Randomized and nonrandomized clinical trials have tried to assess whether or not TMR patients experience an increase in myocardial perfusion. However there have been inconsistencies reported in the literature due to the use of different nuclear imaging modalities to test this metric. The primary purpose of this meta-analysis was to determine whether SPECT, MUGA and PET scans demonstrate changes in myocardial perfusion between lased and non-lased subjects and whether laser type affects myocardial perfusion. The secondary purpose was to examine the overall effect of laser therapy on clinical outcomes including survival, hospital re-admission and angina reduction.Sixteen studies were included in the primary endpoint analysis after excluding all other non-imaging TMR papers. Standardized mean difference was used as the effect size for all quantitative outcomes and log odds ratio was used as the effect size for all binary outcomes.2 and Ho:YAG laser systems demonstrated an increase in myocardial perfusion however this effect was not statistically significant. In addition both laser types displayed statistically significant decreases in patient angina at 3, 6 and 12 months but non-significant increases in survival rates and decreases in hospital re-admissions.Statistically significant improvements in myocardial perfusion were observed between control and treatment groups in myocardial perfusion at 6-month follow up using PET imaging with a porcine model. However non-significant differences were observed in patients at 3 and 12 months using SPECT, PET or MUGA scans. Both COIn order to properly assess myocardial perfusion in TMR subjects, subendocardial perfusion needs to be analyzed via nuclear imaging. PET scans can provide this level of sensitivity and should be utilized in future studies to monitor and detect perfusion changes in lased and non-lased subjects. A significant number of patients currently suffering from coronary artery disease (CAD) experience severe ischemia due to multi-vessel atherosclerotic obstruction, leading to heart failure and impaired myocardial function . ProphylNumerous mechanisms have been proposed as the source of angina relief and improved cardiac function noticed in patients receiving TMR therapy . Denerva(a) Investigate the effect of laser treatment on myocardial perfusion using different nuclear imaging modalities under rest and stress conditions at short-term and long-term follow-up.2 and Ho:YAG laser systems on myocardial perfusion and ischemia and determine whether there is a significant difference in these outcomes between laser types.(b) Compare the overall effects of CO2 and Ho:YAG laser therapy on patient clinical outcomes including angina reduction, survival, and hospital re-admission.Establish the effects of COThis meta-analysis examined the literature on sole and adjunctive TMR/CABG therapy in order to determine the effects of laser treatment on patients with ischemic cardiomyopathy. Specifically, this paper had two endpoints:p-value, mean ± SD or SEM was provided.A comprehensive search was performed using the research engines PUBMED, ScienceDirect, and MEDLINE (via EBSCOHost and OvidSP). Keywords used to identify relevant studies were: “transmyocardial revascularization imaging, TMR and TMLR perfusion, TMLR imaging, TMR, TMR and TMLR angina, TMR and TMLR refractory angina, TMLR and TMR PET scans, nuclear imaging and TMR, TMR versus medical management, nuclear imaging TMR and CABG, myocardial perfusion, and TMR versus control”. Published articles were examined from the earliest date possible to the current date, January 2016. All numerical data was extracted directly from the study text and/or tables. If percentage values were given, only then, were calculations made in order to determine the exact number of patients in an outcome group. No assumptions were made from pictorials or graphs unless a precise For this meta-analysis, eligible studies had to be randomized or non-randomized trials that compared TMR treatment groups with control participants . Trials that examined pre versus post treatment data were excluded from the statistical analysis. Three papers Hughes –21) used used21])2 and/or Ho:YAG laser systems were included and papers using excimer laser treatments were excluded. All procedures were performed via a left thoracotomy or median sternotomy and none were executed via percutaneous methods.Studies examining the effects of COMyocardial perfusion and ischemia were measured in subjects who had undergone nuclear rest and stress testing. For this analysis only PET, MUGA and SPECT scans were used to measure these parameters. MRI and ECHO imaging were excluded and may be considered in future analyses.The primary endpoint of this meta-analysis was to evaluate the effect of lasers on myocardial perfusion using different imaging modalities. Since various studies utilized different terms to describe perfusion effects in subjects with ischemic cardiomyopathy, myocardial perfusion was defined as the rate of blood flow or perfusate through the heart muscle. Under this condition, terms such as “peak filling rate, peak ejection rate, myocardial perfusion and perfusion defect” were included to denote perfusion through the heart. Likewise various studies used different terminology to describe ischemic areas or zones within the heart. In this meta-analysis studies using the terms hibernating, fibrotic, or reversible ischemia were classified together as reversible ischemia. Studies that did not specify whether a defect was reversible or irreversible were simply categorized as ischemic. All other continuous outcomes reported by imaging studies were recorded and analyzed. After assimilating terms there was a final list of five outcome measures included in this meta-analysis: LVEF, LVEDV, ischemia, reversible ischemia, and myocardial perfusion.Nuclear imaging techniques were narrowed down to the three major types currently used for perfusion diagnostics: SPECT, MUGA and PET scans. Studies which quoted the use of MIBI, sestamibi, QGSPECT, or thallium 201 stress testing, were all categorized as SPECT imaging. In addition all types of intravenous contrast mediums and stressing agents were included in each imaging type.The second purpose of this meta-analysis was to examine the clinical outcomes of laser therapy at short and long-term follow up. Survival, hospital re-admission and angina reduction were chosen as important clinical effects of laser treatment. In these studies hospital re-admissions were due to unstable angina and acute MI’s.p-values for both treatment and control groups. For categorical outcomes, values extracted were total participants present at baseline and total participants present in a category at a given time point, for both treatment and control groups. Continuous and binary outcomes were independently recorded by two individuals and cross checked, to ensure no discrepancies arose between collected data.Numerical data was extracted directly from eligible papers and recorded into a master file that was analyzed by a statistician. For quantitative outcomes, values collected included means, sample sizes, standard deviations, SEMs, and/or p-value was available, in which case the p_to_d2 function in the R package ‘MAd’ version 0.8.2 was used [All analyses were conducted in Program R version 3.2.2 . Standarwas used . In ordewas used  adjustmewas used .Electronic databases yielded 570 TMLR citations, which were screened specifically for nuclear imaging studies, resulting in a total of 62 citations Fig. . From th2 lasers and 9 used Ho:YAG laser systems.Tables p < 0.01 and p = 0.01, respectively). It is expected that study groups would differ in unstable angina as patients with severe angina are typically placed into TMR or CABG/TMR treatment arms. Participants with a worse prognostic outcome are preferentially placed into these therapeutic groups, as they are viewed to be more beneficial to this population. This becomes apparent when the proportions of unstable angina patients are further broken down between MM, TMR, CABG and TMR/CABG groups . This is evidence of selection bias, which is present in non-randomized clinical trials. From the 16 papers included in the primary endpoints, 3 were excluded from this analysis as they used porcine subjects [Table Study selection criteria was similar in all eligible studies. Many trials excluded patients who were > 75 years, had an LVEF <30%, advanced heart failure and inability to undergo study tests. Eligible patients had to have a history of coronary artery disease with refractory angina, classified as either CCS class III or CCS class IV, despite receiving optimal medical management on a maximal tolerable dose. For patients receiving sole TMR therapy, they had to present with areas of reversible ischemia, which were considered ineligible for percutaneous coronary interventions or surgical revascularization procedures. For patients undergoing CABG and/or CABG/TMR, they were required to have suitable vessels for grafting as well as demonstrable ischemic areas not amenable to direct revascularization by vein grafts. Patients who had a recent MI (within the last 6 months), chronic atrial fibrillation, myocardial wall thickness <9 mm (assessed by TTE) or major life-threatening comorbidities were excluded from study populations.2 and Ho:YAG laser systems as well as all continuous outcomes  reported in studies using imaging techniques. For patients receiving TMR therapy there were no statistically significant differences noted in perfusion outcomes at rest measured via SPECT both at 3 and 12-month follow-ups . Even though the overall estimated effect (EE) favoured TMR at 3 months via SPECT imaging under stress, this was not considered statistically significant . This was most likely influenced by the results of Burns et al. [All imaging analyses included both COs et al. , as theyp = 0.25) and 12 months  and 12 months .MUGA scans were predominantly used to determine the LVEF of patients post treatment and were usually reported in addition to another imaging modality . Resultsp = 0.53) and 6 months . There was insufficient data to complete analysis at 6 or 12 months post treatment during stress conditions.Considering the novelty and cost of utilizing PET scans for patient follow-up, only one RCT was found to report the effects of TMR via this imaging technique . This st2 and Ho:YAG lasers were analyzed individually for their effect on LVEF, myocardial perfusion, and ischemia for up to 12 months of follow up. Studies that reported these outcome measures with SPECT, MUGA and/or PET under rest or stress conditions were included in the analysis. To determine if CO2 lasers have an effect on LVEF, studies using SPECT or MUGA were analyzed collectively under stress and rest conditions. At 12 months of follow-up, medical management groups showed a statistically significant improvement in LVEF compared to treatment groups . Although CO2 lasers showed an improvement in myocardial perfusion in the treatment group, this effect was not considered significant . In comparing the effect of laser type on myocardial perfusion, 4 studies with 272 participants and 7 studies with 374 subjects using CO2 and Ho:YAG laser systems, respectively were compared. All time points available for both laser types for this outcome were included, up to 12 months of follow-up. Results showed that there is no statistical significance on the effect of myocardial perfusion between the two laser types (p = 0.58).Both lasers were subsequently compared to see if there was a statistical significant difference between their effect on ischemia and myocardial perfusion. For this analysis time points that were available for each measured outcome in both laser groups were compared. This included up to 12 months of patient follow-up. For the comparison of CO2 and Ho:YAG lasers combined at varying time points defined by eligible studies. Seven studies were used to determine the effect of TMR versus MM, sham or CABG patients on 30-day survival. Although results favoured laser therapy, the effect was not statistically significant . Seven studies reported data on angina class reduction of two or more classes. Three different time points were analyzed: 3 months, 6 months and 12 months post treatment. All three time frames showed statistically significant improvements in angina for the laser therapy group compared to control patients .Further analysis examined hospital re-admission rates for patients undergoing laser therapy compared to MM. Three studies provided data for re-admissions at 12 months of follow-up. Again laser therapy was favoured, however this result was not considered significant  perfusion increased by 14% (p < 0.001). Furthermore, at 6 months SPECT scans showed no change in perfusion while PET scans demonstrated improvements in 36% of lased segments. Similar results were reported by Cooley et al. whereby PET results indicated significant SEn/SEp perfusion changes in lased patients (p < 0.0001) but SPECT scans did not (p > 0.05) [Multiple clinical trials have reported the benefits of laser therapy on patients with severe and diffuse coronary artery disease. Significant improvements in clinical symptoms have been demonstrated by many randomized clinical trials and evidence supporting reduced angina, inotropic support, ICU admissions, hospital LOS, and arrhythmias, as well, increased QOL and exercise tolerance have been demonstrated , 34–36.  > 0.05) . FurtherMeasuring subendocardial and subepicardial perfusion is considerably important in evaluating laser effects on perfusion. Since it has been understood that TMR channels occlude via thrombosis, it is the initial blood flow from the left ventricle to the myocardial vascular plexus that alleviates ischemia in a viable area of myocardium . In the 2 and Ho:YAG lasers were analyzed individually, no statistically significant differences were found between CO2 and Ho:YAG lasers in any of the analyzed metrics  except for LVEF. The CO2 laser system did not demonstrate an improvement in the LVEF of lased patients as compared to the MM group. This may be due to conflicting reports on the contractility and wall motion noticed in TMR patients via MRI and echocardiography [2 and Ho:YAG lasers demonstrated an improvement in myocardial perfusion, however this increase was not considered significant. This could be the result of the fact that many studies in this category included SPECT and MUGA imaging as opposed to the more sensitive PET scan, which has demonstrated superiority in measuring subendocardial perfusion. When both lasers were compared against each other to determine whether the type of laser had an effect on myocardial perfusion and ischemia, up to a 12 month follow up, no statistically significant difference was noted. Despite the difference in thermal damage [2 and Ho:YAG lasers, it has been difficult to prove superiority of one laser type over the other. Studies which report increased vascular density [When COiography , 48–50. l damage , thermoal damage , thermall damage , and fib density  with theIn an effort to answer whether TMR therapy has an effect on objective cardiac measures this meta-analysis examined short and long term survival rates and hospital re-admissions. There were no statistically significant differences between control and treatment groups in either 30-day or 12 month survival rates. However the estimated survival rate was higher for those receiving laser therapy as compared to control patients at both 30-days and 12 months. From the studies included in these subsections, 30 day mortality was attributed to unstable angina , sole CASurvival and hospital re-admission rates were reportedly better for TMR patients than control, however this result was not significant. This is encouraging since many patients are re-admitted due to unstable angina and our preliminary baseline characteristics demonstrated a higher proportion of unstable angina in treatment patients. Angina reduction was also analyzed at 3, 6 and 12 months for both laser types collectively. All reported data included a reduction of at least two or more angina classifications. Patients in the treatment group experienced a statistically significant reduction in angina compared to control patients at all three time points. This is consistent with published literature demonstrating the known effect of TMR on angina relief, which can persist 5 years following laser therapy .There were many challenges in putting together a comprehensive analysis on myocardial perfusion and imaging techniques. The primary difficulty arose in being able to standardize outcome measures from all studies. Due to the variability in endpoints and terminology used by each imaging modality, certain outcomes were combined in order to create categories for analysis. This paper only included 16 studies, which specifically looked at cardiac function via 3 imaging modalities, therefore the effect of MRI and ECHO was not taken into consideration. Furthermore, only data from control versus treatment groups were included and 3 out of 16 studies used a porcine model, due to low search results from PET imaging. Some analyses were confounded by time and laser type as multiple time points or laser types were included. All of these factors could have an influence on the results of this paper. In the future, pre versus post treatment imaging data, would need to be analyzed and combined with the current data to determine the overall effect of TMR. In addition MRI and ECHO studies could be included to provide further insight since MRI has been reported to show regional myocardial function with advanced spatial resolution .Currently, angiogenesis has been proposed as the leading theory behind TMR laser therapy, with reports of increased vascular density and neovascularization in lased myocardium. Despite the growing consensus for this theory it has been difficult to detect and monitor changes in perfusion. Nuclear imaging has emerged as a diagnostic tool used to identify perfusion defects, ischemic zones and blood flow in lased segments. Therefore it has become valuable in detecting perfusion changes. This meta-analysis has highlighted the importance of monitoring subendocardial perfusion in TMR patients as opposed to transmural or epicardial. This level of sensitivity can be achieved via nuclear PET imaging. Therefore the current debate regarding increased and/or decreased myocardial perfusion in TMR patients, may be a result of inconsistencies in the type of nuclear imaging modality being used. Future studies, which aim to analyze myocardial perfusion, should include PET scans within their study scope in order to provide sensitive and accurate measures of endocardial perfusion. These results may then explain the significant decrease in angina relief noted at long-term follow-up as well as the increases in myocardial perfusion, survival rates and hospital re-admissions. Further analysis is required to confirm the advantages of PET and its cost-benefit reward for CAD patients.


Narcolepsy type 1 (NT1) is caused by a deficiency or absence of the neurotransmitter orexin. NT1 is also associated with a reduced nocturnal “dipping” of blood pressure (BP). The study objective was to analyze whether nocturnal BP values differed in patients depleted of orexin, versus those in whom production was preserved.We performed a retrospective analysis of the polysomnographic recordings, orexin levels, and BP values of patients with NT1. Data was collected from a total of 21 patients, divided into two groups as follows: those with a complete depletion of orexin (n = 11) (Group1), and those with a remaining, limited presence of orexin (n = 10) (Group 2).The groups did not differ in terms of the clinical features of NT1 or sleep characteristics, with an exception of increased number of cataplexy episodes and increased percentage of sleep stage 2 in the Group 1. Daytime and nocturnal BP did not differ between the groups. Most patients, regardless of group, had a non-dipping blood pressure pattern, and no difference in dipping prevalence was observed between groups. The amplitude of the daytime to nighttime change in BP did not differ between the groups.Non-dipping BP patterns are frequent among patients with narcolepsy type 1, but we saw no evidence that they depended on whether orexin levels were above or below the assay detection threshold. Therefore, our results do not support the hypothesis that in patients with narcolepsy type 1 residual orexin levels play a role in the control of nocturnal BP dipping. Narcolepsy (NC) is a chronic neurological disorder, clinically characterized by the presence of excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. ,2 These Additionally, the circadian rhythms of sleep and wakefulness are strongly related to changes in autonomic and cardiovascular functioning of the organism. One of the most prominent examples of this relationship is the nocturnal dipping of blood pressure (BP)—a significant lowering of BP values during the night. The signTransitioning deeper into sleep, from stage 1 to the slow-wave stage, is accompanied by a consequent reduction in BP values, as well as an increase in the cardiovascular activity associated with cortical arousal during the REM period. Since orexin plays critical role in arousal and sleep regulation, these observations suggest that orexin may be involved in controlling nocturnal BP—a hypothesis for which a number of studies have provided support.,12 IntraThe aim of this study was to further clarify this issue and determine if orexin has a clinically significant influence on the values of nocturnal BP. To accomplish this, we performed a retrospective analysis of the polysomnographic (PSG) recordings, orexin levels in the cerebrospinal fluid, and BP values of patients with NT1. We focused on the differences between daytime and nocturnal BP, and assessed whether nocturnal BP values differed in patients depleted of orexin versus those in whom production was preserved.The study protocol was accepted by the Independent Bioethical Committee for Scientific Research at the Medical University of Gdansk. Patients’ data was anonymized prior to analysis.Data was collected from patients of the VitalMed Helsinki Sleep Clinic who were diagnosed with NT1, underwent diagnostic multiple sleep latency test (MSLT), and who were HLA- DQB1*0602 positive. Of the 121 subjects in the clinic, 68 had the orexin levels in their cerebrospinal fluid measured. Of this population, we excluded patients due to the following criteria: below the age of 18 at the time of diagnostic workout and/or a diagnosis of cardiovascular diseases . Of the remaining 44 subjects, 21 had full night PSG with beat-to-beat BP measurements available. PSG recordings with BP measurements were performed in all consecutive patients undergoing diagnostic procedures due to suspected narcolepsy, since the continuous BP measurement was available. Therefore there was no selection bias. Therefore, we included a total of 21 subjects in our study. All that patients were drug naïve at the time of PSG recordings. None of them was treated chronically due to cardiovascular diseases, including intake of antihypertensive drugs. Eleven subjects had orexin levels equal to 0 (Group 1), and 10 had orexin levels between 27 and 110 pg/ml(Group 2), with one subject with orexin level 127 pg/ml with typical clinical picture of NT1 with cataplectic episodes and pathological MSLT. Analysis of CSF orexin concentration was done at the Rinnekoti Research Centre . Double measurements were always done in order to be sure about the level. If the levels varied we took the mean of the two values. The level 0 was used only if there were no hcrt in both measurement. It must be noted anyway that the accuracy of the assay is limited at concentrations of orexin below 30 pg/ml.Patients underwent a single PSG study. All the recordings were performed with a SOMNOscreen plus PSG system . Sleep recordings included four electroencephalographic (EEG) leads, two bilateral electro-oculogram leads (EOG), bilateral electromyographic leads (EMG) placed on the chin, and two surface EMG leads placed on the left and right anterior tibialis muscles, which recorded periodic limb movements (PLMs) during both sleep and wake. Respiration was recorded with a nasal cannula, through thoracic and abdominal strains, and by finger oxymetry. Electrocardiogram (ECG) was recorded with single precardial lead. The PSG included non-invasive, beat-to-beat BP measurements that were performed in conjunction with pulse transit time (PTT).  The PSG BP measurements were based upon pulse transit time (PTT) measurements. There was a finger photoplethysmograph  attached to a patient’s finger. Beat-to-beat PTT is measured as the time between R-wave on ECG and the moment of detection of corresponding pulse wave by the finger photoplethysmograph.  A mathemFor the calibration of the system an auscultatory BP measurement with sphygmomanometer was performed on the nondominant arm before the start of the recording. The results of the measurement were noted. The auscultatory BP measurement was repeated at the end of the recording.For the assessment of the cardiovascular system, the mean systolic and diastolic BP  were calculated during the day  and during the night. It was 30 minutes period, with patients staying awake in bed, before switching off the lights. Additionally, the amount by which the mean values of both SBP and DBP were reduced or “dipped” during the night, as compared to the day, and the percentage by which they dipped, were calculated. Patients whose mean blood pressure (SBP or DBP) decreased during the night by less than 10% were considered “non-dippers”. Similar analysis was performed for wake and sleep periods.P values lower than 0.05 were considered statistically significant. To detect any other factors possibly contributing to values of nocturnal dip of systolic and diastolic blood pressure Pearson correlation coefficients (r) were calculated for variables that may impact BP. The analysis was performed for the whole study population (n = 21). Pearson correlation coefficient was calculated for each of selected variables and the value of percentage dip in systolic and diastolic BP.Categorical variables were compared between the groups with Fisher’s exact test. Continuous variables were compared between the groups with the Mann-Whitney-Wilcoxon test. Calculations were performed using SAS statistical software.The clinical features of the patients are shown in The sleep characteristics of the groups are shown in Similarly, the groups did not differ in terms of daytime and nocturnal SBP and DBP, as shown in There was also no difference between the groups in terms of values of blood pressure during wake and sleep periods. Lack of wake/sleep dipping was also noticeable in both groups but again without any significant difference between them. Results of comparisons of blood pressure during wake and sleep periods are shown in As there was one patient in group 2 with highly increased value of AHI, which might have some impact on the values of BP and its dipping, we have performed a parallel analysis, with exclusion of that subject. The groups still did not differ significantly in terms of values of nocturnal dipping (systolic dip (%): 4.2±4.7 vs. 6.4±6.6, p = 0.2; diastolic dip (%): 3.5±5.7 vs. 2.3±7.7, p = 0.3)Both groups did not differ in terms of number of patients with elevated mean values of blood pressure during daytime and nighttime. The normative values were taken accordingly to European Society of Hypertension guidelines: normal mean values of systolic blood pressure: <135 mmHg (daytime) and <120 mmHg (nighttime); normal mean values of diastolic blood pressure: <85 mmHg (daytime) and < 70mmHg (nighttime). The numbValues of Pearson correlation coefficients for correlation between variables that potentially may impact the values of the nocturnal dip of blood pressure are presented in We also analyzed wake/sleep differences in R-R intervals in the ECG recordings. R-R intervals were longer during sleep period in both groups. Increase of R-R interval was smaller in Group 1. None of those differences reached statistical significance. Results are shown in To the best of our knowledge, this is the first NT1 study to compare nocturnal BP between patients with the concentration of orexin above or below the detection threshold. We report two primary findings: 1) patients with narcolepsy have a decreased or absent wake-sleep reduction of their blood pressure, and 2) the nocturnal reduction of BP in these patients was not related to the presence of residual orexin in the cerebrospinal fluid.Of the 21 patients in our study, only four subjects exhibited a nocturnal decrease in their SBP and DBP that was larger than 10% of their respective daytime values. While we did observe a noticeable drop in the BP values of patients in both groups, on average, they did not reach the threshold level of 10%. We also observed a similar pattern while analyzing difference between wake and sleep periods. There was no difference between the groups in this analysis as well. Those findings are in agreement with previously published studies performed on human subjects. In one, Grimaldi and colleagues compared 10 patients with narcolepsy to 12 healthy controls, and found a non-dipping pattern of BP in the narcolepsy group. SimilarlIt must be remembered that we have analyzed only 30 minutes of daytime activity of the patients, before Lights Off moment. Taking into consideration 24-hour recording of BP could influence the final results. Nevertheless, our finding, as it was underlined above, are in agreement with studies using 24-hour BP recordings. ,20We analyzed also wake/sleep change of ECG recording, comparing change between wake and sleep periods in R-R intervals. We have found a sleep–related prolongation of R-R intervals in both groups. The difference was smaller in orexin-depleted subjects than in patients with detectable levels of orexin, although the difference did not reach statistical significance. This results remains in agreement with previously published studies pointing at deranged cardiac control in NT1 patients. ,27–29Finally, our results confirm similar observations made in animal studies; Bastianini and colleagues measured an increase in BP during sleep and a blunted nocturnal BP dip in hypocretin-deficient mice, compared to wild-type animals. Taken toOne possible explanation could be a disordered sleep architecture. In support of this, a study by Grimaldi and colleagues found that patients with NT1 were characterized by increased sleep fragmentation, arousals, and PLMs compared to controls—with the number of PLMs being significantly associated with reduced dipping. AdditionAnother possibility is that orexin deficiency influences the control mechanisms of the cardiovascular system, leading to a disordered nocturnal BP pattern. In this study, while all included patients were diagnosed with NT1, they differed in their respective orexin concentrations (orexin concentration below the detection threshold versus a decreased but detectable level of orexin). Importantly, we found that the amount of BP dipping and the prevalence of non-dippers, did not differ between groups. If orexin is responsible for the circadian patterns determining BP, then differences in its concentration should lead to differences in nocturnal BP changes. While it is possible that the clinical features of narcolepsy and/or sleep characteristics could also contribute, the groups in our study did not differ in either of those respects . Instead, the primary difference between groups was the concentration of orexin in the cerebrospinal fluid. Therefore, our results indicate that orexin has a limited role in the control of nocturnal BP.There is a third possibility—a threshold effect of orexin. It is possible that there is some  level of orexin above which the neurotransmitter may influence the cardiovascular system. As all the patients participating in our study had very low or undetectable level of orexin it is possible that the concentration of the neurotransmitter was too low in both groups to produce visible impact on values of BP or heart rate.It is important to note, however, that our conclusion is at odds with studies performed in animal models. In one, Kayaba found that orexin knockout mice had lower values of BP compared to wild-type animals. SimilarlWe have performed an analysis of correlations between various factors, such as age, BMI, sleep characteristics, orexin level and the values of the blood pressure dip. The only significant correlation was with age, which does not influence our conclusions, as both groups did not differ in terms of age.There are two methodological limitations of our study. First, PTT-based BP recording during PSG still is not validated against traditional cuff-based method. Cited papers focusing on the validation of PTT-based BP measurements  described a situation different from typical PSG recording. Moreover, according to Schmalgemeier et al. (25) the measurement can be biased by 4.1 mmHg for SBP and by 2.3 mmHg for DBP. This potential bias must be remembered while looking at wake/sleep differences in values of BP. On the other side, PTT-based measurements give the precision of beat-to-beat BP recording and allow avoidance of disturbing sleep with noise of the filling the cuff.Second, we have compared BP values from 30 minutes of restful awakening and from the nighttime. Although this allows to observe wake/sleep difference in BP values, it must be remembered that to classify a patient as a “dipper” or “non-dipper” full 24-hour recording must be analyzed. An approach similar to ours (use of PTT and data collected from PSG recording) was recently used in a study focusing on relation between sleep apnea and BP in children.An a-priori power analysis was not performed which is a limitation of the study. This problem was discussed before the study and taking into consideration a small sample of available subjects decision of performing the study was taken. Another limitation of our study was the small number of participants, which is a result of the low prevalence of NT1, as well as of the criteria required for inclusion in the study. However, the rigoristic criteria used in this study, as well as the vigilant attention paid to the diagnostic procedures, allowed us to compare two NT1 patient groups that differed only in their orexin concentration. Another weakness of our study is lack of control group of healthy subjects with orexin level measured. It must be noted that reduction of nocturnal dipping in comparison to healthy subjects was already shown in previously published papers. ,20 The oIn conclusion, our study showed that non-dipping BP patterns are frequent among patients with narcolepsy type 1 with detectable orexin level and in patients with orexin level below the detection threshold. We saw no evidence that non-dipping BP patterns depend on whether orexin levels were above or below the assay detection threshold. Therefore our results do not support the hypothesis that in patients with narcolepsy type 1 residual orexin levels play a role in the control of nocturnal BP dipping.Since a lack of nocturnal dipping is related to an increased risk for organ damage, patients with narcolepsy should regularly undergo medical assessments that include 24-hour ambulatory BP measurements, echocardiography, and tests of kidney function.


To assess relationships between carotid artery atherosclerosis and retinal arteriolar and venular diameters.2]+0.16xDiastolic Blood Pressure[mmHg]–0.18 x Age[Years]–1.91.The community-based longitudinal Asymptomatic Polyvascular Abnormalities Community Study (APAC) included a sub-population of the Kailuan study which consisted of 101,510 employees and retirees of a coal mining industry. Based on the Chinese National Census 2010 and excluding individuals with history of cerebrovascular ischemic events, 4004 individuals were included into the APAC. All participants underwent a detailed clinical examination including blood laboratory tests and carotid artery duplex ultrasound examination. The cerebrospinal fluid pressure (CSFP) was estimated using the formula: CSFP[mmHg] = 0.44xBody Mass Index[kg/m2:0.12), thicker retinal arteries were associated with a thinner common carotid artery intima-media thickness (IMT) :-11.2,-2.61) after adjusting for thicker retinal nerve fiber layer , lower diastolic blood pressure , younger age , and less abdominal circumference . Thicker retinal vein diameter was associated (r = 0.40) with higher estimated CSFP  after adjusting for wider retinal arteries , thicker retinal nerve fiber layer thickness  and male gender .In multivariable analysis (goodness of fit rThinner retinal artery diameter was significantly, however weakly, associated with increased common carotid artery IMT. It suggests that retinal microvascular changes were only week indicators for an atherosclerotic carotid artery pathology. Thicker retinal vein diameter was associated with higher estimated CSFP, confirming associations between higher estimated CSFP and higher incidence of retinal vein occlusion. The microvascular system of the retina can be regarded as part of the cerebrovascular system. The central retinal artery is a branch of the ophthalmic artery and indirectly of the internal carotid artery. Using the retinal arterioles as surrogate for the intracranial arterioles may thus offer possibilities for a non-invasive assessment of the cerebrovascular system ,2. The cThe Asymptomatic Polyvascular Abnormalities Community study (APAC) is a community-based observational study which examined the epidemiology of asymptomatic polyvascular abnormalities in Chinese adults ,10. The As described in detail previously , the intEach study participant underwent a bilateral carotid artery duplex sonography and we determined the intima-media thickness (IMT). According to the recommendations published by the Society of Radiologists in Ultrasound Consensus Conference, a carotid artery stenosis (≥50%) was categorized into several grades . Blood cAs described and applied in previous population-based studies, all study participants underwent ocular fundus photography . Simultaneous stereoscopic 45°color fundus photographs centered on the optic disc (Diabetic Retinopathy Study standard field 1) and on the macula (Diabetic Retinopathy Study standard field 2) were obtained from each eye. Using a computer assisted quantitative assessment software , we determined the retinal vessel diameters in the right eyes of each study participant, so that the data of only one eye per individual were taken for the statistical analysis. The average retinal arteriolar or venular width was measured applying the Big–6 formula. It was presented as the central retinal arteriolar equivalent or central retinal venular equivalent. The arteriovenous ratio was calculated as central retinal venular equivalent divided by the central retinal arteriolar equivalent. The method has been described in detail in previous population-based studies . The repP-value was <0.10. From the list of independent parameters we then dropped step by step those parameters which either showed a high collinearity or which were no longer significantly associated with the outcome parameter. The cut-off value for high collinearity was a variance inflation factor (VIF) of higher than 2. We finally repeated the multivariable analysis in a reverse manner, with artery IMT as dependent variable and retinal artery diameter as independent variables after adjusting for other parameters such as age, gender, blood pressure, level of education and concentration of high-density lipoproteins and low-density lipoproteins. We calculated the standardized regression coefficient beta and non-standardized regression B and the 95% confidence intervals (CIs) of B. In the multivariable linear regression analysis, a P-value smaller than 0.05. was considered to be statistically significant.We used a commercially available software program  for the statistical analysis. Continuous variables were described by their means ± standard deviations and categorical variables were presented as percentages. The main outcome parameters of the study were the retinal vessel diameters. Only one eye per study participant was included into the statistical analysis. In a first step of the analysis, we performed a univariate analysis of the associations between the retinal vessel diameters and other ocular and systemic variables. In a second step, we conducted a multivariable linear regression analysis, with the retinal vessel diameters as dependent variable and all those parameters as independent variables which were associated with the retinal vessel diameters in the univariate analysis. The cut-off value for the P<0.001), gender , abdomen circumference , hip circumference , and level of education . There was no significant difference in mean arterial pressure , body mass index , waist circumference . The mean retinal arteriolar and venular calibers were 153.6 ± 19.77 μm and 232.14± 26.13 μm, respectively.The study included 4004 participants (1720 (43.0%) women) with a mean age of 59.7 ± 11.0 years  Fig 1)..Fig 1). P<0.001; equation of the regression line: Arterial Diameter (μm) = 0.24 x Venous Diameter (μm) + 98)  = -0.41 x Age (Years) + 178)  + 98) . Retinal) + 178) .P<0.001), lower body mass index (P<0.001), lower hip and abdomen circumference (P<0.001), lower frequency of alcohol consumption (P = 0.001), lower systolic, diastolic and mean blood pressure (P<0.001), lower prevalence of anti-hypertensive therapy (P<0.001), lower estimated cerebrospinal fluid pressure (P<0.001), lower prevalence of fatty liver disease (P<0.001), thinner common carotid artery IMT (left and right) (P = 0.001), slower pulse wave velocity at the upper arm (left and right) (P<0.001), lower blood concentration of uric acid (P = 0.004), larger neuroretinal rim area (P<0.001) and volume (P = 0.007), thicker retinal nerve fiber layer (P<0.001), and lower vertical cup/disc diameter ratio (P = 0.01) (P = 0.05) and lower blood concentrations of triglycerides (P = 0.07) and total bilirubin (P = 0.06) and thinner full retinal fovea thickness (P = 0.04)  . There w = 0.04) .P = 0.94), tea drinking frequency (P = 0.97), estimated cerebrospinal fluid pressure (P = 0.94), blood concentration of triglycerides (P = 0.85), blood concentration of uric acid (P = 0.68), use of anti-hypertensive medication (P = 0.62), frequency of alcohol consumption (P = 0.76), internal carotid artery IMT(left) (P = 0.33), internal carotid artery IMT(right) (P = 0.62), fatty liver disease (P = 0.35), blood concentration of total bilirubin (P = 0.15), vertical optic cup/disc diameter ratio (P = 0.07), neuroretinal rim area (right) (P = 0.23), diastolic blood pressure (P = 0.08), pulse wave velocity upper arm (right) (P = 0.07), and female gender (P = 0.06).In the following multivariable linear regression due to reasons of collinearity, we dropped step by step the parameters of waist circumference (VIF: 5.5), common carotid artery IMT (left) (VIF: 5.1), and pulse wave velocity upper left arm (VIF: 4.2) and neuroretinal rim volume (VIF: 3.5). Due to missing statistical significance, we then dropped body mass index (2: 0.12), thicker retinal arteries were associated with younger age (P<0.001), less abdominal circumference (P = 0.003), lower diastolic blood pressure (P<0.001), thicker retinal nerve fiber layer (P<0.001) and thinner IMT of the initial segment of the subclavian artery (P = 0.01). If the subclavian artery IMT was replaced by the common carotid artery IMT, a thinner common carotid artery IMT was significantly associated with a thicker retinal artery diameter (P = 0.002)  .P = 0.03; B: 0.000; 95%CI: -0.001, 0.000) after adjusting for older age , male gender , higher systolic blood pressure , lower level of education , higher prevalence of fatty liver disease , lower concentration of high-density lipoproteins  and higher concentration of low-density lipoproteins .In a reverse manner, thicker common artery IMT was associated with thinner retinal artery diameter (P = 0.01), higher body mass index (P = 0.02), higher waist circumference (P<0.001), and abdomen circumference (P = 0.001), higher frequency of drinking tea (P = 0.05), higher prevalence of snoring (P = 0.03), lower systolic blood pressure (P = 0.02), lower cognitive function score as tested in the mini mental test (level of education) (P = 0.02), higher blood concentration of creatinine (P = 0.04), larger optic disc area (P<0.001), larger neuroretinal rim area (P<0.001) and volume (P<0.001), thicker retinal nerve fiber layer (P<0.001), and lower vertical cup/disc diameter ratio (P = 0.001) (P = 0.05), lower level of education (P = 0.08), higher heart rate (P = 0.04), faster pulse wave velocity at the upper right arm (P = 0.01), higher prevalence of a previous ischemic cerebral stroke (P = 0.007), lower cognitive function score as tested in the mini mental test  (P = 0.06), lower cognitive function score as tested in the Montréal test , lower blood concentration of high-density lipoproteins (P = 0.07), higher white cell blood count (P = 0.09) and internal carotid artery IMT (right) (P = 0.07)  . There w = 0.07) .P = 0.79), Montréal cognitive assessment test orientation total score (P = 0.60), mini mental state examination educational level (P = 0.34), Montréal cognitive assessment test total score (P = 0.14), level of education (P = 0.71), status of marriage (P = 0.68), white blood cell count (P = 0.77), internal carotid artery IMT (right) (P = 0.91), hip circumference (P = 0.65), pulse wave velocity (P = 0.47), optic disc area (P = 0.65), blood creatinine concentration (P = 0.57), neuroretinal rim volume (P = 0.52), stroke history (P = 0.35), snoring (P = 0.26), high-density lipoproteins concentration (P = 0.25), tea drinking frequency (P = 0.17), and history of diabetes mellitus (P = 0.11).In the multivariable analysis due to reasons of collinearity, we dropped waist circumference (VIP: 12.3), pulse wave velocity upper left arm (VIP: 6.3), abdomen circumference (VIF: 5.4), neuroretinal rim area (VIF: 5.2), and vertical cup/disc ratio (VIF: 3.3). Due to lack of statistical significance, we then dropped mini mental state examination results (2: 0.12), thicker retinal veins were associated with younger age (P<0.001), female gender (P<0.001), higher body mass index (P = 0.002), lower systolic blood pressure (P<0.001), higher heart rate (P = 0.037), and thicker retinal nerve fiber layer (P<0.001)  after adjusting for male gender , and thicker retinal nerve fiber layer . Heart rate was no longer significantly (P = 0.08) associated with retinal vein diameter in that model. If we added retinal artery diameter to the model, the regression coefficient increased to r = 0.40 and thicker retinal vein diameter was correlated with higher estimated cerebrospinal fluid pressure (P<0.001), male gender (P<0.001), thicker retinal nerve fiber layer thickness (P = 0.03) and wider retinal arteries (P<0.001)  . If we rP<0.001) .In our community based study, thicker retinal artery diameter was associated with younger age, less abdominal circumference, lower diastolic blood pressure, thicker retinal nerve fiber layer and thinner common carotid artery IMT. The parameters with the strongest association were lower blood pressure and thicker retinal nerve fiber layer, while the association with common carotid artery IMT was relatively weak. In a reverse manner, thicker common artery IMT was associated with thinner retinal artery diameter after adjusting for older age, male gender, higher systolic blood pressure, lower level of education, higher prevalence of fatty liver disease, lower concentration of high-density lipoproteins and higher concentration of low-density lipoproteins. Thicker retinal vein diameter was associated with higher estimated cerebrospinal fluid pressure after adjusting male gender, thicker retinal nerve fiber layer thickness and wider retinal arteries. The strongest relationship was between wider retinal vein diameter and wider retinal arterial diameter and retinal nerve fiber layer thickness.P = 0.001) and retinal venular caliber  after controlling for age, gender, systolic blood pressure, total cholesterol and high-density lipoproteins, cholesterol, prior cardiovascular disease, carotid plaque and the retinal fellow vessel. Torres´ study and our investigation agree in the association between a thicker carotid artery IMT and thinner retinal arteries. They differ in the strength of the correlation. While in Torres´ study the association was relatively strong (adjusted beta: -0.25), the adjusted beta value in our study was considerably lower (beta: -0.06). Reasons for the discrepancy between the results of both studies may have been differences in the study population . Both studies also differed in the number of study participants, and in particular in the study design. In our study, thickness of the retinal nerve fiber layer was relatively strongly correlated with retinal arterial diameter while in Torres´ investigation the retinal nerve fiver layer thickness was not measured. The results of our study were in agreement with former ophthalmological studies in which optic nerve damage was strongly associated with a thinning of the retinal arteries [The results of our study agree with findings obtained in previous investigations. Wong and colleagues showed in their landmark study the association of retinal microvascular abnormalities, including retinal arteriolar narrowing, with incident stroke . The latarteries ,16. Thisarteries .The retinal vein diameter was not significantly associated with the carotid artery IMT in multivariable analysis in our study population. This result cannot directly be compared with findings obtained in other studies since an association between venular diameter and atherosclerotic changes of the cerebroafferent arteries has not intensively been examined yet. Miller and colleagues examined the relationship between retinal vessel diameter and the incidence of coronary artery disease in 448 patients with type 1 diabetes . After aInterestingly, thicker retinal vein diameter was associated with a higher estimated CSFP in our study after adjusting for wider retinal artery diameter, male gender and thicker retinal nerve fiber layer . It agreOur study has potential limitations. Our study population was a randomly selected out of the population of the Kailuan Study, which, despite its large sample size was not fully representative for the Chinese population. Our study sample however was drawn from the Kailuan study population by using a stratified random sampling method based on the Chinese National Census from 2010. In that context, one may also discuss the "healthy worker effect", including the "healthy hire" and "healthy survivor" effect, that is present in many occupational cohort studies. It may be associated with a confounding effect. Second, our study was a cross-sectional investigation the study design of which did not allow drawing longitudinal conclusions on a causal relationship between retinal vessel diameter and atherosclerotic changes of the carotid arteries. Third, although we examined the retinal veins and explored associations between the retinal vein diameters and CSFP, we did not investigate the venous part of the neck vessels and we did thus not compare retinal vein measures with measurements of cerebrofugal veins. Future studies may address that topic.In conclusion, thinner retinal artery diameter was significantly, however weakly, associated with increased common carotid artery IMT as a surrogate for atherosclerosis, after adjusting for optic nerve damage, younger age, higher blood pressure, and obesity. It suggested that retinal microvascular changes were only week indicators for the atherosclerosis of the carotid artery. Thicker retinal vein diameter was associated with higher estimated CSFP in multivariable analysis. Confirming previous studies on an association between higher estimated CSFP and higher incidence of retinal vein occlusion, it suggested an anatomical and functional relationship between renal vein diameter and brain pressure.


Supplemental Digital Content is available in the text. P≥0.1) in brachial systolic, mean, or diastolic BP. However central aortic systolic blood pressure was significantly higher in patients compared with controls . Patients had reduced total arterial compliance, increased pulse wave velocity, and larger backward compression waves compared with controls. LVM index was significantly higher in patients than controls . The magnitude of the backward compression waves was independently associated with variation in LVM (P=0.01). Using a novel, noninvasive hemodynamic assessment, we have shown abnormal conduit vessel function after coarctation of the aorta repair, including abnormal wave reflections that are associated with elevated LVM.Patients with repaired coarctation of the aorta are thought to have increased afterload due to abnormalities in vessel structure and function. We have developed a novel cardiovascular magnetic resonance protocol that allows assessment of central hemodynamics, including central aortic systolic blood pressure, resistance, total arterial compliance, pulse wave velocity, and wave reflections. The main study aims were to (1) characterize group differences in central aortic systolic blood pressure and peripheral systolic blood pressure, (2) comprehensively evaluate afterload (including wave reflections) in the 2 groups, and (3) identify possible biomarkers among covariates associated with elevated left ventricular mass (LVM). Fifty adult patients with repaired coarctation and 25 age- and sex-matched controls were recruited. Ascending aorta area and flow waveforms were obtained using a high temporal-resolution spiral phase-contrast cardiovascular magnetic resonance flow sequence. These data were used to derive central hemodynamics and to perform wave intensity analysis noninvasively. Covariates associated with LVM were assessed using multivariable linear regression analysis. There were no significant group differences ( Patients with repaired coarctation of the aorta (CoA) are thought to have increased afterload due to abnormalities in vessel structure and function. However, blood pressure, which is the simplest measure of afterload, is not universally elevated in these patients. This may simply be because of inaccuracies introduced when measuring blood pressure brachially rather than centrally. It is also possible that blood pressure itself is a limited measure of vascular and cardiac load after CoA repair. In particular, it may not adequately characterize arterial wave reflections that may be more prevalent in this group.1 We have also shown that it is possible to use the same high temporal-resolution phase-contrast magnetic resonance data to perform noninvasive wave intensity analysis (WIA).3 This allows the assessment of wave reflections, which has not previously been done in the CoA population.Characterization of central aortic hemodynamics and wave reflections is difficult, requiring simultaneous measurement of aortic pressure and flow. We have recently demonstrated the ability to assess central aortic systolic blood pressure (c-SBP) using a combination of phase-contrast magnetic resonance and oscillometric brachial artery blood pressure.Cardiac MR (CMR) also provides accurate assessment of left ventricular (LV) hypertrophy, which is known to be a risk factor for adverse cardiac events. Thus, using CMR, it is possible to accurately assess all aspects of conduit vessel function and determine their relationship to end-organ effects.In this study, we recruited 50 patients with repaired CoA (without recoarctation) and 25 age- and sex-matched healthy controls. The aims of the study were to use high temporal-resolution CMR imaging to (1) characterize differences in c-SBP and peripheral systolic blood pressure (p-SBP) between patients and controls, (2) comprehensively evaluate afterload (including wave reflections) in the 2 groups, (3) identify possible biomarkers among covariates associated with elevated LV mass (LVM), and (4) substantiate in vivo observations with 1-dimensional (1D) computer simulations of wave travel in repaired coarctation.Fifty patients with CoA repaired in childhood and 25 healthy controls were recruited. Control subjects were volunteers from the same geographic area (Greater London) and were matched by age (within 2 years) and sex. Exclusion criteria were (1) irregular heart rates, (2) contraindications to CMR such as MR-incompatible implants, (3) pregnancy, (4) aortic stenosis, (5) coarctation associated with major or unrepaired congenital heart disease , (6) coarctation stents, or (7) echocardiographic or CMR evidence of recoarctation (diastolic flow continuation in descending aorta or coarctation index [CI] <0.7). Patients receiving antihypertensive medications were included if this was reported as stable, chronic therapy. The study was performed with local research ethics committee approval and written informed consent was obtained.4 The temporal resolution was 9.6 ms, the spatial resolution was 2.1×2.1 mm, and the breath-hold was ≈11 s .All imaging was performed on a 1.5-T MR scanner  using 2 spine coils and 1 body-matrix coil. A vector electrocardiographic system was used for cardiac gating. The flow-imaging plane was planned using orthogonal long axis cine images of the ascending aorta and was placed just above the sinotubular junction . These data were used for the derivation of all subsequent hemodynamic indices. The sequence was a prospectively triggered, spiral, velocity-encoded spoiled gradient echo acquisition, accelerated with SENSE .5 or a balanced, steady-state free precession sequence.6 A radial k–t SENSE sequence was used to calculate LV volumes and LVM as previously described (online-only Data Supplement).7Aortic arch morphology was assessed in patients using gadolinium-enhanced MR angiography with a coronal 3D fast-field-echo sequenceBrachial SBP (p-SBP), diastolic BP (DBP), and mean BP were measured by automated oscillometric sphygmomanometry during flow imaging (Datex Ohmeda) on the patient’s right arm. Small-adult, adult, and large-adult cuff sizes were chosen according to subject arm circumference. Volunteers lay supine in the CMR scanner with the arm at the level of the heart, and there was a period of acclimatization (at least 15 minutes) before measurements were taken.8 Segmentation of the ascending aorta was performed on the modulus image using a previously validated semiautomatic registration-based algorithm (online-only Data Supplement).9All images were processed using an in-house plug-in for the open source DICOM software OsiriX .10Aortic arch anatomy was evaluated by measurement of aortic diameter in the transverse aortic arch between innominate and left common carotid artery, distal aortic arch (repair site), and the descending aorta at the level of the diaphragm . Two metrics were derived from these measurements: (1) transverse arch index (TI), quantifying the degree of transverse arch hypoplasia: transverse arch diameter divided by descending aorta diameter. (2) CI, quantifying the degree of recoarctation: aortic isthmus (repair site) diameter divided by descending aorta diameter. Aortic arches were also characterized as “gothic” if the arch had an acutely angulated triangular conformation.1 The equation of an exponential pressure–area relationship is:12The aortic area waveforms were calibrated using a previously validated exponential pressure–area model and described below.p(t) is the synthesized pressure curve, pd is the brachial DBP, Ad is the diastolic area, systolic A(t) is the area curve, and β is the scaling factor, initially set as follows:where As and Ad are the systolic and diastolic aortic areas, respectively. As c-SBP is, in general, lower than p-SBP, this initial starting β is the theoretical maximum.where 14 The estimated c-SBP was the peak of the optimized synthesized pressure curve.Calibration of this model consisted of iteratively reducing the scaling factor β to minimize the difference between the measured brachial mean BP and the mean of the synthesized pressure curve. This calibration scheme was based on the validated assumption that the difference between DBP and mean pressure is constant in the large arteries.16 Therefore, the Bramwell–Hill equation18 was used to obtain local pulse wave velocity, c, in the ascending aorta, using the aortic area waveform and c-SBP:Because of the possible early reflection site related to the repaired coarctation, conventional single cut methods of calculating wave speed (such as the Q/A method) are unreliable.Ad is the diastolic cross-section area, ΔA is As−Ad, and ΔP is the central pulse pressure (c-SBP–DBP). This method has been shown in computer simulations to be robust in the presence of early wave reflections.15 Characteristic impedance, Zc, was calculated by:where ρ is assumed to be 1060 kg/m3.where Q and A curves into the respective forward and backward components by expressing the relationship between wave speed and changes in flow and cross-sectional area, as previously described .2 Using this system, 4 different waves may be characterized: forward compression waves, forward expansion waves, backward compression waves (BCW), and backward expansion waves.In WIA, waves are regarded as a summation of incremental wave fronts; it is, therefore, possible to separate the + and dA− plots. Using these data, we calculated the reflection magnitude as: Areabackward/Areaforward.The type of wave and their magnitude (area under the wave) were determined by the analysis of the net and separated WIA plots in Matlab. The areas under the separated waveforms were calculated by numeric integration. Area waveforms were also separated into forward and backward components, by integration of dA−1) was calculated in Matlab using a 2-element windkessel model as previously described,19 using single cardiac cycle phase-contrast flow curves and both central  and brachial  pulse pressure (SBP–DBP). Briefly, the aortic flow curve was inputted into the model with measured arterial resistance, and TAC was tuned so that pulse pressure generated by the model equaled measured pulse pressure. Resistance was indexed to body size by multiplication with BSA and TAC by dividing by BSA.Arterial resistance (Woods Units) was calculated by dividing mean BP (mm Hg) by cardiac output (L/min). Total arterial compliance , 2 additional scenarios were simulated. First, the diameter of a segment in the descending aorta was reduced by 25% to mimic a mild residual aortic coarctation, while maintaining the normal distensibility. Second, the stiffness of the narrowed section was increased by 5 orders of magnitude to mimic the effect of a stiffened coarctation repair zone.A validated 1D model of the systemic vascular treeSTATA 13.1 and Graphpad Prism 5f were used for statistical analysis and figures. Data were examined for normality and where appropriate, non-normally distributed variables were log transformed to ensure normal distribution before analysis. Descriptive statistics are expressed as mean  when normally distributed, and geometric mean  when non-normally distributed, unless specified. Proportions are expressed as percentages.t test was used to compare differences in parametric data between coarctation patients and controls; Welch correction was used for unequal variances. Proportions test was used to compare proportions among groups. The level of α considered for statistical significance was 0.05.The independent samples Pearson correlation coefficient was used to analyze simple linear relationships between measures of arch morphology and hemodynamics. Multivariable linear regression analysis was also used to determine covariates independently associated LVM. The model was adjusted for: BSA, sex, age to ascertain independent associations. We also adjusted for case/control to control for unmodeled covariates.P=0.03); however, there was no difference in BMI or BSA between groups . Eighteen of fifty patients (36%) underwent repair in the neonatal period and 34 of 50 (68%) patients had their repair <1 year of age. End-to-end anastomosis was performed in 34 of 50 (68%) patients, extended end-to-end anastomosis in 4 of 50 (8%) patients, subclavian flap angioplasty in 10 (20%) patients, and Dacron/Gore-Tex patch augmentation in 2 (4%) patients. A bicuspid aortic valve was present in 26 of 50 (52%) patients. Eighteen percent of patients underwent a second procedure for recoarctation; 20% of patients were receiving stable antihypertensive therapy. A single agent was prescribed in 8 patients and a combination of agents in 2 patients .th percentile, 0.78–1.14). In keeping with this finding, no patient had diastolic continuation on Doppler assessment in the descending aorta and the mean arch velocity was 2.0 m/s (1.9–2.2 m/s). There were no cases of significant aortic arch hypoplasia with all patients having TI >0.7; the median TI was 1.04 . Ten of fifty patients (20%) had a “gothic” arch. As expected, TI and CI were all significantly lower in patients than controls, Table There were no cases of recoarctation on CMR, with all cases having a CI >0.7: group median CI was 0.91 (10th–90thP≥0.1) in brachial SBP, mean BP, or DBP (Table P=0.01) in patients (113 mm Hg [110–117 mm Hg]) compared with controls  patients. No control subjects had c-SBP>125 mm Hg or p-SBP>140 mm Hg. There was a moderate correlation between p-SBP and c-SBP .There was no significant group difference P≥0. in brachZc were present and, therefore, the pulsatile load imposed by the aortic root was similar in the groups. There was no significant difference in cardiac index or systemic vascular resistance index between the groups, Table TAC calculated using both brachial and central pressures was lower in patients compared with normal controls. However, differences in compliance were more significant when calculated using central, rather than brachial pulse pressure. In addition to evidence of global stiffening, there were also signs of increased ascending aortic stiffness. Specifically, local pulse wave velocity was greater in patients compared with controls Table . However5 [0.0008–0.0014]) compared with controls (0.0007 cm5 [0.0005–0.0009]), (P=0.01). In addition, the BCW arrived significantly earlier (P=0.003) in patients (88 ms [80–97]) compared with controls (111 ms [99–123]). The magnitude of the BCW was higher in subjects categorized as centrally hypertensive (c-SBP>125 mm Hg), 0.0017 cm5 versus 0.0008 cm,5P=0.02. There was a significant linear relationship between BCWlog and c-SBP  after adjustment for body size, age, sex, and TACcentral. There were no significant differences in the magnitude of the forward compression wave or forward expansion wave between patients and controls . The m1 ms 99–13). The mP=0.07 and 0.17, respectively), TACcentral (P=0.29 and 0.95) or BCW (P=0.14 and 0.06). There was no significant difference in these metrics in subjects with a gothic arch.In patients, there was no significant relationship between either CI or arch index and c-SBP (P<0.00005) in LVM index between patients and controls, 72 g/m2 (68–76 g/m2) versus 59 g/m2 (55–63 g/m2). There was no difference in LVM index between patients with bicuspid and those with tricuspid aortic valves (P=0.7).There was a significant difference  higher LVM was observed in patients and was significantly associated with the magnitude of the BCW.In this study, we used advanced CMR techniques to simultaneously assess all the components of afterload  in patients with repaired coarctation and no significant recoarctation. The main findings of the study were (1) central SBP was higher in patients compared with controls, although there was no significant difference in brachial SBP; (2) patients postcoarctation repair were characterized by lower TAC, higher local wave speed, and increased BCW, without differences in aortic root 22 is a consistent finding across studies, and it is confirmed in this study. One obvious cause of reduced TAC is the coarctation repair site itself, which is essentially stiff fibrous scar. However, ascending aortic stiffness (measured remotely from repair site) was also elevated, suggesting a more generalized remodeling phenomenon. Remodeling may also occur as a compensatory mechanism to restore tensile stress to homeostatic levels. Interestingly, local characteristic impedance was not increased in patients because of the opposing effects of wall stiffening and aortic root dilation. This emphasizes that the observed differences in pulsatile load are more related to abnormalities in the distal portions of the aorta (such as the repair site). A limitation of this study was that local vessel properties distal to the repair site were not assessed.23 Consequently, it is not known whether descending aortic stiffness is also increased and this is an important area to investigate in a future study.The simplest measure of afterload is SBP. However, assessment of SBP alone does not specify which components of afterload are abnormal. Therefore, we assessed total and local arterial stiffness, as well as resistance and cardiac output in patients with repaired coarctation. The main findings were reduced TAC and increased ascending aortic stiffness consistent with a postrepair aortopathy. Abnormal aortic stiffness after repair24 and our findings suggest that this is an important mechanism in the generation of wave reflections.The presence of abnormal wave reflection has not previously been assessed in patients with repaired coarctation. Therefore, the increased magnitude of the BCW in patients is an important and novel finding. In patients with significant recoarctation, anatomic impedance mismatching at the site of stenosis would result in wave reflection. In this study, patients with recoarctation were specifically excluded and there was no significant relationship between BCW magnitude and anatomic narrowing. Therefore, an alternative mechanism for the generation of BCWs is required. To investigate possible causes, we used a 1D computer model of the vasculature that can replicate basic pressure and flow physiology. In a model with a mild anatomic narrowing, a small additional BCW was produced. However, only after increasing the stiffness of the repair site did the magnitude of BCW reflect the in vivo findings. Stiffening of the repair site is consistent with fibrous scar,26It should be noted that there were some important differences between the in vivo and 1D model results. For instance, in the modeled WIA data, there is an early backwards expansion wave that is not present in the in vivo data. However, as this phenomenon has not been demonstrated in any previous in vivo studies, we believe it is an artifact of the model itself. A more important difference is related to the morphology of the BCW. In the modeled data, patients seem to have 2 backwards compressions waves. The first is presumably related to reflections from the coarctation repair site, whereas the second later wave  is likely the result of more peripheral vasculature reflections. In contrast, most patients have only one BCW, although it did arrive slightly earlier than in controls. One possible explanation for this disparity is the relatively low temporal resolution of phase-contrast magnetic resonance, which may cause summation of the 2 backwards waves present in most patients. This would result in the appearance of an earlier arriving, higher magnitude single BCW in patients compared with controls. Wave entrapment and vascular horizon effects could further increase wave summation. This would prevent resolution of separate waveforms, but could explain the earlier arrival of the BCW in patients. In normal subjects, wave entrapment reduces the importance of more distally generated reflected waves. This results in a composite BCW that seems to arise more proximally in the vasculature—the vascular horizon. Because an earlier arriving wave would be more susceptible to summation, wave entrapment might help explain the usual single BCW seen in patients. An earlier arriving BCW could also explain the surprisingly small difference in BCW arrival times in patients versus controls. This could be investigated by performing noninvasive WIA distal to the repair site and would represent an important improvement for future studies. Nevertheless, our findings are consistent with previously published fluid structure interaction models of coarctation. These studies emphasize the role of stiffening as an important possible source of increased BCWs from the arch.In this study, there were no significant differences in the forward compression or expansion waves between patients and controls. However, these waves can modify the morphology of the aortic pressures curve. For instance, the “protodiastolic” forward expansion wave is thought to cause the late systolic inflections that occur in the absence of reflected waves. This was evident in our data Figure , but was27 as seen in our data. This phenomenon is because of patient-specific pressure augmentation and explains the elevated central, but not brachial SBP in our patients. Importantly, a significant proportion of patients would be reclassified as hypertensive using c-SBP. These data suggest that reliance on brachial blood pressure may potentially result in undertreatment of at-risk patients. Failure to address blood pressure adequately in this young population has implications for cardiovascular risk reduction; furthermore, it may also influence cognitive function in later life.29We found no difference in brachial measured SBP between patients and controls. Although this is in keeping with previous studies, it does not mean that afterload is normal post coarctation repair. It is well recognized that brachial SBP overestimates central SBP,30 measured central blood pressure in postcoarctation repair patients and normal volunteers, and in contrast to our study observed no difference in c-SBP. This may be partly because of their exclusion of any patient with high brachial artery blood pressure. However, another possible reason was their use of the SphygmoCor device to measure c-SBP. This device uses a generalized transfer function to derive central blood pressure from radial tonometric data. The algorithms used are based on a noncongenital population and may not be valid in subjects with abnormal arterial function. In particular, generalized transfer functions may not adequately control for the abnormal wave reflections that may be present in patients post coarctation repair.32 We used a novel CMR technique to derive c-SBP that is based on exponential modeling of the aortic distension curve.1 As this method uses patient-specific data as its initial starting point and for calibration, it should be able to better model pressure amplification.Our study is not the first to measure c-SBP after repair of coarctation. Swan et al10 Our data were acquired at rest, and studies have observed greater exercise hypertension in patients with a “gothic arch.”33 However, Ntsinjana et al34 using quantitative  analysis of arch angulation found no association with exercise blood pressure after adjustment for CI.We found no difference in any hemodynamic parameters between patients with and without “gothic” aortic archs.36 In multivariable analysis, the most important hemodynamic association with LVM was the magnitude of the BCW. This is in keeping with previous human and animal studies that have shown that wave reflections play a prominent role in determining LV structure and function. In the multiethnic study of atherosclerosis, backward waves have been shown to be associated with both LVM37 and heart failure events.38 Furthermore, Hashimoto et al39 identified that antihypertensive therapy reduced backward waves, which may have an important role in mediating the ventricular response to therapy. The exact mechanism by which early BCWs contribute to the development of increased LVM is uncertain. However, it may be related to reflected waves altering the temporal evolution of LV pressure. For instance, Kobayashi et al40 showed a more profound hypertrophic response in rats banded in the descending aorta compared with the ascending aorta. This was thought to be because of late systolic loading due to wave reflections being a more potent hypertrophic stimulus. Irrespective of the mechanism, these data demonstrate that afterload cannot simply be thought of as SBP.In this study, patients with repaired coarctation had elevated LVM, which has been shown to strongly predict increased cardiovascular morbidity and mortality.Comprehensive noninvasive assessment of hemodynamics was made possible in this study because of the novel CMR and signal processing techniques used. All of the hemodynamic data were derived from a single high temporal-resolution phase-contrast acquisition, obtained during a breath-hold. These data provide the prerequisite area and flow data needed to derive central systolic pressure, resistance, TAC, local pulse wave velocity, and wave intensity when combined with simultaneous brachial noninvasive blood pressure measurement.In this study, TAC was assessed using a technique based on 2-element Windkessel modeling. This technique is known to be an improvement on the stroke volume/pulse pressure method, which overestimates TAC. However, this technique has been criticized because it does not account for wave reflections. Nevertheless, it does provide and easily understood metric of arterial buffering that captures the simpler elements of pulsatile load. Consequently, we believe that it is a useful adjunct to the more sophisticated WIA performed in this study.15We also used the Bramwell–Hill equation for the derivation of local pulse wave velocity/characteristic impedance, rather than the flow-area (QA) or impedance-based methods. This was because we anticipated significant early reflections during the early part of systole, which would have resulted in errors in estimation of pulse wave velocity.WIA provides useful insight into wave reflections in the time domain, it is relatively simple to implement but requires high temporal-resolution data flow imaging to resolve waveforms, which have short durations.central, and characteristic impedance during routine CMR assessment is feasible, whereas performing noninvasive WIA may be more challenging to implement. However, the association with LVM suggests that these parameters may be useful biomarkers. Further studies assessing their relationship to outcomes and response to therapies are necessary.The ability to assess c-SBP, TACA significant limitation of this study is the possibility of cascading errors resulting from inaccuracies in the multiple acquisition and processing steps required to perform noninvasive WIA. These errors could originate from residual aliasing in the reconstructed images, incorrect segmentation, inaccurate blood pressure measurement, and inadequate assumptions. Nevertheless, the relationship between LVM and BCW does add credence to our findings.15Central SBP was derived by calibrating aortic area curves to mean and DBP using an exponential pressure–area relationship. This method was originally validated using noninvasive carotid tonometry (over a similar pressure range in this study), rather than using preferred invasive pressures. Unfortunately, micromanometer pressure catheters are not available for the magnetic resonance imaging environment and the alternative, fluid-filled catheters, have unfavorable frequency response and damping characteristics, which limit their use for this purpose. We have also previously described the use of a more complicated “arctangent” pressure–area model; however, this method cannot be reliably calibrated using noninvasive local pulse wave velocity (Q/A method), as it underestimates wave speed in the presence of significant early wave reflections, as observed in coarctation patients.5 do not have an easily understandable physical meaning: in contrast to the W/m2 units of conventional WIA. Nevertheless, the waveforms produced by noninvasive WIA are qualitatively similar to invasive WIA in the literature—and given a linear pressure–area relationship would be directly proportional. Area and flow waves can, therefore, be considered analogous to pressure and velocity waves as found in the WIA literature.The units of noninvasive WIA in this study, cmThis study aimed to describe all relevant central hemodynamic parameters underlying the vascular abnormalities in CoA. We have shown that this can be performed within a single breath-hold, using a high temporal-resolution phase-contrast acquisition in the ascending aorta with simultaneous oscillometric blood pressure measurement. These data provide central blood pressure, systemic vascular resistance, TAC, local pulse wave velocity, and wave reflections.We have shown that patients with repaired coarctation have higher c-SBP, stiffer aortas, and abnormal wave reflections, despite similar p-SBP to controls. Elevated LVM in this population is associated with the magnitude of the BCW. Consequently, therapies that can influence TAC and wave reflections may represent important drug development targets for the future.41 Conventional clinical assessment using brachial blood pressure and anatomic imaging may fail to identify patients with vascular dysfunction, thereby leading to inappropriate undertreatment. Future therapeutic interventions should be targeted to the vascular abnormalities, which occur in this population.Understanding the vascular abnormalities in patients with CoA is important if we wish to modify the cardiovascular risk and excess mortality in this population.This research has been supported by the British Heart Foundation (MQ [FS/11/76/29037] and [FS/16/28/32327]) and the National Institute for Health Research, Great Ormond Street Hospital, UCL Biomedical Research Centre award.None.