P < 0.001). We conclude that use of RAS inhibitor in CSA-AKI patients after renal functional recovery is associated with lower risk of ensuing CKD development.Acute kidney injury (AKI) is an independent risk factor for ensuing chronic kidney disease (CKD). Animal studies have demonstrated that renin-angiotensin system (RAS) inhibitor can reduce ensuing CKD after functional recovery from AKI. Here we study the association between ensuing CKD and use of RAS inhibitor including angiotensin converting enzyme inhibitor or angiotensin II type 1a receptor blocker starting after renal functional recovery in our prospectively collected observational AKI cohort. Adult patients who had cardiac surgery–associated AKI (CSA-AKI) are studied. Patients with CKD, unrecovered AKI, and use of RAS inhibitor before surgery are excluded. Among 587 eligible patients, 94 patients are users of RAS inhibitor which is started and continued after complete renal recovery during median follow-up period of 2.99 years. The users of RAS inhibitor show significantly lower rate of ensuing CKD  and longer median CKD-free survival time . Multivariate Cox regression analyses further demonstrate that use of RAS inhibitor is independently associated with lower risk of ensuing CKD (hazard ratio = 0.46,  Acute kidney injury (AKI) is common and associated with higher morbidity and mortality globally1235678951112Although the mechanisms underlying AKI-CKD transition are incompletely understood in humans, animal studies have shown a number of pathogenetic mechanisms such as maladaptive repair1618Recently, animal studies have demonstrated that activation of intrarenal renin–angiotensin system (RAS) after AKI underlies the possible mechanism for development and progression of ensuing CKD20212 before surgery (75 patients), unrecovered AKI (69 patients), follow-up less than 3 months after recovery from AKI (99 patients) and regular medication with RAS inhibitor including angiotensin converting enzyme (ACE) inhibitor or angiotensin II type 1a receptor blocker (ARB) before AKI (184 patients). Of the 587 eligible patients, 94 patients were users of RAS inhibitor which was started after complete renal recovery defined as the decrease of serum creatinine (SCr) level to within 0.3 mg/dl above the baseline and continued during the median follow-up period of 2.99 years , diagnosis of CKD or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m99 years . The othP < 0.001). At discharge from hospital, 87.2% of users and 26.8% of non-users had treatment with anti-HTN agents (P < 0.001). In contrast, more non-users of RAS inhibitor had congestive heart failure (CHF), metastatic cancer and immunosuppressant treatment.The clinical characteristics of the study population were shown in 2 (P = 0.005). The median CKD-free survival time 1079 days in users was much longer than 520 days in non-users (P = 0.011).In the follow-up period after complete renal recovery from AKI, there was no significant difference of SCr at AKI recovery between two groups . Of all 2 . In userP < 0.001). The other factors significantly protective against ensuing CKD were higher levels of baseline hemoglobin and eGFR. Conversely, variables significantly associated with risk of ensuing CKD included older patients, higher SCr level at AKI, diabetes mellitus (DM), CHF, HTN and hyperuricemia. The Kaplan-Meier curve revealed significant protection of RAS inhibitor from ensuing CKD again , severe proteinuria at AKI, PAOD, hyperuricemia, hyperlipidemia, smokers, metastatic cancer and non-users of anti-HTN agents. No benefits for heart transplant recipients and statins or immunosuppressant users could be due to different pathogenesis of its correspondingly underlying disease or its specific drug effect.There are some limitations in our study. First, this was an observational study. Well designed-clinical trials should be initiated in the future to prove the protective effect of RAS inhibitor on ensuing CKD after complete renal recovery from AKI. Second, 10.2% of patients without CKD development received follow-up period less than one year which may underestimate the incidence of ensuing CKD after AKI. It might take longer time for our patients to develop CKD because most patients had mild AKI and median duration required for ensuing CKD development was far more than one year. Third, only patients with CSA-AKI were included. To extend our findings, we need more studies to investigate the effect of RAS inhibitor after complete renal recovery from AKI due to the other mechanisms. Finally, urinalysis was not checked as frequently as SCr. Therefore, any abnormal findings in urine representing the residual renal damage in patients could not be timely noticed. Even though these limitations, this prospectively collected observational cohort study provided the strong evidence that use of RAS inhibitor after complete renal recovery from CSA-AKI was associated with risk reduction by 54% for ensuing CKD after multivariate adjustment.In conclusion, in patients without CKD history, use of ACE inhibitor or ARB was associated with lower risk of ensuing CKD development after complete renal recovery from CSA-AKI. Our study highlights the important role of RAS activation in AKI-CKD transition. Use of RAS inhibitor should be included in the strategies for post-AKI care.2 by Taiwanese MDRD equationThis was a prospectively collected observational cohort study based on the National Taiwan University Hospital Study Group on Acute Renal Failure (NSARF) database established in the surgical intensive care units (SICU). We screened patients in this database who were ≥18 years old and hospitalized in the SICU of National Taiwan University Hospital (NTUH) for postoperative care of cardiac surgery with CPB between January 1, 2000 and December 31, 2011. We excluded patients who did not have AKI after surgery. Other exclusion criteria were history of CKD, preoperative eGFR <60 ml/min/1.73 mThe study was approved by the Institutional Review Board of NTUH. A waiver of informed consent was obtained because there was no breach of privacy and no interference with patient care.Preoperative demographic data were obtained at SICU admission. These variables included age, gender, smoking history, DM , HTN (using anti-HTN agents or systolic/diastolic blood pressure >140/90 mmHg at admission), CHF (defined as New York Heart Association (NYHA) functional class III or IV), PAOD , chronic obstructive pulmonary disease (with long-term bronchodilators), hyperlipidemia (with lipid-lowering agents) and CAD . Chronic hepatitis and metastatic cancer were also recorded according to diagnostic codes prior to admission.Laboratory data such as baseline SCr, albumin, hemoglobin were recorded at SICU admission. SCr at the peak of AKI was also obtained. Urine protein at AKI was recorded according to urine dipstick test. Mild proteinuria and severe proteinuria were defined by the result of trace to 1 + and 2 + to 4 + respectively. Baseline eGFR was calculated using Taiwanese MDRD equationMedications such as anti-HTN agents , lipid-lowering agents (statins), immunosuppressants after heart transplant were recorded during hospitalization and at discharge. Users of RAS inhibitor were defined as starting ACE inhibitor or ARB between 1 and 6 months after complete renal recovery from AKI and continuing the medication during follow-up, while the others were defined as non-users.In addition to data collection during hospitalization and at discharge, we also leveraged an electric medical record to keep track of important covariates when patient visited our outpatient department, including SCr, medications and diagnosis of comorbidity.2 The endpoint was stage 3 CKD development during the follow-up period. All of the longitudinal measurements of SCr and eGFR during hospitalization and follow-up period were obtained for each enrolled patient. Stage 3 CKD was determined by eGFR below 60 ml/min/1.73 mP < 0.05 was considered statistically significant. We constructed a univariate and multivariate Cox regression model to investigate the association between use of RAS inhibitor and CKD development. Variables significantly associated with CKD development in the univariate analysis (P < 0.05) were included in the multivariate Cox regression model. The survival curves for CKD development were plotted using Kaplan-Meier method. Subgroup analyses were also performed to estimate the HR. Subgroups of variables deemed clinical relevant to CKD development, which included age, sex, DM, HTN, CHF, CAD, PAOD, hyperlipidemia, hyperuricemia, metastatic cancer, smoking status, AKI stage, urine protein at AKI, surgical procedures, medication use such as anti-HTN agents, statins or immunosuppressants were identified.We performed statistical analyses with the SAS software, version 9.4. Continuous variables were presented as mean , and the difference between users and non-users of RAS inhibitor was compared with the Student’s t-test. Categorical variables were summarized as percentages and analyzed with the chi-square test. Two-sided How to cite this article: Chou, Y.-H. et al. Renin-Angiotensin System Inhibitor is Associated with Lower Risk of Ensuing Chronic Kidney Disease after Functional Recovery from Acute Kidney Injury. Sci. Rep.7, 46518; doi: 10.1038/srep46518 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Aortic blood pressure, pulse wave velocity, and augmentation index were assessed by applanation tonometry. Endothelial function was studied by forearm post-ischemic flow mediated vasodilatation and by pulse wave analysis with beta 2-adrenoceptor agonist stimulation. Skin microvascular reactivity was assessed by laser Doppler fluxmetry and iontophoresis. Treatment with doxazosin or ramipril reduced aortic and brachial blood pressures , with greater reductions in aortic than brachial systolic blood pressures (P = 0.021) and aortic/brachial pulse pressure ratio (P = 0.005). Compared to doxazosin, ramipril reduced carotid-femoral and carotid-radial pulse wave velocity (both P < 0.05). Forearm endothelial dependent and independent vasodilatation, assessed by post-ischemic flow mediated vasodilatation and glyceryl trinitrate, and by pulse wave analysis remained unchanged by both doxazosin and ramipril. In addition, skin microvascular endothelial dependent (acetylcholine) and independent vasodilatation (sodium nitroprusside) remained unchanged. In conclusion, ramipril reduced indices of aortic stiffness, suggesting that angiotensin converting enzyme inhibitor therapy may have effects beyond blood pressure reduction. However, treatment did not appear to influence endothelial function. Evidence of endothelial dysfunction and its possible improvement by antihypertensive treatment might require more advanced hypertension.We aimed to study whether inhibition of the renin–angiotensin–aldosterone system has effects on vascular structure and function beyond the effects on blood pressure reduction alone. Patients with mild-to-moderate hypertension  and at EudraCT (# 2007-000631-25). Hypertension is characterized by an increased sympathetic vascular tone, early vascular remodelling of small resistance arteries, and impaired endothelial function –3. Thus,Antihypertensive treatment plays a key role to reverse hypertension induced structural vascular changes. Activation of the renin–angiotensin–aldosterone system (RAAS) increases the formation of angiotensin II, which mediates vasoconstriction and promotes inflammation, endothelial dysfunction, oxidative stress, and structural vascular changes . AngioteThis study aimed to investigate the possible influence of the RAAS on indices of central and peripheral vascular structure and function, and on endothelial function beyond the effects on blood pressure. Thus, we compared the effects of blocking the RAAS by the ACE inhibitor ramipril to reducing noradrenergic sympathetic vascular tone by the alpha 1-adrenoceptor blocker doxazosin in patients with uncomplicated mild-to-moderate hypertension. We assessed central BP and indices of aortic stiffness by pulse wave analysis, and endothelial function was examined by several methods in the forearm skeletal muscle and in the skin microcirculation, to reflect both conduit and resistance artery function.Women and men 18 years of age or older with mild-to-moderate primary hypertension were considered eligible for the Doxazosin–Ramipril Study if their office BP, obtained as a mean of 2 or more measurements by standard techniques in the supine position with an appropriate cuff size and mercury sphygmomanometer, was >140 mm Hg systolic and/or >90 mm Hg diastolic. Ambulatory BP monitoring had been performed in most patients to confirm the diagnosis of hypertension. All subjects were previously untreated or free from antihypertensive or other drug therapy with potential influence on BP, vascular, or endothelial function for at least 4 weeks. Secondary hypertension was ruled out by physical examination and routine biochemical examinations. Patients with BP >180/110 mm Hg, coronary artery disease, congestive heart failure, or atrial fibrillation or flutter, diabetes mellitus, or chronic kidney disease were excluded.Randomization to double-blind treatment with doxazosin 4 mg od or ramipril 5 mg od for 2 weeks with forced titration to doxazosin 8 mg od and ramipril 10 mg od for an additional 10 weeks was performed by a computer-generated list in blocks of four, stratified by sex. The two study drugs had identical appearance and were provided in identical containers for each patient, with the contents blinded for both patient and investigator .The study included 71 patients (63 with never treated hypertension); 10 patients (5 women and 5 men) discontinued due to reported side-effects (8 on doxazosin and 2 on ramipril). No serious side-effects were reported. Thus, we here report on 61 patients . All participants achieved the targeted 10 weeks of treatment with 8 mg doxazosin od or 10 mg ramipril od. Only 2 women on ramipril and 1 on doxazosin were premenopausal (i.e. <45 years of age), and no participant used systemic used hormone replacement therapy.Patients arrived in the morning after fasting overnight for the investigations at weeks 0 and 12. They were undertaken on 2 consecutive days on both occasions, to avoid pharmacological interference of the examination protocols on vascular function. The patients were asked to take their study medication approximately 2 h before the investigations to achieve peak plasma concentrations, but to refrain from caffeine containing beverages, fruit juices or vitamin C, and any other medication (including thrombocyte inhibitory drugs for 7 days and non-steroid anti-inflammatory drugs for 48 h). Examinations were performed in the supine position following a 20 min period of rest in a quiet room kept at 21–24 °C constant temperature.For the purpose of the vascular function studies, brachial BP was obtained in the supine position by an oscillometric device  on the right arm with an appropriately sized cuff as a mean of three readings 1 min apart.Applanation tonometry was performed using a SphygmoCor device  according to current recommendations . Radial x pulse pressure. Body mass index (in kg/m2) was calculated as weight/height2.Pulse pressure was calculated as systolic minus diastolic BP. Mean arterial pressure was calculated as diastolic BP + 1/3 x µ x blood flow velocity/baseline brachial artery diameter, where µ is blood viscosity, which was assumed to be 0.035 dyne x s/cm2 [n = 20).Endothelium dependent flow mediated vasodilatation (FMD) was measured by ischemia induced reactive hyperaemia in the non-dominant arm according to current recommendations . Vasodil x s/cm2 . The intEndothelial function was also assessed by beta 2-adrenoceptor agonist induced changes in the pulse waveform . Radial Endothelium dependent and independent forearm skin microvascular vasodilatation was assessed by laser Doppler fluxmetry and transcutaneous iontophoretic administration  of small amounts of acetylcholine  and sodium nitroprusside  for 60 s, as described previously . Skin miRoutine biochemistry was analysed by standard procedures from fasting blood samples obtained into Vacutainer tubes  on ice from an indwelling antecubital venous catheter after 20 min of supine rest.The co-primary outcomes in the Doxazosin–Ramipril Study were changes in endothelial function assessed by FMD and in haemostatic function measured by the generation of thrombin–antithrombin complex (those results will be presented elsewhere). A meta-analysis indicates a 1% increase in FMD to be associated with a 13% lower risk for a future cardiovascular event, after adjustment for confounding risk factors . Thus, aP) of 0.05. The statistical program used was JMP version 11.1 .Data are presented as mean values ± SD  or medians and interquartile range, as appropriate. Skewed variables were logarithmically transformed. Group comparisons were made by the analysis of variance or by multivariate analysis of variance. Multiple linear regression analysis was used to assess effects of treatment. To account for potential confounders concerning PWV and AIx, the initial multivariate mode always included baseline mean arterial pressure, heart rate, height, and age; gender did not affect the results. All results were similar if mean arterial pressures at week 12 instead of baseline values were included in the model. All statistical tests were 2-sided and carried out to a significance level (P < 0.001) in the doxazosin group, and 51.4 ± 13.6 and 60.3 ± 9.7 mm Hg (P < 0.001) in the ramipril group, respectively.Background characteristics of the two study groups are presented in Table P = 0.021) with no difference between doxazosin and ramipril.Antihypertensive drug treatment reduced aortic and brachial BP in both study groups Table ; Fig. 1.P = 0.030) and −1.4 ± 6.0 (P = 0.22) mm Hg for doxazosin, and −7.5 ± 8.7 (P < 0.001) and −4.2 ± 8.2 (P = 0.006) mm Hg for ramipril, respectively. Although the absolute changes in aortic  pulse pressure were greater (P = 0.016) in the ramipril group, the changes in the aortic to brachial pulse pressure ratios were similar in the two groups  Table ; Fig. 1.Data on brachial artery diameter and function are presented in Table This study in patients with uncomplicated mild-to-moderate hypertension compared the effects of reducing noradrenergic sympathetic vascular tone by the alpha 1-adrenoceptor blocker doxazosin to blocking the RAAS by the ACE inhibitor ramipril to assess the possible influence of the RAAS on vascular structure and function beyond the effects on blood pressure. As expected, treatment with both doxazosin and ramipril for 12 weeks reduced brachial systolic and diastolic BP. This confirms an important role for both sympathetic vasoconstrictor nerve activity mediated by noradrenaline and for the RAAS through actions of angiotensin II in the control of vascular smooth muscle tone and BP in man. Furthermore, we found greater treatment induced reductions in aortic than in brachial systolic BP, and this did not differ between the two drugs. Our observations of larger reductions in central than in peripheral BP on ramipril are in agreement with findings with other ACE inhibitors , 36. MorCarotid-femoral PWV provides a good reflection of aortic stiffness, and antihypertensive treatment reduces PWV. Compared to doxazosin, ramipril reduced carotid-femoral PWV. These results persisted when accounted for potential confounding influence . This is in agreement with the previous observations that inhibition of the RAAS with ACE inhibitors or angiotensin receptor blockers –39 reducPulse pressure amplification, as compared to brachial pulse pressure, reflects pulsatile flow and gives information about central haemodynamic and microvascular damage. Thus, central pulse pressure is an indirect indicator of central aortic stiffness . AccordiIn this study, doxazosin or ramipril did not change post-ischemic FMD (considered to reflect mainly conduit artery endothelium dependent vasodilatation) or the forearm blood flow response to glyceryl trinitrate. These results were consistent also when the ratio FMD to glyceryl trinitrate  was calculated, suggesting that drug treatment did not alter endothelial function. Consistent with these findings, endothelial dependent vasodilatation assessed by pulse wave analysis before and after beta 2-agonist stimulation (considered to reflect mainly resistance artery endothelium dependent vasodilatation) revealed little effect on reflection index by treatment with doxazosin or ramipril. In hypertensive patients with established coronary artery disease, suggesting more advanced atherosclerotic vascular disease, the ACE inhibitor quinapril, but not enalapril or the angiotensin receptor blocker losartan, improved endothelial function , whereasWe also investigated skin microcirculation by laser Doppler fluxmetry during iontophoresis of acetylcholine and sodium nitroprusside, and by local heating of the skin to evaluate treatment induced effects on endothelial function. This technique in the skin circulation has been shown sensitive to detect the early disturbances in endothelial function in man . HoweverTaken together, our results with three different validated non-invasive techniques to investigate endothelial function in various peripheral vascular beds were consistent. They suggest that antihypertensive treatment by reducing noradrenergic sympathetic vascular tone or by blocking the RAAS for 12 weeks does not influence endothelial dependent or independent vasodilation. However, these results should be interpreted with caution as the study population was relatively small and the variability of the methods for assessing endothelial function is not trivial. Nevertheless, this may be taken to suggest that our study population with uncomplicated mild-to-moderate hypertension had relatively normal endothelial function, where treatment induced improvement is difficult to detect. This is in consort with the observation that vascular remodelling develops at an earlier stage than endothelial dysfunction in hypertension . More adThere are several strengths to this double-blind randomized controlled study conducted in mostly never treated hypertensive patients. First, we compared the effects of blocking the RAAS with alpha 1-adrenoceptor blockade as an active control to assess the potential confounding effects of BP reduction by the ACE inhibitor. In addition, potential residual confounding effects of the magnitude of BP reduction were accounted for in the statistical analyses. However, the greater reduction in BP by ramipril than by doxazosin could have influenced our results on indices of vascular function. Second, we simultaneously studied several vascular beds. Third, we used several methods to evaluate endothelial function, and we included tests for both endothelium dependent and independent vasodilatation. However, there are important limitations to consider. First, the study population was of limited size, although this was justified by proper calculations of the required sample size. This may explain why we did not find changes in endothelial function by treatment. Second, the treatment period was 12 weeks and we cannot exclude that prolonged treatment could reveal other results. However, effects on BP and indices of aortic stiffness were already evident, and others have shown that changes in endothelial function can be demonstrated within 8–12 weeks in different study groups , 53. FinIn conclusion, doxazosin and ramipril similarly reduced central BP more than brachial BP, suggesting that both neurogenic sympathetic vasoconstriction and the RAAS are important for the control of central and peripheral BP. Ramipril reduced indices of aortic stiffness, suggesting that the effects of ACE inhibitor therapy go beyond the effects of BP reduction. However, we were unable to demonstrate an effect of treatment on endothelial function. Evidence of endothelial dysfunction and possible improvement by antihypertensive treatment might require more advanced hypertensive disease.


P<0.0001). Aortic waveform parameters, controlling for demographics, antihypertensives, diabetes and cardiovascular disease (CVD), were higher in non-Europeans than in Europeans. Further adjustment for brachial BP or lifestyle factors (particularly BMI) reduced many differences but several remained. Despite even further adjustment for mean arterial pressure, pulse rate, height and total:high-density lipoprotein cholesterol, compared with Europeans, South Asians had higher levels of all measured aortic waveform parameters , whereas Pacific people had 9% higher loge  (P<0.0001). In conclusion, aortic waveform parameters varied with ethnicity in line with the greater prevalence of CVD among non-white populations. Generally, this was true even after accounting for brachial BP, suggesting that waveform parameters may have increased usefulness in capturing ethnic variations in cardiovascular risk. Heavy alcohol consumption, smoking and especially BMI may partially contribute to elevated levels of these parameters.Little is known about how aortic waveform parameters vary with ethnicity and lifestyle factors. We investigated these issues in a large, population-based sample. We carried out a cross-sectional analysis of 4798 men and women, aged 50–84 years from Auckland, New Zealand. Participants were 3961 European, 321 Pacific, 266 Maori and 250 South Asian people. We assessed modifiable lifestyle factors via questionnaires, and measured body mass index (BMI) and brachial blood pressure (BP). Suprasystolic oscillometry was used to derive aortic pressure, from which several haemodynamic parameters were calculated. Heavy alcohol consumption and BMI were positively related to most waveform parameters. Current smokers had higher levels of aortic augmentation index than non-smokers (difference=3.7%,  In addition, an understanding of ethnic variations in arterial function may help to identify the population groups to be targeted in public health interventions.Cardiovascular disease (CVD) prevalence is increased in Polynesian and South Asian people relative to white/European populations.8 have expanded the scope of measurable variables from the aortic pressure waveform such as aortic BP, augmentation index (Alx), backward pressure (Pb) amplitude and excess pressure integral (EPI).7 These parameters are important because they have been shown to predict CVD incidence independently of and more strongly than brachial BP.7 A few studies have examined differences in aortic waveform parameters between South Asian and European people,11 although these studies did not assess parameters derived from wave separation6 or reservoir wave7 analyses. Another drawback is that some of these studies investigated selected populations that either excluded people with high BP10 or included only those with BP-related morbidity (such as patients with heart failure11). This restriction may result in poorly representative samples and the inability to fully explore the relationship between ethnicity and arterial function. In addition, we are not aware of any studies that have evaluated differences between Polynesian and European people.New methods12 cigarette smoking has been shown to increase brachial BP,13 whereas smoking cessation has been demonstrated to reduce brachial BP,14 and a meta-analysis showed that weight loss reduced brachial BP.15 Although these intervention studies demonstrate that reducing these three factors decreases brachial BP, it is not known whether they are associated with various aortic waveform parameters.Identifying determinants of arterial waveform measures helps to define suitable strategies for improving arterial function. Three possible determinants are alcohol consumption, smoking and body mass index (BMI). A meta-analysis showed that alcohol reduction decreased brachial BP among heavy drinkers,The first objective of this study was to explore ethnic differences in arterial waveform parameters between Europeans and people from Polynesian and South Asian groups. We aimed to include a wide range of arterial function measures, which may reveal new ethnic variations. Our second objective was to examine associations between these parameters and alcohol consumption, smoking and BMI.−1. All baseline data were collected between 2011 and 2012. Ethics approval was provided by the Ministry of Health Multi-region Ethics committee. Written, informed consent was obtained from each participant. Full details of the study design have been published elsewhere.16The present study is a baseline  analysis of the ViDA (Vitamin D Assessment) study, a randomised controlled trial of the health effects of vitamin D supplementation in 5110 people. Participants were recruited from patient registers of family doctors in Auckland. Inclusion criteria were men and women aged 50–84 years and resident in Auckland at recruitment. Participants were excluded if they had been diagnosed with a terminal illness and/or in hospice care, intended to leave New Zealand during the follow-up period, took vitamin D supplements (including cod liver oil) of >600 IU per day, had a history of specific medical conditions  and/or had a baseline serum calcium >2.50 mmol l3 Therefore, in the current study, the Pacific group was further broken down into specific categories of adequate sample sizes: Samoan, Tongan and Other Pacific (those from other Pacific groups).Demographic and lifestyle information, along with both history of diabetes and CVD, were collected via questionnaires administered by trained interviewers using a standardised protocol. Ethnicity was defined by self-identification. Participants were initially categorised into four main ethnic groups: Pacific, Maori (both Polynesian groups), South Asian and European/Other. Subsequently, we excluded 'Other' (non-European) people from the 'European/Other' group as we aimed to have Europeans only in our ethnic comparisons. Brachial BP has been found to vary between individual Pacific groups.Alcohol consumption was assessed with the question, 'How often do you have six or more drinks on one occasion?' Responses were categorised into three groups: 'Never', '⩽1 per month' and 'weekly, daily or almost daily'. Smoking was assessed by asking participants whether they had previously smoked cigarettes, and whether they described themselves as ex-smokers or current smokers. Responses were classified as 'non-smoker', 'ex-smoker' or 'current smoker.' Participants were also asked the number of years since quitting (for ex-smokers) and the number of cigarettes smoked per day.To adjust for the effect of antihypertensive medications on the waveform parameters, details of all prescriptions dispensed for participants before and after their interview dates were collected from the Ministry of Health. To determine that measured BP parameters have been influenced by prescribed drugs, these medicines must have been taken just prior to the interview. Therefore, antihypertensive use was defined as the prescription of an antihypertensive drug with days of supply that encompassed the interview date.2 A blood sample was taken, and collected aliquots were stored at −80 °C (−112 °F) and later measured for both serum total cholesterol and HDL (high-density lipoprotein) cholesterol on a Siemens Advia 2400 analyser .Height was measured with a stadiometer to the nearest 0.1 cm, and weight with digital scales to the nearest 0.1 kg. These measurements were made without shoes and in light clothing. BMI was calculated as body weight (kg) per height (m).R6.5 cardiovascular monitor; Pulsecor, Auckland, New Zealand), with an appropriately sized cuff positioned over the left upper arm. The BP+ device has been shown to: (1) yield central systolic BPs that are highly correlated with those assessed by catheter measurement at the ascending aorta or aortic arch17 and, (2) measure central systolic BP with good intratest and intertest reliability .18 To improve the quality of the waveforms used in analyses, we decided a priori to exclude readings with a signal-to-noise ratio of <6 dB.After 15 min rest while sitting, BP (±1 mm Hg) was measured three times with an Omron T9P oscillometric device  placed above the cubital fossa of the left arm and the mean of the two closest measurements were used for analyses. Suprasystolic oscillometry was carried out using a BP+ device  . A meta-analysis has shown AIx to predict CV events.5AIx, an index of arterial stiffness and wave reflection,20 The amplitude of backward pressure (Pb) was then calculated. Pb determined from this technique has previously been shown to be similar to values obtained using aortic flow waveforms measured by Doppler ultrasound.21 Further, independently of brachial BP, Pb has been shown to predict mortality22 and CV events.6Wave separation analysis was used to separate the aortic pressure waveform into forward and backward components.7 Peak reservoir pressure was calculated as the amplitude of the reservoir pressure waveform, which has been found to associate positively with the risk of cardiovascular events independently of brachial BP.20 Excess pressure was calculated as measured pressure minus reservoir pressure.23 The integral of the excess pressure waveforms (area under these waveforms) over the cardiac cycle was used to calculate EPI. EPI measures pressure that is associated with excess ventricular work and has been shown to predict CV events independently of brachial SBP.7Aortic pressure was separated into reservoir and excess components using custom-written Matlab software (Mathworks). Reservoir pressure was calculated from pressure measurements, as described elsewhere.25 PWV is a known predictor of CV events, as demonstrated in a meta-analysis.26Aortic pulse wave velocity (PWV) was calculated from validated algorithms and derived PWV values have been shown to predict CV events independently of brachial BP.χ2-tests . Because of the positively skewed distribution of EPI, this was converted to loge for analyses. Associations between independent variables and arterial waveform parameters were examined by multivariate linear regression, adjusting for covariates (listed in footnotes of tables) that are determinants of BP variables. In separate models and in accordance with research similar to ours,27 correction was made for pulse rate as this influences the timing of reflected pressure waves and is a known contributor to the shape of the aortic pressure waveform.28 The significance of main effects was examined with the F-test. Potential interactions between sex and independent variables of these waveform relationships were examined but as these were not statistically significant, we did not report sex-specific results. All analyses were performed using SAS version 9.3  and statistical significance was set at P<0.05 (two-sided).Equality of variance across groups was checked with Levene’s test. Inter-ethnic differences in participant characteristics were assessed with analysis of variance (for continuous variables) and n=41 or <1% of the total sample size, indicating a minimal loss of data). The participants were 3961 Europeans, 321 Pacific people, 266 Maori and 250 South Asians. The composition of the Pacific group was as follows: 105 (33%) Samoan, 82 (26%) Tongan and 134 (42%) Other Pacific. The Other Pacific group predominantly comprised Cook Island Maori people (57%); the remainder being Niuean (25%), Indigenous Fijian (12%), Tahitian (1%) and Other (5%).P<0.0001). Smoking prevalence (combined proportion of ex-smokers and current smokers) was higher in Maori and lower in South Asians with respect to Europeans (P<0.0001 for relationship between smoking and ethnicity). Supplementary analyses (not tabulated) revealed that, on average , ex-smokers quit smoking 28 years ago (interquartile range: 22 years), and the median number of cigarettes smoked per day among current smokers was approximately just under 10 (58% smoked ⩽10 per day). Compared with that of Europeans, BMI was higher in both Maori and Pacific but lower in South Asians . Compared with Europeans, Maori had higher levels of brachial SBP, brachial DBP, aortic SBP, AIx, Pb, peak reservoir pressure and loge(EPI). Pacific people had higher levels of brachial SBP, brachial DBP, aortic SBP, Pb, peak reservoir pressure, loge(EPI) and PWV with respect to Europeans. Relative to Europeans, South Asians had higher levels of AIx, Pb and loge(EPI).Ethnic differences in arterial waveform parameters between European and non-European groups are shown in P⩽0.004), except for aortic SBP (P=0.32) and peak reservoir pressure (P=0.76). At a given brachial SBP, compared with Europeans, South Asians had higher levels of AIx, Pb and loge(EPI). Compared with Europeans, at the same brachial SBP, Maori had lower PWV, whereas Pacific people had higher loge(EPI) but lower AIx and PWV.For the comparisons adjusted for brachial SBP , all parP⩽0.034; P=0.50). For the same brachial DBP, South Asians had higher levels of all waveform parameters relative to Europeans, except for PWV. With respect to Europeans, Pacific people had higher levels of aortic SBP and loge(EPI), whereas Maori had higher levels of loge(EPI).Similarly, at a fixed brachial DBP, all waveform parameters varied with ethnicity , with Other Pacific people having higher AIx than both Samoans  and Tongans . There were no other differences among the Pacific groups .We additionally examined differences in arterial waveform parameters within Pacific groups , adjusted for age, sex, antihypertensive use, diabetes and CVD (plus pulse rate for AIx). AIx varied across the Pacific groups (P⩽0.005). In each case, the beta-coefficients for people who consumed the most were more than double that of those whose consumption was ⩽1 per month. AIx varied with smoking (P<0.0001), with smokers having higher levels of this variable than non-smokers. Specifically, AIx was higher in ex-smokers than in non-smokers  but notably even more so in current smokers . BMI had positive relationships with all parameters except AIx and Pb .Adjusted associations between modifiable factors and arterial waveform parameters are illustrated in P=0.004), smoking (P<0.0001) and BMI (P<0.0001) . When the models for P=0.015) and loge(EPI) (P=0.007), whereas smokers (particularly current ones) had higher loge(EPI) than non-smokers (P=0.0002).Pulse rate was positively associated with heavy alcohol consumption . Maori and Pacific people had higher levels of arterial waveform parameters than Europeans but, in most cases, these differences were markedly attenuated (by between 11% and 72%) when BMI was controlled for. Adjustment for heavy alcohol consumption had a predominantly minor impact on these differences, changing these by between 2% and 15%. Controlling for smoking resulted in primarily small changes (by <1–12%) to the Pacific, Maori and South Asian regression coefficients.e(EPI)  than Europeans. In contrast, after this adjustment, South Asians had higher levels of aortic SBP , AIx (β=1.7% P=0.0028), Pb , peak reservoir pressure , loge(EPI)  and PWV  with respect to Europeans.Following this, we evaluated the cumulative contributions of several variables to the ethnic differences . As illuOur results show that New Zealanders of non-European ethnicity have higher levels of arterial waveform parameters than those of European ethnicity. For the same brachial SBP or DBP, these parameters varied with ethnicity, with South Asians particularly having higher levels of these measures relative to Europeans. Heavy alcohol consumption and BMI were positively and directly related to nearly all waveform parameters, whereas smoking was positively and directly associated with most of these. These lifestyle factors together made large contributions to a number of ethnic variations in these waveform parameters. But several ethnic differences remained and, despite further accounting for mean arterial pressure, pulse rate, height and total:HDL cholesterol ratio, South Asians nonetheless had higher levels of all aortic waveform parameters relative to Europeans.30 We extend this prior research by showing that these ethnic groups additionally differ in aortic waveform parameters. Other new ethnic variations were the higher AIx, Pb and EPI we observed among South Asians with respect to Europeans. In line with this, a relatively small study reported South Asians to have higher stiffness index than Europeans.10The higher levels of brachial SBP we observed among Pacific people relative to Europeans concurs with findings in previous studies.3 Despite this consistency, we cannot rule out the possibility of intra-ethnic differences after consideration of limitations with regard to sample size and representativeness (discussed below).Another original finding was that, within the Pacific group, there were very few differences in aortic waveform parameters. In accordance with our results, Samoan and Tongan adults have been found to have similar brachial SBP.7 they may mediate disparities in CVD prevalence that exist between the ethnic groups studied in this paper.4 Therefore, interventions directed at improving arterial function in these populations might reduce these CVD disparities. Further, several of the waveform differences were notable in size. For example, loge(EPI) was 0.13 higher in Pacific people than the reference group, indicating that EPI was e0.13 or 1.14 times higher (a 14% difference) than among Europeans. Although these results show that the ethnic variations are potentially of clinical significance, longitudinal analyses are required to establish the contribution of these waveform variations to ethnic differences in CVD incidence.Given that aortic waveform parameters varied with ethnicity and that they predict cardiovascular events,7 Thus, we investigated how these parameters vary with ethnicity at a given brachial SBP or DBP. Our finding that they varied with ethnicity suggests that, across ethnic groups, it may be difficult to compare arterial function and its associated cardiovascular risk using brachial BP alone.Previous studies have not examined whether, at a fixed brachial SBP or DBP, the ethnic groups we studied have different or similar levels of aortic waveform parameters. Such comparisons are of significance because brachial BP is a widely used measure of arterial function but various central BP parameters may be more important predictors of cardiovascular morbidity and/or mortality.lower brachial SBP. This indicates that the parameter level at a hypertension threshold of 140 mm Hg of brachial SBP in Europeans, for instance, would correspond to a lower brachial SBP in South Asians. Therefore, to more accurately reflect these parameters (but not necessarily risk of CVD), brachial SBP and DBP cut-off points for defining hypertension may need to be set at different levels for the non-European groups we studied.Further, these results have implications for defining hypertension or the risks associated with high BP. For example, at a given brachial SBP, South Asians had higher parameter levels than Europeans . Therefo15 We extend this prior research by showing that relationships additionally exist for several non-brachial measures  differences of ~0.2 s.d.s of waveform parameters, which should be adequate to identify clinically meaningful differences.In summary, we found new differences in arterial function between European and non-European people, including measures of wave reflection and excess cardiac work. Several of these, particularly South Asian differences, remained unexplained as they were independent of numerous BP-related factors including demographics, lifestyle and physiological variables. As these varied in line with recognised differences in CVD prevalence between these populations and several were notable in size, the observed variations are potentially important mediators of ethnic CVD disparities. Across ethnic groups, at the same brachial BP, aortic waveform parameters vary with ethnicity, suggesting that the former has limited usefulness in capturing ethnic variations of these parameters. In other words, brachial BP cannot act as a surrogate for these parameters and ethnic differences in the latter will be better monitored by quantifying these parameters (using monitors such as the BP+device used in the current study). Finally, heavy alcohol consumption, smoking and BMI were positively and directly associated with these parameters, supporting interventions aimed at reducing these three risk factors as strategies to improve arterial function. Reducing BMI may be a particularly important strategy as this modifiable factor made a large contribution to ethnic differences in the waveform parameters.


Renal sympathetic denervation has been studied as a potential therapeutic option for patients with therapy-resistant hypertension; however, a significant proportion of patients do not show a significant reduction in blood pressure and are classified as non-responders. The objective of the present study was to assess whether a redo renal denervation procedure increases response rates.We present a case series of three consecutive renal denervation non-responders treated with the multi-electrode radiofrequency St. Jude EnligHTN catheter after an average of 22 months. Patients were followed for 6 months.Mean age was 66 years and two patients were male. Patients were previously treated using either ReCor’s Paradise system, the Vessix V2 system or the Covidien OneShot system. Mean office blood pressure one year after the initial procedure was 187/102 mm Hg with a mean 24 h ambulatory blood pressure of 166/102 mm Hg. All patients underwent a successful redo procedure using the EnligHTN system because of persistent therapy-resistant hypertension. At 6 months a significant drop in both office and ambulatory blood pressure of −27/−6 mm Hg and −15/−13 mm Hg, respectively, was observed. No significant renal artery stenosis was observed at 6 months.In patients with therapy-resistant hypertension who do not respond to an initial renal denervation procedure, a redo procedure using the St. Jude EnligHTN system may help to significantly improve blood pressure control. Controlling blood pressure in hypertensive patients remains a challenge and treatment targets are frequently not achieved despite multiple antihypertensive drugs . Renal sThree consecutive patients who did not show a relevant reduction in both office and ambulatory blood pressure after renal sympathetic denervation because of therapy-resistant hypertension are presented. All procedures were carried out at the Erasmus Medical Center, Rotterdam, the Netherlands, between December 2012 and March 2013. Initial denervation was performed with the Paradise system , the OneShot system  and the Vessix V2 system , respectively [Office blood pressure recordings were collected in accordance with the Standard Joint National Committee VII Guidelines and ESC/ESH Guidelines . Twenty-Redo procedures were performed at 22.3 ± 4.6 months after the initial procedure. At the time of the redo procedure all patients were free of adverse events related to the index procedure, showed no signs of renal artery stenosis – diagnosed using either computed tomography (CT) or magnetic resonance (MR) angiography – and had preserved renal function.All patients were preloaded with 300 mg aspirin, if naïve, and advised to continue with aspirin for at least 1 month. All procedures were performed under conscious sedation using 1 to 3 mg of midazolam and 50 to 100 µg of fentanyl. After local anaesthesia, common femoral artery access was obtained by echo-guided puncture and a 6 Fr sheath was introduced. Under fluoroscopic guidance the short 6 Fr sheath was exchanged for an 8 Fr RDN or IMA tipped guiding sheath, which is recommended for the easier use of the St. Jude EnligHTN system. Pre-procedurally, 100 IU heparin/kg were administered to achieve an active clotting time >250 s. After engaging the renal arteries by using a no-touch technique with the help of a standard high-torque Balance Heavyweight (BHW) coronary guidewire, selective renal artery angiograms were made and an appropriate basket size was chosen . The BHW guidewire was exchanged for the EnligHTN ablation catheter and its tip positioned proximally to the bifurcation of the main renal artery. The basket catheter, containing four bipolar platinum-iridium electrodes, was then opened and the impedance of each electrode on the basket was monitored. After a total of four ablations were performed successfully the basket was collapsed and retracted proximally while another four ablations were performed in the same artery. A total of eight ablations were performed in each vessel, except for one artery in one patient in which the basket could not be engaged due to the very steep take-off of the right renal artery.All patients were discharged home the following day. All patients were followed according to a dedicated follow-up protocol including office visits at 1, 3 and 6 months, office blood pressure measurement at each time point and ambulatory blood measurements at 3 and 6 months. Additionally, a 12-lead ECG, blood and urine collections and a 6-month assessment of renal artery patency using either CT or MR angiography were done in all patients.Patient demographics and baseline characteristics are depicted in Table Patient 1 was a 76-year-old obese female with persistent headaches, known atrial fibrillation and hypertension since the age of 36. Due to repeated episodes of life-threatening gastrointestinal bleeding coumadin was stopped and replaced by aspirin. Secondary causes of hypertension were excluded. With a mean office blood pressure of 207/93 mm Hg (24 h ambulatory blood pressure monitoring 155/75 mm Hg) despite the use of three antihypertensive drugs, she underwent a first RDN using the ReCor Paradise system. After an uneventful recovery her blood pressure remained uncontrolled and she suffered from an ischaemic stroke. One year after the initial treatment, office blood pressures remained 193/93 mm Hg and given her clearly hypertension-related comorbidities, a second procedure combining a redo RDN procedure and a percutaneous left atrial appendage closure was performed. Due to the very steep take-off of her right renal artery only a left-sided ablation could be performed successfully. After a successful recovery, office blood pressures significantly dropped to 131/75 mm Hg . The headaches resolved and renal function increased from 56 ml/min at baseline to 61 ml/min at 6 months.Patient 2 was a 59-year-old Caucasian male with persistent headaches and a 40-year history of hypertension for which he received six antihypertensive drugs. Renal function was preserved. With a mean office blood pressure of 165/100 mm Hg and a 24 h ambulatory blood pressure of 161/109 mm Hg he underwent a successful bilateral RDN procedure using the Vessix V2 RDN system after secondary causes of hypertension were excluded. One year after the initial procedure his clinical condition remained stable with no improvement in blood pressure control. Both office and ambulatory blood pressure remained unchanged  despite a stable medication regimen. Given his persistent headaches and persistent refractory hypertension, a redo denervation was scheduled. After intensive follow-up at 1, 3 and 6 months, ambulatory blood pressures started to decrease slightly to 159/110 at 3 months and 152/103 at 6 months, while office blood pressure remained stable.Patient 3 was a 60-year-old Caucasian male with a history of insulin-dependent diabetes, hypercholesterolaemia and hypertension of more than 10 years. The patient was a heavy smoker (over 20 pack-years). Despite two percutaneous coronary interventions, the patient suffered from stable angina CCS Class II and severe fatigue. Both renal and cardiac functions were preserved. The patient was on six antihypertensive drugs and was referred for RDN with an office and ambulatory blood pressure of 184/103 mm Hg and 162/98 mm Hg, respectively. One year after a successful bilateral RDN using the Covidien OneShot system, blood pressures remained unchanged and angina worsened to class III. Given his extensive number of comorbidities, persistent grade III hypertension with a mean office blood pressure of 195/98 mm Hg (ambulatory 164/98 mm Hg), a redo procedure was scheduled in combination with a further coronary angiogram. After a successful bilateral RDN using the EnligHTN system, the coronary angiogram showed severe three-vessel disease. The patient was discussed by the heart team and accepted for coronary artery bypass surgery which was performed soon thereafter. The patient recovered quickly and uneventfully. Along with a significant reduction in both office and ambulatory blood pressure to 165/99 mm Hg and 146/86 mm Hg his symptoms of fatigue resolved and angina reduced to class I. The number of antihypertensive drugs was reduced to two at 6 months.In the present case series, we report the outcome of three consecutive patients with persistent grade III hypertension despite an initial technically successful RDN procedure one year previously, while still being on optimal medical therapy. A second RDN procedure using the St. Jude EnligHTN system proved to be safe in all patients with no procedure-related adverse events up to 6 months. Drops in ambulatory systolic blood pressure ranged from 9 mm Hg in patient 2, to 20 mm Hg in patient 3.Uncontrolled hypertension is independently associated with the incidence of stroke, coronary and peripheral artery disease, heart failure, sudden death and renal insufficiency , 15. ConDespite the growing body of evidence supporting the potential additional value of renal sympathetic denervation in patients with therapy-resistant hypertension, responders have not been clearly identified yet. The hypothesis of the present study was to test if a second denervation using the multi-electrode EnligHTN system could lead to a higher degree of sympathetic nerve damage and subsequently lead to a higher level of blood pressure reduction as a surrogate endpoint. Two previous studies have evaluated the effectiveness of a second denervation procedure. A case report by Lambert et al. reported on a 79-year-old hypertensive patient who experienced a drop of 40 mm Hg in systolic office-based blood systolic blood pressure 6 months after an initial procedure using the Medtronic Symplicity system . With thIn the Symplicity HTN-I study, a mean reduction in renal norepinephrine spillover of 47% was reported. However, the 95% confidence interval ranged from 28 to 65% . The hypTo the best of our knowledge this is the first report of the potential performance of a redo RDN procedure using the EnligHTN RDN system in three patients with persistent refractory hypertension. Despite their rather distinct baseline characteristics and risk profile, the redo procedure significantly helped in improving blood pressure control and physical condition in two patients and modestly reduced blood pressure in one patient. Given the lack of validated alternative treatment options in these high-risk patients, we believe that a redo RDN using the EnligHTN system can be a safe and effective option to improve blood pressure and potentially reduce future adverse cardiovascular events.The present study was limited by the small number of patients with extensive comorbidities. Two of the three patients received additional treatment in combination with the redo denervation procedure. However, it is unlikely that the left atrial appendage closure and/or coronary artery bypass surgery led to the significant blood pressure reductions observed in both patients with a 20-year history of hypertension. Finally, we cannot confirm that the redo procedure might have had a similar effect if devices other than the EnligHTN system had been used.Redo RDN using the EnligHTN system may be a safe and effective option to improve blood pressure control in patients with persistent therapy-resistant hypertension after the initial RDN procedure.


Gastroesophageal reflux disease (GERD) without symptoms or silent GERD can be easily missed in patients with hypertension. We aimed to investigate the prevalence of GERD, specifically the prevalence of silent GERD in hypertensive patients, and to explore its possible predictors.  Consecutive patients with hypertension referred to the cardiovascular clinic of Suining Central Hospital in 2016 were screened for this study. A Reflux Disease Questionnaire (RDQ) and an esophagogastroduodenoscopy (EGD) were employed for the evaluation of silent GERD. Included patients were divided into silent-GERD group and non-GERD control group. The demographic characteristics and antihypertensive agent prescriptions were collected and compared between the two groups.  The prevalence of silent GERD and GERD in patients with hypertension was 15.1% and 31.4%, respectively. 66 patients were included in the silent-GERD group, and 298 patients were included in the non-GERD control group. Abdominal obesity and untreated hypertension were positive predictors, while controlled hypertension was a negative predictor for silent GERD. The prescription of calcium channel blockers was not a predictor for it.  High prevalence of GERD, specifically silent GERD, could be found in patients with hypertension. Abdominal obesity and untreated hypertension were positive predictors for silent GERD, while controlled hypertension was a negative predictor for it. Gastroesophageal reflux disease (GERD) is a common disorder defined as the presence of acid reflux-related symptoms or esophageal mucosal damage caused by the reflux of gastric contents into the esophagus . Patient“Silent GERD” refers to esophageal mucosal injury  visible in EGD without typical or atypical GERD symptoms . ResearcHypertension is a cardiovascular disorder commonly observed in general practice . HyperteIt is common to observe silent GERD and hypertension concurrently, since many risk factors are shared by these two diseases. Risk factors including age, obesity, male sex, smoking, alcohol consumption, and education level have been reported to be significantly associated with both silent GERD and hypertension –17. MoreSince both silent GERD and hypertension are common and share many common risk factors, we postulate that a higher prevalence of silent GERD exists in patients with hypertension. Because these patients have no symptoms, they cannot seek medical therapy for GERD. However, these patients are still at risk of developing GERD-related complications. Esophageal bleeding and stenosis may occur among patients with erosive esophagitis . Most imConsecutive patients referred to the cardiovascular clinic of Suining Central Hospital between January 2016 and December 2016 were screened for this study. No patients enrolled in the study received remuneration. Requirements for participation included any one of the following: (1) diagnosis with primary hypertension (diagnosed before enrollment in the study and/or current use of antihypertensive medications); (2) classification in the New York Heart Association (NYHA) functional class I–III ; and (3)The present study was based on a standard protocol including the following three steps: (i) initial patient assessment, which included a complete collection of baseline characteristics and a face-to-face interview; (ii) the Reflux Diagnostic Questionnaire (RDQ); and (iii) endoscopy. All subjects needed to complete the self-reported RDQ questionnaire before endoscopy. Informed consent was obtained from all subjects before the protocol was administered.(1) Baseline Characteristics. Baseline data were collected including gender, age, height, weight, body mass index (BMI), waist circumference, and educational status; routine laboratory parameters were assessed: blood and urine examination and blood biochemical analysis. The BMI was calculated as weight (kg)/height2 (m2). Weight status was categorized according to the Chinese criteria [2), normal (BMI ≥ 18.5 kg/m2 and BMI < 24 kg/m2), overweight (BMI ≥ 24 kg/m2 and BMI < 28 kg/m2), and obese (BMI ≥ 28 kg/m2). Waist circumference was divided into two categories according to the Chinese criteria [criteria : underwecriteria : normal (2) Face-to-Face Interview. The interview obtained details on the following: smoking status, drinking status, history of diabetes mellitus, history of hyperlipidemia, family history of hypertension, and treatment with medications within the previous 4 weeks . The control status of hypertension was included when the subjects were receiving antihypertensive therapy. Regarding smoking, the participants were asked if they currently smoke. Smoking status was divided into current smokers and nonsmokers. For alcohol consumption, the amount of alcohol intake was recorded as the frequency of alcohol consumption over the past year, and alcohol consumption more than once a week was considered as “drinking alcohol.” Alcohol intake was categorized as drinking alcohol or not.The Reflux Diagnostic Questionnaire (RDQ) is a reliable and well-validated instrument to diagnose GERD and can be easily applied by primary care physicians in a community setting . The ChiUpper gastrointestinal endoscopy was employed to examine the presence of reflux endoscopic lesions. All upper gastrointestinal endoscopies were conducted after an overnight fast with standard endoscopes  and by the same experienced endoscopist (Xiaojuan Jin). Diagnosis and classification of reflux esophagitis were based on the Los Angeles classification (grades A–D) . BarrettThese criteria were consistently applied, and endoscopic pictures were reviewed by another experienced endoscopist (Xiaoqi Long). Generally, the final endoscopic diagnoses were made by the second endoscopist. A third endoscopist (Bin Yang) would join in and review all the endoscopic pictures if there is any discordance that occurred. The final endoscopic diagnoses will be made by a vote followed by the discussion among all these three endoscopists. Patients who returned for endoscopic reassessment for any reason were excluded from the analysis to prevent duplication of cases.Hypertension was defined as average systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or normal blood pressure in subjects currently taking antihypertensive medication .Measurement of blood pressure: two readings of systolic and diastolic blood pressure were taken from the right arm of each subject in a sitting position after a 10-minute rest using a standard clinical mercury manometer . The mean value of the two readings was recorded as the blood pressure .(1) Definitions. Antihypertensive treatment was defined as treatment with antihypertensive medication for greater than 20 days per month. Controlled hypertension was defined as normal blood pressure (systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg) among subjects who were receiving treatment [reatment . UntreatGERD was diagnosed based on the presence of reflux symptoms and/or the presence of reflux esophagitis or Barrett's esophagus. Silent GERD was defined as the presence of reflux endoscopic lesions (erosive esophagitis or Barrett's esophagus) but with an RDQ score ≤ 12. A subject with asymptomatic GERD was defined according to the RDQ score (>12) . PatientThe study was performed in accordance with the principles of the 1975 Declaration of Helsinki and approved by the Ethical Committee of Suining Central Hospital. Informed consent was obtained from each participant.t-tests were used to analyze categorical and continuous variables. Logistic regression methods were applied for variables for the multivariate analysis. The odds ratios (OR) and 95% confidence intervals (CIs) were obtained. Two-tailed P value < 0.05 was considered to be statistically significant.All analyses were performed using SPSS software . Categorical data were presented as percentages, while continuous data were presented as means with standard deviations. Chi-square tests and independent sample Of 2699 patients with hypertension for this study, a total of 439 patients met the inclusion criteria. Among these patients, 2 did not complete the questionnaire effectively. One patient did not complete the EGD examination. Based on the results of the RDQ test and the EGD, the prevalence of silent GERD was 15.1% (66/436). Among these patients, 87.9% (58/66) were Los Angeles (LA) grade A, 9.1% (6/66) were LA grade B, and 3.0% (2/66) were Barrett's esophagus . Both ofP = 0.037 and P = 0.012, resp.). Conversely, the waist circumference but not the BMI was significantly larger in the silent-GERD group compared to the non-GERD control group   .P = 0.034 and P = 0.014, resp.)  and those taking no antihypertensive agents (9.1% versus 2.7%) were significantly higher in the silent-GERD group compared to the non-GERD control group  .Multivariate analysis was performed for the following parameters: education level, abdominal obesity, treatment with prescriptions of calcium channel blockers, controlled hypertension, and untreated hypertension. Statistically significant differences were identified in the univariate analysis (results in The assignments of the demographic data and silent-GERD-related factors in hypertensive patients are shown in P ≤ 0.001) and untreated hypertension  were positive predictive factors for the occurrence of silent GERD, while controlled hypertension was a negative predictive factor for silent GERD  compared with the control group  compared to the non-GERD control group. This finding is consistent with an early 6-year follow-up study in Japan which found that the prescription of calcium channel blockers in patients with newly developed GERD is significantly higher than that in patients who did not develop GERD [It is also worth noting that the prescription of calcium channel blockers in this study was significantly higher in the silent-GERD group P = 0.0 comparedlop GERD . AlthougAnother interesting phenomenon that we have found in our study is that the prevalence of symptomatic GERD is also higher in patients with hypertension. Symptomatic GERD was diagnosed in 16.3% (71/436) of patients in our study which was higher than symptomatic GERD in normal subjects without hypertension. According to the previous study, the prevalence of symptomatic GERD was reported to be 5.6% in subjects without hypertension [Our study has some notable features. First, we included both patients with erosive esophagitis and patients with Barrett's esophagus in our silent-GERD group. Although patients with Barrett's esophagus but without symptoms should be included in the silent-GERD group as defined by Fass and Dickman , most reIn conclusion, we have shown that patients with hypertension have a high prevalence of GERD, specifically silent GERD. Abdominal obesity and untreated hypertension were positively associated with silent GERD, while controlled hypertension was negatively associated with it.


Perceptions of asthma control often vary between patients and physicians. This cross-sectional survey provided UK-specific data on actual and perceived asthma control in patients (18–75 years) attending routine asthma reviews in primary, secondary and tertiary settings. Differences between healthcare professionals’ (HCP) and patients’ perceptions of asthma control were evaluated via an online questionnaire and compared to a control—the validated asthma control test (ACT)—which patients completed. Treated patients (at least a short acting ß-agonist) with a documented diagnosis of asthma were enroled and consented within a month of their last appointment. Patients were grouped according to the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) 2014 treatment guidelines (BTS/SIGN steps 1–5). A total of 260 patients were screened: 234 were eligible for enrolment: 33, 52, 50, 49 and 50 patients in steps 1–5, respectively. Seventy per cent (164) were women. The percentage of patients aged 45–64 years was 47.4%. HCPs classed 70% (164) as non-smokers. 84.2% of patients and 73.9% of HCPs perceived that asthma was controlled but ACT results suggest that asthma was only controlled in 54.7% of patients (ACT score ≥20). Patients in steps 4 and 5 had the highest levels of uncontrolled asthma. Correct agreement between ACT score with perceptions of controlled or uncontrolled asthma occurred in 67.9% of patients and 68.8% of HCPs; the poorest levels of agreement occurred in patients in steps 4 and 5. Uncontrolled asthma is common in UK patients. High proportions of patients and HCPs have incorrect perceptions of asthma control, especially in relation to patients with asthma in steps 4 and 5. Asthma patients and their doctors often misperceive whether the disease is under control, according to a British study. Andrew Menzies-Gow from Royal Brompton Hospital in London and Gavin Chiu from Boehringer Ingelheim UK in Bracknell used an online questionnaire to assess perceptions of asthma control among 234 patients and their healthcare providers. All participants had at least intermittent asthma that required occasional treatment; many had more severe disease. The researchers found that 84% of patients and 74% of doctors thought the asthma was well controlled, but results of the Asthma Control Test indicated only 55% of patients objectively achieved disease control. Correct agreement between the validated test and more subjective perceptions occurred in only 68 % of patients and 69% of doctors. Addressing this mismatch could go a long way to improving asthma control among British patients. Both physician- and patient-related factors were identified in a substantial proportion of patients who died. The authors concluded that many patients who were treated as having mild or moderate asthma had poorly controlled, under-treated asthma rather than mild or moderate disease. They recommended that an assessment of recent asthma control should be undertaken at every asthma review; and appropriate interventions should be implemented for patients with NWC asthma. It has been suggested that it is not asthma per se that causes the burden of illness but uncontrolled asthma.4Despite the existence of evidence-based guidelines and availability of effective medications, asthma is still a major health problem in the United Kingdom.5 Given that the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) 2014 treatment guidelines5 are based on patient-reported symptoms as well as HCP-identified symptoms, appropriate treatment may not be prescribed if a patient does not understand what NWC asthma is, and does not report his/her symptoms to the HCP. Patients who do not report symptoms run the risk of under-treatment and of NWC asthma with its consequent morbidities.A number of factors have been identified as contributing to poor levels of asthma control in the United Kingdom: inadequate provision and updating of personal asthma action plans; under-treatment of mild–moderate asthma; lack of medical assessment of factors that trigger or exacerbate asthma; poor inhaler technique; inadequate adherence to medication; patients’ lack of knowledge about the causes and triggers of asthma; and a poor perception of what constitutes well-controlled asthma among both HCPs and patients.http://www.asthmacontroltest.com).7 ACT scores ≥20 identifies well-controlled asthma and scores <20 represent not well-controlled asthma.The asthma control test (ACT) is a self-administered, online, validated questionnaire that enables a patient to evaluate his/her level of asthma control over the preceding 4 weeks  of the FAS: 33, 51, 48, 48 and 47 patients in steps 1–5, respectively.The recruitment target was 320 but this was not achieved during the study period. It proved particularly difficult to recruit a sufficient number of patients in step 1 . A total of 260 patients were screened: 234 were eligible for the study: 33, 52, 50, 49 and 50 patients in steps 1–5, respectively ) (Table n = 164) of the study population (Table n = 111) were aged 45–64 years. One-third of patients  had been diagnosed with asthma >30 years before they completed the questionnaire. Medications taken at baseline are summarised in Table 5 Several patients were assigned to the inappropriate step based on the medications they were taking: seven patients in steps 1–2 were taking a long acting/inhaled corticosteroid; and 32 patients in step 5 were not taking oral corticosteroids . Among the 63 ex-smokers, the median number of pack years was 4, with a range of 0.2–30. Only seven patients were current smokers; the median pack years for this group was 5.25 .HCPs and patients were independently asked about the patient’s reported smoking history. The majority of patients were non-smokers (The ACT results suggest that asthma was controlled in 54.7% of patients (ACT score ≥20), with levels of uncontrolled asthma highest in patients in steps 4 and 5. 84.2% of patients and 73.9% of their HCPs perceived that their asthma was controlled Fig. .Fig. 1Ton = 125) believed that their asthma was controlled and 114/128 (89.1%) HCP assessments were in concordance with the ACT scores. Only 34/106 (32.1%) patients with ACT scores <20 and 47/106 (44.3%) of their HCPs thought that the asthma was uncontrolled  were explored in the study reported in this paper. Both patients and HCPs considered that asthma was better controlled than the ACT scores indicated. It is noteworthy that patients were more likely to overestimate the level of asthma control achieved than HCPs. A small proportion of patients thought that their asthma was not controlled, even though their ACT results indicated good levels of control. It is possible that these patients were being over-treated because of a misperception about their level of asthma control, and were, therefore, at risk of the adverse effects of the excessive medication.Although HCPs were slightly better than patients at classifying poor asthma control correctly, they did not identify 100% of patients who needed further intervention to achieve good control. In particular, they overestimated levels of asthma control in patients in steps 4 and 5, who are at the most risk of exacerbations and adverse outcomes. This could be a chance finding because the study lacked the power to make comparisons between the different steps. Differences in the age distribution of patients in each step may also have affected the comparisons. Alternatively, overestimation of control may be due to HCPs’ tendency to assess asthma control on the basis of patients’ self-reports of symptoms and/or their conviction that the current medication was effective. These factors should be explored further so that HCP assessment of levels of asthma control can be improved.8 Data from the 2006 European National Health and Wellness Survey indicated that 44.8% (1.88 million) of the 4.67 million UK patients who were being treated for asthma had NWC asthma.4 When compared with ACT scores, half of the European patients studied  did not have well-controlled asthma but 64.7% of patients considered that their asthma was controlled. The REALISE investigators also concluded that asthma control in Europe is poor: >80% of the 8000 patients surveyed in 2012 considered their asthma to be controlled, even though objective measurements suggested 45% had NWC asthma and 34.8% had partially controlled asthma.2 Nearly one-fifth (19.5%) of patients who did not regard their asthma as serious had visited the emergency department in the previous year for asthma-related reasons. The United Kingdom has one of the highest asthma-related death rates in Europe: more than 20 people die from the disease each week.9These data are in agreement with the results of similar studies that have identified high levels of uncontrolled asthma in UK patients, especially in patients in steps 4 and 5 (2014 guidelines).2 An analysis of UK 2010–2011 data showed that 21.5% of NWC patients in a sample of 701 UK patients with asthma reported visits to the Accident and Emergency department compared to 14.1% of patients with well-controlled asthma.10 In addition, patients with NWC asthma were more likely to visit their doctors  or be hospitalised than patients with well-controlled asthma. Poor asthma control was associated with several negative outcomes, such as diminished health-related quality of life, high use of healthcare resources, and work and activity impairment.10 A study published in 2013 estimated the total direct cost of treating asthma in the United Kingdom as over £758 million.11 Although only ~2.7% of the study population had uncontrolled asthma and multiple exacerbations, their care accounted for nearly £53 million (~7% of care costs).11The REALISE study identified a high level of oral steroid use, emergency department visits and hospitalisations in the 12 months prior to the survey, even in patients whose asthma was controlled at the time of the survey.A major strength of this study is that it was conducted in clinical practice rather than a study setting. Patients were attending routine asthma reviews in primary, secondary and tertiary clinics. They represent a ‘real-world’ sample of patients across the clinical spectrum of asthma (steps 1–5 of the BTS/SIGN 2014 guidelines) rather than a pre-selected group of patients  who would be eligible for recruitment into a trial. Hence, these results can be applied to a wide range of patients. The data can be used to educate both patients and HCPs about the need to critically evaluate the effectiveness of therapy in order to prevent under- and over-treatment.The CONSORT statement does not apply to this study since it was not a randomised trial. The interpretation of data from this study should take into account that it was an observational study of a non-randomised sample of patients. The generalisation of the results to the target population of patients with asthma has not been established. Assessments of asthma control were limited to the previous 4 weeks and may have been subject to poor or incomplete recall.n = 234) was too small to provide the power for detailed statistical comparisons between patients with different levels of asthma severity. The study design meant that it was not possible to perform sensitivity analyses to examine the possible impact of potential confounders such as comorbidities or age on the study outcomes. A larger, randomised study, with sufficient statistical power to determine differences between the various steps and that assessed patients using current BTS/SIGN guidelines (www.brit-thoracic.org.uk), could be conducted to define levels of asthma control in patients at different points along the disease spectrum. Monitoring adherence to medication would provide useful information about the impact of adherence on asthma control.The sample size . Patient consent was obtained prior to the study commencement.The study was carried out in compliance with the Declaration of Helsinki, in accordance with the Good Epidemiological Practice – IEA Guidelines for proper conduct of epidemiological research and relevant standard operating procedures. Standard medical care  was the responsibility of the patient’s HCP.Adult patients were enroled in the study if they had a confirmed diagnosis of asthma; were being treated for the condition; and were attending routine asthma reviews in primary, secondary and tertiary settings Fig. . Inclusi5Patients were divided into five groups based on the BTS/SIGN treatment guidelines steps 1–5) (2014 guidelines) ; or a smoking history of >10 pack years.The study was not designed to achieve statistical power but to produce data for descriptive purposes. Patient data were analysed for the whole study population and for each BTS/SIGN step (2014 guidelines). The number of pack years was calculated for each patient who described him/herself as an ex- or current smoker, using the following equation:No statistical comparisons were made among the BTS/SIGN groups. All analyses were conducted on the FAS, which included all patients who took part in the patient survey. A PPS excluded patients who had violated the study inclusion criteria.There were no missing data since data were not submitted to the study database until all of the online fields of the questionnaires had been completed by the patient or HCP.The data that support the findings of this study are available from the corresponding author on reasonable request.


Cardiovascular Magnetic Resonance (CMR) imaging with adenosine stress is an important diagnostic tool in patients with known or suspected coronary artery disease (CAD). However, the method is not yet established for CAD patients with pacemakers (PM) in clinical practice. A possible reason is that no recommendations exist for PM setting (paused pacing or asynchronous mode) during adenosine stress. We elaborated a protocol for rhythm management in clinical routine for PM patients that considers heart rate changes under adenosine using a test infusion of adenosine in selected patients.n = 19; 40,4%), atrioventricular (AV) block  and bradyarrhythmia in permanent atrial fibrillation . In patients with SND, normal AV-conduction and resting HR >45 bpm at the time of CMR and in AF the PM was deactivated for the scan. In intermittent AV-block a test infusion of adenosine was given prior to the scan. All patients with permanent higher degree sinuatrial or AV-block or deterioration of AV-conduction in the adenosine test were paced asynchronously during CMR, in patients with preserved AV-conduction under adenosine the pacemaker was deactivated. CMR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement.47 consecutive patients  with MR conditional PM and known or suspected CAD who underwent CMR in clinical routine were studied in this prospective observational study. PM indications were sinus node dysfunction  or deterioration of AV conduction in the adenosine test  asynchronous pacing above resting heart rate did not interfere with intrinsic rhythm, no competitive stimulation was seen during the scan. 10 of 15  patients with intermittent AV-block showed preserved AV-conduction under adenosine. As in SND and AF deactivation of the PM showed to be safe during CMR, no bradycardia was observed.The adenosine test was able to differentiate between mandatory PM stimulation during CMR and safe deactivation of the device. In patients with permanent sinuatrial or AV-block (Our protocol for rhythm management during adenosine stress CMR showed to be feasible and safe and may be recommended for pacemaker patients undergoing routine CMR. CMR as a non-invasive imaging modality is firmly established in the clinical workup for patients with known or suspected CAD. Beside cine imaging and scar detection with Late Gadolinium Enhancement (LGE) ischemia detection plays a major role in CAD , 2. It hIn patients with cardiac conduction disorders underlying or concomitant CAD is common , 5. HoweIn MR conditional PM no inhibited mode can be chosen. Only deactivation (ODO-mode) or asynchronous pacing   are avaiWe recently published first data on adenosine stress CMR in pacemaker patients in a small retrospective study and found no relevant complications under a predefined pacing protocol . HoweverIn conclusion the diagnostic value of perfusion analysis by CMR in CAD is well known but still no recommendations exist for PM programming in MRI conditional devices during adenosine stress. We sought to test the safety of a protocol for rhythm management in those patients that is adapted to the adenosine response in PM patients with different underlying conduction disorders.In this prospective observational study we analyzed 47 consecutive patients with MR conditional PM who underwent routine adenosine stress CMR including cine imaging, adenosine stress perfusion and LGE from april 2015 to december 2016. Inclusion criteria were presence of a MR conditional pacemaker system, indication for adenosine stress CMR for the evaluation of known or suspected CAD, age > 18 years. Exclusion criteria were implantation <6 weeks from the scan, epicardial or abandoned pacemaker leads, bronchial, asthma, impaired renal function, ejection fraction <35%, presence of an antitachycardia device.n = 26; 55.3%) and bradyarrhythmia in permanent AF . Eight patients (17.0%) were PM dependent (HR <30 bpm). Impulse generator/lead models were Advisa  and Ensura  MRI SureScan/CapSureFix 5076 Novus , CapSureSense 4074 (ventricular) . For detailed baseline characteristics see Table Patients had a mean age of 72.1 ± 11.0 years. 19 (40.4%) had known CAD, 8 (17.0%) previous MI. All other patients had intermediate pretest probability of CAD . EchocarCMR was performed more than six weeks after PM implantation in all individuals according to ESC guidelines . Prior tDevices were programmed to MR safe mode following manufacturer’s instructions immediately prior to the scan and reprogrammed immediately thereafter. Programming was performed according to a predefined protocol: To avoid interference of intrinsic rhythm with PM-stimulation in patients with SND and resting heart rate HR > 45 bpm no pacing (ODO)-mode was engaged during the scan - also when atrial fibrillation (AF) was present. In individuals with SND and HR ≤ 45 bpm the pacemaker was set to asynchronous atrial stimulation . All patients with permanent second or third degree AV block and those with deterioration of AV-conduction in the adenosine test were continuously paced in asynchronous mode. Pacing rate was set 10 bpm above spontaneous heart rate with a minimum of 60 bpm. VOO mode at 60 bpm was chosen in AV block with sinus rate > 45 bpm to avoid competitive atrial stimulation, DOO mode at 60 bpm in AV block with sinus bradycardia ≤45 bpm. In patients with intermittent AV-block and preserved AV-conduction (i.e. no progression to second or third degree AV-block in the adenosine test) the PM was deactivated as in SND. Patients in AF at the time of the scan were paced VOO at 60 bpm if resting heart rate was ≤45 bpm. Table As previously described  patientsS. maximum specific absorption rates were limited to 2.0 W/kg.CMR scans were performed with a 1.5 T wide bore system  using a 4-channel body array and an 8-channel spine coil. Maximum gradient field was 33 mT/m (Z-Engine) with a slew rate of 100 T/m/As previously published  our stanp < 0.001, paired t-test). Thus only in patients with both pathologic PQ-interval and pathologic Wenckebach point worsening of AV-conduction and drop of HR were observed. The adenosine test was well tolerated by the patients; no adverse reactions were seen. Figure 15 patients (31.9%) with intermittent AV-block and preserved AV-conduction at the time of CMR were tested. 5 of them (33.3%) showed deterioration of AV conduction with a drop of HR. All of those individuals had both prolonged PQ-interval (220 to 305 ms) and pathologic Wenckebach point (70 to 90 bpm). Two patients showed worsening of AV-conduction to AV-block II Mobitz II, three patients developed AV-block III. One patient had pathologic PQ-interval (230 ms) and normal Wenckebach point (130 bpm) and showed acceleration of HR from 70 to 85 bpm without progressive AV-block. One patient had normal AV-conduction (190 ms) and pathologic Wenckebach point (115 ms) and showed an increase in HR from 85 to 95 bpm. Seven of 15 patients with intermittent AV-block (46.6%%) had normal PQ-interval and normal Wenckebach point. None of them showed higher degree AV-block in the test, heart rate increased from 66 ± 8.6 to 75 ± 11.4 bpm  at the time of the scan with deactivated (ODO) pacemaker adenosine administration accelerated HR from 60.1 ± 9.1 to 76.0 ± 9.3 bpm . AV-conduction was not significantly influenced by adenosine; no higher degree AV block occurred. When sinus rate was <45 bpm  AOO pacing at 60 bpm led to permanent capture, no acceleration of HR under adenosine was noticed. Of 4 patients in AF in 3 HR remained unchanged during stress perfusion, one patient had acceleration of HR from 110 to 125 bpm.There were no adenosine induced adverse events. Asynchronous stimulation of patients with permanent AV-block or progressive AV-block under adenosine 10 bpm above resting HR did not cause competitive pacing or arrhythmia during MR. Patients with preserved AV-conduction under adenosine and deactivated PM did not develop higher degree AV-block in CMR, HR increased from 67.6 ± 9.1 to 77.6 ± 11.3 bpm. Two patients with SND were in AF at the time of CMR. In patients with SND and normal AV-conduction i.e. normal PQ interval and normal Wenckebach point  in specific conduction disorders can be challenging due to possible alterations of HR and heart rhythm under adenosine. Until now no guidelines for clinical routine have been established addressing this issue. We therefore elaborated a protocol for rhythm management intending to minimize the risk of arrhythmia due to competitive PM stimulation on the one hand and possible bradycardia on the other. In this study our protocol proved to be safe and feasible. No complications of adenosine stress CMR related to the presence of a PM or the underlying cardiac conduction disorder occurred.The present study is in line with our previous findings  that in The adenosine test in patients with intermittent AV-block was useful to differentiate patients that can be examined with deactivated devices from those with mandatory PM stimulation. One could argue that asynchronous pacing for all patients with AV-block may be chosen. However, with intact AV-conduction under adenosine the risk of proarrhythmia due to competitive ventricular stimulation cannot be excluded. Deterioration of AV-conduction was only observed in patients with both prolonged PQ interval and pathologic Wenckebach point. Larger studies have to show if CMR can be performed without previous testing in patients without first degree AV-block at rest and normal Wenckebach point. We believe that screening for occult AV-dysfunction by measuring the PQ-interval and Wenckebach point prior to CMR in SND is useful because SND patients may develop binodal disease  that doeThe investigated pacing protocol showed to be feasible and safe. However, adenosine stress CMR has to be compared to other diagnostic strategies, namely when the high supervisory expense in this setting is considered. We encourage prospective randomized studies to clarify which imaging strategy is the best choice for PM patients in terms of safety and clinical value.This study is limited by the relatively sample size. Adverse effects may only appear in a larger cohort of patients. Furthermore we did not test a high dose adenosine protocol, which may be more effective in ischemia detection .Our protocol for rhythm management in patients with MR conditional PM appears to be feasible and safe and may be used for adenosine CMR in clinical routine until larger studies exist.