) and re-hospitality (2I = 68%). After removal of one study  AND (“heart failure” or “chronic heart failure”) with no restriction on subheadings . Similar but adapted search terms were used for the other literature databases or search engines. In order to increase sample size, widen population coverage and increase statistical power, we included results for both RCTs and observational studies.vs. control group without NPPV in patients with diagnosis of stable CHF; (ii) were RCTs or observational studies with at least a 1-month follow-up for each group; and (iii) contained sufficient information to estimate the pooled WMDs or the pooled ORs and their corresponding 95% CIs.The study selection criteria were as follows: (i) compared NPPV treatment  The following information was extracted from published reports by use of a standardized protocol: first author's last name, year of publication, study design, country of origin, number of enrolled patients, subject characteristics at baseline , follow-up duration, concomitant medication, and end-points.The methodological quality of eligible studies was assessed with criteria adapted from guidelines for the evaluation of articles on prognosis . he litehttp://www.cc-ims.net/revman, accessed on 16 November 2015) was used for the pooled analysis. The between-study heterogeneity was tested by the chi-square-based Cochran's Q statistic and the inconsistency index (I2). Statistically significant heterogeneity was considered with a chi-square P < 0.10 and 2I > 50%. Results showing no significant heterogeneity were analyzed by the fixed-effects model and those with significant heterogeneity were analyzed by the random-effects model. Pooled WMDs or ORs were reported with 95% CIs, and a two-tailed P < 0.05 was considered statistically significant for all analyses. In addition, sensitivity or subgroup analyses were conducted to seek more narrowly drawn subsets of reports of studies by removing an individual study each time or studies with similar features to assess individual effects. Finally, we assessed publication bias using Nfs. Any calculated Nfs value smaller than the number of retrieved reports of studies indicated publication bias. We calculated the Nfs0.05 as Nfs0.05 = (ΣZ/1.64)2 - k, where k is the number of reports of studies included in the analysis.RevMan 5.3 software, developed by the Cochrane Collaboration (