Neurological events associated with transcatheter aortic valve implantation are major contributors to morbidity and mortality. Choosing an appropriate endpoint to determine neuroprotection device efficacy is a key difficulty inhibiting the translation of the innovation from the laboratory to the bedside. Cost and sample size limitations inhibit the feasibility of using the rate of clinical  events as the primary efficacy endpoint. This paper focuses on consensus opinions from the 2013 Yale-University College London (UCL) Device Innovation Summit.Neuroimaging, specifically diffusion-weighted magnetic resonance imaging (DW MRI), may serve as a surrogate endpoint for clinical studies detecting cerebral events in which cost and sample-size limitations prohibit the use of clinical outcomes. A major limitation of using imaging to prove efficacy in cardiac device studies is that no standardized endpoint exists. Ongoing trials investigating cerebral protection devices for transcatheter aortic valve implantation are utilizing and reporting various qualitative and quantitative DW MRI values; however, single lesion volume, number of new lesions, and total lesion volume have been found to be the most reproducible and prognostically important imaging measures.DW MRI may be a useful surrogate endpoint for clinical studies detecting cerebral events to determine the device’s success in neurological protection. Consensus from the 2013 Yale-UCL Device Innovation Summit specifically recommends the reporting of mean single lesion volume, number of new lesions, and total volume, and encourages European Union (EU)-US regulatory consensus in the guidance of implementing this endpoint. Neurological events contribute to the morbidity and mortality associated with transcatheter aortic valve implantation (TAVI). Neuroimaging, specifically diffusion-weighted magnetic resonance imaging (DW MRI), may be a useful tool for assessing clinical outcomes of both unprotected TAVI as well as in the evaluation of cerebral protection devices.The current state of neuroprotection for TAVI is of great interest among inventors and clinicians involved in cardiac device development and implementation, and was thus a primary focus of the 2013 Yale-University College London (UCL) Cardiac Device Innovation Summit. This meeting provided a forum for engineers and clinicians to openly discuss the complexities of cardiac embolic protection devices, and address the unmet needs of the regulatory approval process to enhance percutaneous valvular device innovation and clinical implementation.The 2013 Yale-UCL summit focused on second-generation TAVI, neuroprotection device development and evaluation as adjunct to TAVI, percutaneous mitral valve devices and left ventricular support devices, and novel percutaneous coronary devices including biodegradable stent technologies and targeted biologics. An expert faculty of Europe-based and US-based regulators, industry partners, funders, engineers and clinicians led various discussions throughout the 2-day conference, which was publicized within the Yale and UCL campuses and open to all, with no registration fees. The meeting was sponsored by Yale University and UCL.Choosing an appropriate endpoint to determine device efficacy is a key difficulty inhibiting the translation of the innovation from the laboratory to the bedside. The Yale-UCL summit developed consensus recommendations regarding the selection of study endpoints, specifically for clinical trials investigating strategies for neuroprotection in TAVI. Below, we will provide a brief discussion of TAVI-related stroke and current strategies for neuroprotection, and provide our conclusions recommending neuroimaging, specifically DW MRI, as a cost-effective and potentially even clinically meaningful endpoint to investigate efficacy of cerebral protection devices for use in cardiac procedures.There are several accepted therapies to treat severe aortic stenosis but each is associated with significant risks. The ‘Placement of AoRTic TraNscathetER’ PARTNER trial and other smaller studies have demonstrated the superiority of TAVI to standard medical therapy for inoperable patients with aortic stenosis and its non-inferiority to surgical valve replacement for high risk patients, with such findings evident up to 2 years post procedure ,2. Furthet al. determined the incidence of stroke within the first 24 h of TAVI to be 1.5% ± 1.4%; other studies have found similar results [Indeed, the PARTNER trial demonstrated a two to three times higher risk of stroke with TAVI compared with standard medical therapy or surgery , and the results ,8. Furth results ,10. Impr results ,12.The TAVI procedure involves the introduction of bulky devices into atherosclerotic arteries and a calcified aortic valve, and thus lends itself to cerebral embolization of plaque debris. The majority of TAVI-related strokes are in fact periprocedural and >50% occur within the first 24 h of the procedure ,13. The The importance of new lesions found on DW MRI, many of which are clinically silent, remains unclear; however, studies utilizing DW MRI have found new lesions in 58% to 91% of patients undergoing TAVI ,16. TherThe incidence of stroke within 30 days of the TAVI procedure is estimated to be between 1.7% to 6.7%, and there continues to be an increased risk of stroke in the years following the procedure -21. Postet al. found that 80% of newly detected lesions on DW MRI demonstrated reversal during the 3-month follow-up period; however, apparent lesion reversal does not necessarily mean normalization of brain tissue [Further, Kahlert n tissue . In factn tissue .Given the increased risk of stroke associated with TAVI, both adjunctive pharmacotherapy to prevent thrombosis and neuroprotective devices may be indicated. The literature is scarce regarding the appropriate antithrombotic regimen for TAVI, and the few studies that have been conducted have focused both on antiplatelet therapy (including aspirin and clopidogrel) and anticoagulant agents . The only published clinical trial to date randomized 79 patients undergoing TAVI to receive a 300-mg loading dose of clopidogrel on the date of procedure plus post-procedural maintenance therapy consisting of 3 months of 75 mg of clopidogrel daily plus aspirin 100 mg lifetime or aspirin 100 mg alone. The results demonstrated no clinical benefit from the addition of 3 months of clopidogrel maintenance therapy . This fiIn addition to antithrombotic therapy, patients undergoing TAVI may also benefit from the use of cerebral protection devices. The temporal pattern and location of cerebral infarcts and silent ischemic lesions following TAVI indicate periprocedural mechanical embolization as the most likely pathophysiologic mechanism of periprocedural stroke. We thus believe that there is a role for cerebral protection devices in preventing stroke associated with TAVI. The ideal protection device is safe, effective, easy to use, can accommodate various anatomies, demonstrates minimal interference with the TAVI procedure, and importantly, covers all three major cerebral inflow aortic arch vessels. Notably, using protection devices may make the TAVI procedure more cumbersome, complicated, and time consuming, and may thus drive up costs. Results from the ‘Action in Diabetes and Vascular disease: PreterAx and DiamicroN Controlled Evaluation’ (ADVANCE) study link procedural time with the incidence of stroke, suggesting that a fast and simple procedure may be one of the most important factors for stroke prevention . In addition, lower contemporary stroke rates associated with TAVI raise the question of whether cerebral protection devices and/or adjunctive pharmacotherapy should be recommended for all patients undergoing the procedure. Future randomized controlled trials are needed to determine which patient groups would benefit from these preventative measures. If the increased stroke risk associated with TAVI remains an issue in the future, the implementation of embolic protection devices may be valuable in reducing both clinically evident and occult strokes; however, if further studies suggest that these risks have already been reduced, additional devices may not be warranted.Current embolic protection devices under clinical investigation include the Edwards Embrella Embolic Deflector , the Keystone Heart TriGard™ Embolic Deflection Device , and the Claret CE Pro™  Table . While tThe only published human study of the Embrella device reports the results of its implantation in three patients undergoing TAVI and one patient undergoing BAV alone. Though no patient developed new neurological symptoms or stroke, a new 5-mm acute cortical infarct was found on predischarge cerebral MRI in the patient who had undergone BAV but remained asymptomatic . UnpubliImplantation of the Keystone Heart TriGard device in 15 patients resulted in no procedural complications and 1 patient suffering a transient ischemic attack 2 days after the procedure . DW MRI Results of the first in-human studies of neuroprotection devices show promise in reducing the occurrence of neurologic events and thus improving outcomes in TAVI. DW MRI has been used to indicate periprocedural cerebral ischemia after unprotected TAVI in numerous studies ,29,30. TNeuroimaging modalities, specifically transcranial Doppler ultrasound (TCD) and DW MRI are useful for detecting acute ischemic stroke and have provided additional information about microembolization in TAVI. TCD uses low frequency pulsed sound to allow visualization of the circle of Willis vessels and can identify high-intensity transient signals (HITS) and microembolic signals (MES). Studies have found the detection of HITS in all patients undergoing TAVI and the majority of MES occurring during balloon valvuloplasty and valve delivery . UnfortuChoosing an appropriate endpoint for a clinical trial can be complex. In fact, between 10% to 15% of medical devices that enter the EU regulatory pathway lack relevant endpoints, which is considered grounds for objection. The penetration rate of devices in general, and in TAVI specifically, is significantly delayed in the US compared to Europe mostly due to FDA requirements for reasonable assurance of safety and effectiveness of a device prior to its approval .For clinical trials investigating neuroprotection devices for use in cardiac procedures, the investigators must prove that the device is able to reduce the occurrence and/or severity of cerebral events. Ideally this would be accomplished by reporting an actual reduction in the rate of stroke, transient ischemic attack, and other neurologic events according to Valve Academic Research Consortium-2 definitions . BecauseNeuroimaging, specifically DW MRI, may serve as a surrogate endpoint for clinical studies detecting cerebral events in which cost and sample size limitations prohibit the use of clinical outcomes Table . DW MRI,One important issue to consider is that evidence for long-term consequences of lesions detected by DW MRI is lacking. Indeed, recent studies have implied that DW MRI lesions after TAVI are not related to self-sufficiency or mortality 1-year post procedure and that there may even be less cognitive decline post TAVI compared with surgery, despite a higher incidence of embolic lesions ,38. ThesAnother major limitation of using DW MRI in clinical trials is that no clear definition of the endpoint exists. Qualitative measurements include lesion number and vascular territory involved and quantitative measurements include total lesion volume, average lesion volume, and maximum lesion volume. All are key neuroimaging endpoint parameters to follow the efficacy of neuroprotection, however, the endpoint must be standardized to allow for cross-study comparison.Ongoing clinical trials investigating cerebral protection devices for TAVI are utilizing various DW MRI measures to determine device efficacy. The ongoing Prospective Randomized Outcome Study in Patients Undergoing TAVI to Examine Cerebral Ischemia and Bleeding Complications (PROTAVI) trial, which is randomizing patients eligible for TAVI to undergo the procedure with or without the Embrella deflection device, will analyze the rate of new DW MRI brain lesions at 7 days post procedure. Likewise, the DEFLECT I trial is a single arm study enrolling up to 60 patients in the EU, Canada, and Brazil to undergo TAVI with the Keystone Heart TriGard in place using the presence of new DW MRI lesions post procedure compared with a historical control group as a measure of device success.Although DW MRI lesion presence and rate of occurrence are being used as endpoints, total lesion volume is the most reproducible measurement when performed in an experienced core laboratory, and along with geographic location, provides the best measure of overall burden of ischemic injury, and may therefore be a more appropriate endpoint measure. Though it fails to identify the functional region of the brain involved, studies have identified DW MRI lesion volume as an independent predictor of clinical outcome after acute stroke ,40. SpecLastly, in 2011, the FDA issued draft guidance for clinical trial imaging endpoints for studies intending to confirm drug efficacy, recognizing that the use of imaging may assist in the assessment of safety and efficacy as well as patient eligibility. US regulatory requirements have been an impediment to early clinical testing of new devices, which US investigators have mostly outsourced overseas. During the Yale-UCL summit, the FDA expressed its goals to encourage medical device innovation, enhance regulatory science, and facilitate early feasibility clinical studies in the US. Consensus from the Yale-UCL summit called for validation of imaging endpoints in neuroprotection trials involving medical devices and encouraged European regulatory bodies and the FDA to work with the clinical and device industry to support this position.In summary, stroke is a major contributor to morbidity and mortality in TAVI and the development of effective cerebral protection devices may optimize clinical outcomes. Though periprocedural outcomes may already be better than previously thought, it is still necessary to confirm the rates of neurological events in a consistent and reliable manner. Sample size requirements and rising costs of clinical trials are prohibitive to the use of clinical event rates as device efficacy endpoints. The 2013 Yale-UCL Summit developed consensus opinions regarding this topic. DW MRI may be a sensitive and specific surrogate endpoint for clinical studies detecting cerebral events to determine the device’s success in neurological protection; however, further research is needed. Finally, for clinical trial investigators using DW MRI as an endpoint to detect cerebral events, we recommend the reporting of mean single lesion volume, number of new lesions, and total volume, as we have concluded that these values are the most reproducible and potentially even prognostically meaningful DW MRI measures.BAV: Balloon aortic valvuloplasty; CVA: Cerebrovascular accident; DW MRI: Diffusion-weighted magnetic resonance imaging; EU: European Union; FDA: US Food and Drug Administration; TAVI: Transcatheter aortic valve implantation; UCL: University College London.The authors are investigators in the ongoing DEFLECT I trial .All authors have met the full criteria and requirements for authorship. SMM contributed in the conception and design of the manuscript as well as drafting of the manuscript. AB supervised drafting of the background section, ‘Review of adjunctive pharmacology and neuroprotection devices for TAVI’ and SV supervised drafting of the sections involving neuroimaging. AJL and MM directed and led the Yale-UCL Summit, including the sessions discussed in this article. All authors contributed in revising the manuscript critically for intellectual content. All authors have provided final approval of the manuscript submitted.AJL and MM organized and led the 2013 Yale-UCL Cardiac Device Innovation Summit, which the remaining authors participated in. AJL is an associated Professor of Cardiology at Yale University School of Medicine and directs the Yale Cardiovascular Research Group (YCRG) and the Yale Valve Program. MM is a consultant cardiologist at the Heart Hospital, University College London, and leads the Structural Heart Intervention program. SMM is a medical student at Yale University School of Medicine conducting research with AJL at YCRG. AB is a consultant cardiologist at University Hospitals Bristol in the UK and heads clinical research in the Department of Cardiology there. SV is an Associate Professor of Medicine/Cardiology and Radiology, and Director of Advanced Cardiovascular MR and CT Research at the Department of Radiology and Cardiology at Stony Brook University Medical Center.


CMR is generally accepted as the gold standard for left ventricular (LV) volumes and function assessment. The conventional CMR approach involves several breath-holds to cover the entire heart with short-axis acquisitions. Recently, compressed sensing (CS) techniques emerged as a means to considerably accelerate data acquisition. CS principally relies on: 1) transform sparsity, 2) incoherence of undersampling artifacts, and 3) nonlinear reconstruction. PURPOSE: To compare a novel CS-based single breath-hold multi-slice cine technique with the standard multi-breath-hold technique for the assessment of LV volumes and function.The novel single breathhold multi-slice CS cine sequence was implemented on a 1.5T MAGNETOM Aera . It realizes incoherent sampling by distributing the readouts pseudo-randomly on the Cartesian k space grid and by applying a pseudo-random offset from frame-to-frame during prospective ECG-triggering. Thus, 3 long-axis and 4 short-axis slices Figure  were acqTwelve volunteers  and 14 patients  with different LV pathologies were studied. Good image quality of the single breathhold multi-slice CS acquisitions was obtained in 10/12 volunteers and 12/14 patients and all CS data were of adequate quality for 4D-analysis. LVEFCS and LVEFStandard were similar  with an excellent correlation (Figure This is the first clinical experience with a novel CS-based cine sequence. These preliminary results demonstrate the potential of this fast single breath-hold technique to replace the multi-breath-hold standard technique for the assessment of LV volumes and function.D. Piccini, M.Zenge, M.Schmidt and M. Nadar are Siemens employees. Other funding than that was not received.


Sickle cell disease (SCD) is a common inherited hemoglobinopathy. Adults with SCD manifest both systolic and diastolic cardiac dysfunction, though the age of onset of dysfunction has not been defined. Left ventricular (LV) rotational mechanics have not been studied in children with SCD. The aim of this study was to investigate whether cardiac rotational mechanics differed between children with SCD and age-matched controls.Basal and apical LV short-axis images were acquired prospectively in 213 patients with SCD  and 49 controls  from the Muhimbili Sickle Cohort in Dar es Salaam, Tanzania. The magnitude of basal and apical rotation, net twist angle, torsion, and untwist rate were obtained by two-dimensional speckle-tracking. The timing of events was normalized to aortic valve closure.P = .012), although no difference was observed in apical rotation (P = .37). No statistically significant differences in torsion or net twist angle were detected. Rotation rate at the apex (P = .001) and base (P = .0004) were significantly slower in subjects with SCD compared with controls. Mean peak untwisting rate was also significantly slower in patients with SCD (P = .006). No associations were found between hemoglobin concentration and apical rotation, basal rotation, net twist, and torsion.Mean basal rotation was significantly lower in patients with SCD compared with controls (This study demonstrates alterations in LV rotational mechanics in children with SCD, including lower basal rotation, peak differential twist, and untwist rate. These abnormalities denote subclinical changes in LV systolic and diastolic performance in children with SCD. Future work may reveal an association between rotational metrics and long-term patient outcomes. Sickle cell disease (SCD) is a common hemoglobinopathy, the sequelae of which can be life threatening.Conventional echocardiographic measures of LV function, such as shortening fraction and ejection fraction, have not been demonstrably different when patients with SCD and unaffected individuals have been comparedA nested case-control study was undertaken, including study participants with SCD and unaffected control patients from the Muhimbili Sickle Cohort (MSC) in Dar es Salaam, Tanzania.Cases were recruited prospectively from patients enrolled in the MSC and controls from children who had attended the clinic for sickle screening and were determined not to have SCD. Inclusion criteria included age between 9 and 19 years and, for patients with SCD, sickle status confirmed by hemoglobin (Hb) electrophoresis and high-performance liquid chromatography, while controls without SCD had the HbAS or HbAA phenotype by electrophoresis. Blood pressure was measured twice after 5 min of rest using an automated digital device  and the mean calculated. Axial temperature, height, and weight were recorded, and a clinical examination was performed to exclude acute complications. Exclusion criteria included history of blood transfusion within the previous 2 months, symptoms of sickle crisis within the previous 2 weeks, febrile illness within the 7 days before echocardiography, fever or signs of acute illness on the day of echocardiography, and known or echocardiographically identified hemodynamically significant congenital heart disease.The study was approved in the institutional review board of Children's Hospital Colorado (Reference No. COMIRB protocol #10-0030) and by the Muhimbili University of Health & Allied Sciences Research and Publications Committee (Reference No. MU/RP/AEC/Vol.XIIV/01). Written informed consent was obtained from all study participants.Rotation was defined as circumferential myocardial motion around the centroid, or long axis, of the ventricle.For each patient, measurements of LV chamber size and fractional shortening were made from short-axis basal images. From the apical window, LV peak systolic mitral annular velocity (LV S′), LV peak early diastolic mitral annular velocity (LV E′), early diastolic mitral inflow (LV E), duration of late diastolic mitral inflow , and duration of the late diastolic a wave in pulmonary vein inflow (pulmonary vein a-wave duration) were made. The LV myocardial performance index was also calculated from mitral inflow and aortic outflow spectral Doppler patterns.Short-axis images of the base and apex of the left ventricle were obtained using the VividQ platform  and an M4S, 5S, or 7S probe, depending on patient characteristics and image quality. Frame rates of >75 and <125 frames/sec were accepted. An acquisition of five consecutive beats was obtained. An apical view was also obtained for the purposes of measuring end-diastolic LV length and performing spectral Doppler measurement of mitral inflow and aortic outflow. End-diastolic LV length was measured from the apical four-chamber view as the distance from the mitral valve to the apex of the left ventricle.Commercially available software  was used to perform speckle-tracking analysis. A single cardiac cycle was isolated for the base, and a region of interest was identified. The magnitude and timing of basal rotation was calculated. The process was repeated for the short-axis apical image. Net twist was calculated as the difference between apical and basal rotation. Torsion was calculated by dividing the net twist by LV end-diastolic length. This process was repeated two additional times and an average over three cardiac cycles was calculated.Hb phenotype was determined by alkaline Hb electrophoresis  and by quantification of Hb fractions, including HbF, by high-performance liquid chromatography . In subjects with SCD, the most recent steady-state Hb, total bilirubin, conjugated bilirubin, and lactate dehydrogenase levels were obtained from MSC records . Full blood counts were performed using an automated cell counter . Biochemical tests were performed using an automated chemistry analyzer .t test was used to compare mean values between two patient groups. Simple linear regression was used to evaluate associations between independent variables and a continuous, dependent variable. Pearson correlation was used to evaluate associations between measures of rotational mechanics and Hb or laboratory measures of hemolysis in the children with SCD. A P value < .05 was determined to be the threshold for statistical significance. Analyses were compared when the five children with HbSB+ were included or excluded from the patients with SCD and no material differences were observed, and therefore all reported analyses include both the HbSS and HbSB+ cases.SAS version 9.2  was used to perform statistical analyses. Continuous variables are presented as mean ± SD or median (interquartile range), and categorical variables are presented as proportions. The Student independent two-sample Eleven consecutive patients were evaluated separately by two independent observers (H.H.H. and G.A.), who evaluated net twist, torsion, twist rate, and peak untwisting rate in a blinded fashion. To reflect the methodology used in this study, each measurement was made on what the investigator felt was the best cardiac cycle among the five that were acquired. A single observer (H.H.H.) performed serial analysis of the same 11 patients 2 months later using the same methodology to determine intraobserver variability. Analysis included calculation of intraclass correlation coefficients of variation.Three hundred subjects were recruited into the study. On the day of the echocardiographic assessment, 22 subjects were excluded before echocardiography because they were unwell, while seven subjects were excluded after echocardiography because of minor structural cardiac abnormalities. Four additional subjects were excluded after speckle-tracking analysis because of poor image quality. Thus a total of 262 participants were included in the present analysis, consisting of 213 patients and 49 unaffected controls see .P = .0042), lower mean Hb levels (P < .0001), and lower systolic (P < .0001) and diastolic (P = .0002) blood pressures. The SCD group also had lower body mass index Z scores (P < .0001) and lower height-for-age Z scores (P < .0001). The SCD group had significantly greater LV dilation in both the long- and short-axis dimensions, as assessed by LV end-diastolic dimension Z score and LV length (P < .0001 for both comparisons). The LV sphericity index was significantly lower in the SCD group (P = .006), indicating that the left ventricle more closely approximated a sphere, which has a sphericity index of 1. No difference was observed in fractional shortening (P = .16) or in tissue Doppler measurements of LV function. However, the LV myocardial performance index was significantly different in the SCD group .Baseline demographic and conventional echocardiographic data are summarized in The results for intraobserver and interobserver variability are summarized in P = .006).n = 216), B-type natriuretic peptide (n = 106), and lactate dehydrogenase (n = 199), in patients with SCD only, but none were significant (data not shown). We also performed a quartile analysis with regard to torsion, comparing Hb, lactate dehydrogenase, and B-type natriuretic peptide between the highest and lowest quartiles; there was no significant difference in any biomarker between those with the most robust torsion and the least.There was no significant association between age and net twist in the SCD group. Similarly, there was no association between net twist and mean arterial pressure. We also assessed relationships between the most clinically relevant measures of LV rotational mechanics  and Hb (This study reveals significant differences in LV rotational mechanics between Tanzanian children with SCD and age-matched controls. To our knowledge, this is the first study in children with SCD to evaluate rotational mechanics and to detect early declines in these measures of systolic and diastolic LV performance.et al.Other investigators have demonstrated reductions in both LV and right ventricular strain in both adults and children with SCD. Sengupta et al.Lower peak untwisting rate correlates with diastolic dysfunction in other populations.Children with SCD have been shown to have LV dilation in proportion to the degree of anemia, though with a preserved shortening fraction.et al.Further support for the notion that the patients with SCD under study are manifesting early ventricular dysfunction is provided by the findings of other investigations of the effect of increased preload, and hence end-diastolic diameter, on LV torsion. Dong et al.Ahmad As subjects were recruited from a regional care center for SCD, sonographers and study interpreters were not blinded to the disease state of each group.Longitudinal data are required to understand the development and progression of systolic and diastolic dysfunction over time and any associations with morbidity or mortality of SCD.This study demonstrates that despite normal fractional shortening, subclinical systolic and diastolic cardiac dysfunction is present in children with SCD, as assessed by rotational mechanics. Further studies are needed to evaluate the onset and progression of alterations in ventricular mechanics in children with SCD, as these indices may be predictors of adverse outcome later in life.


To evaluate a combined protocol for simultaneous cardiac MRI (CMR) and contrast-enhanced (CE) whole-body MR angiography (WB-MRA) techniques within a single examination.n = 48) with low-moderate risk of cardiovascular disease (CVD) were recruited. The protocol was divided into four sections: (1) CMR of left ventricle (LV) structure and function; (2) CE-MRA of the head, neck, and thorax followed by the distal lower limbs; (3) CMR LV “late gadolinium enhancement” assessment; and (4) CE-MRA of the abdomen and pelvis followed by the proximal lower limbs. Multiple observers undertook the image analysis.Asymptomatic volunteers (n = 29 of 48 volunteers) and interobserver radiological opinion was consistent in 96.7% of 1488 vessel segments assessed.For CMR, the mean ejection fraction (EF) was 67.3 ± 4.8% and mean left ventricular mass (LVM) was 100.3 ± 22.8 g. The intra-observer repeatability for EF ranged from 2.1–4.7% and from 9–12 g for LVM. Interobserver repeatability was 8.1% for EF and 19.1 g for LVM. No LV delayed myocardial enhancement was observed. For WB-MRA, some degree of luminal narrowing or stenosis was seen at 3.6% of the vessel segments (involving Combined assessment of WB-MRA and CMR can be undertaken within a single examination on a clinical MRI system. The associated analysis techniques are repeatable and may be suitable for larger-scale cardiovascular MRI studies. •We report the use of whole body MR angiography and cardiac MR as a single examination.•Healthy volunteers with elevated cardiovascular disease risk were scanned.•Vessel segments and cardiac function were assessed by Radiologists and Physicists respectively.•The protocol took an average of 51 minutes to complete, and analyses were repeatable.•This combined cardiovascular MRI protocol will be used for better targeting of future interventions. Cardiovascular disease (CVD) accounts for a significant burden of mortality and morbidity in developed societies. Although the majority of CVD deaths are from coronary heart disease (CHD) or stroke, the disease is often spread across all vascular territories and may present elsewhere first, e.g., in the arteries of the legs. Disease in more than one vascular bed  is known to have a cumulative effect on worsening prognosis, so early detection and stratification of the whole-body burden of CVD  is desirable. Primary prevention of CVD events is effective, but targeting suitable treatment, such as protective drug therapy and/or procedural interventions, to those most likely to benefit remains a challenge. Current decisions are based on estimated CVD risk, but risk scores do not have good external validity, and a significant number of events occur in those deemed to be at low or intermediate risk. Therefore, a method to screen for “pre-clinical” cardiovascular disease may help to improve how primary prevention is targeted.Cardiac MRI (CMR) has developed into the imaging standard for evaluating cardiac left ventricular (LV) structure and function.Recent advances in MRI hardware such as radiofrequency (RF) coil connectivity have resulted in the emergence of the whole-body MR angiography (WB-MRA) technique,For data analysis, quantitative methods for 3 T CMR are widely describedThe present study was undertaken to incorporate CMR and WB-MRA into a single 3 T “hybrid” clinical protocol capable of acquiring images of the vascular tree together with assessment of heart structure, function, and late gadolinium enhancement (LGE) within a single examination. The protocol consists of four sections, each made up of sequences  as follows: (1): CMR of LV structure and function; (2) contrast-enhanced (CE)-MRA of the head/neck/thorax and the distal lower limbs (contrast medium injection 1); (3) CMR of LGE; and (4) CE-MRA of the abdomen/pelvis (contrast medium injection 2).To date, no work has been reported looking at the role of this combined protocol in a low or intermediate risk cohort, nor to assess the technical reproducibility of the study in such a population. The primary objectives of the study were therefore: (1) to implement this MRI protocol on a cohort of asymptomatic volunteers with known risk of CVD but with no previous clinical diagnosis; and (2) to evaluate data analysis strategies for CMR and WB-MRA with input from multiple observers in order to establish the intra- and interobserver repeatability. WB-MRA combined with CMR and LGE represents an attractive proposal for cardiovascular work given its systemic assessment of the heart and vascular tree. The WB-MRA technique on its own is known to correlate better with future cardiovascular risk than current scoring mechanisms in a high-risk population.n = 48 volunteers  were recruited after providing informed consent. Inclusion criteria were as follows: (1) >40 years; (2) free from CVD or other indication for statin therapy as recommended by the Scottish Intercollegiate Guidelines Network (SIGN) report 97 (www.sign.ac.uk) published in February 2007, and (3) had a serum B-type natriuretic peptide (BNP) level greater than their gender-specific median indicating non-specific stress on the cardiovascular system. Exclusion criteria included: (1) pregnancy; (2) known primary muscle disease; (3) known atherosclerotic disease, including unstable angina, previous myocardial infarction, peripheral arterial disease, amputation, revascularization, hypertension, heart failure, or cerebrovascular event; (4) known diabetes; (5) active liver disease; (6) other known illness or contraindication to MRI; (7) participation in a clinical trial; (8) inability to give informed consent; (9) known alcohol abuse; and (10) blood pressure of greater than 145/95 mmHg.Following local ethical committee approval, Imaging was performed  using a 3 T (102 × 32) Magnetom Trio Scanner  with a coil combination using head (12 elements), neck (four elements), body (two coils of six elements each), spine (up to 24 elements), and peripheral angiography (16 elements) RF coils. Preliminary three-plane “localizer” images were acquired for WB-MRA via the use of 500 mm field-of-view (FOV) gradient echo fast low-angle shot (FLASH) sequences covering the anatomy from head to foot. Localizer images were positioned with an “overlap” between each FOV of at least 75 mm but adjustable according to patient height c. As parECG-gated segmented breath-hold cine TrueFISP images were acquired in the LV 4ch and 2ch orientations. Following this, a stack of short axis images were acquired from the atrio-ventricular ring to the LV apex using 2D ECG-gated breath-hold segmented cine TrueFISP sequence with retrospective gating .®, Guerbet, France) followed by 20 ml saline flush was delivered at the left or right antecubital fossa using a Spectris Solaris power injector  at a rate of 1.5 ml/s. Timing was controlled by a coronal 2D Care Bolus acquisition (MR fluoroscopy), and the contrast-enhanced acquisition for station 1 commenced when contrast agent arrival was noted at the top of the aortic arch. Post-contrast data for station 4 were acquired immediately after completion of station 1, and these were acquired three times consecutively to account for variable arterial transit times.Unenhanced CE-MRA “mask” data were acquired for each station using a 3D TurboFLASH sequence, and the scanner table was preset to move at a rate of 50 cm/s. A 10 ml “standard dose” of 0.05 mmol/ml gadoteric acid  8–10 min after initial contrast medium injection in order to identify the null point inversion time (TI) for the myocardium. Subsequently, at a mean of 11 min post-contrast medium administration (range 9–16 minutes) a short-axis stack of ECG-gated segmented 2D PSIR images were acquired in order to highlight any LGE within the myocardium. The mean TI used was 376 ms (range 300–450 ms).Unenhanced 3D Turbo-FLASH “mask” data were acquired for each station . The secFinally, the pre- and post-contrast WB-MRA data were subtracted and the resulting images were stitched using a multi-modality work platform . Multiplanar reconstructions (MPR) and maximum intensity projections (MIP) were also generated for further radiological interpretation.n = 48) were analysed once by each of a team of four experienced medical physics observers in order to assess interobserver variation. Additionally the datasets were divided into four groups of n = 12, and one group was assigned to each medical physics observer for further segmentation, resulting in four independent assessments of intra-observer variation. For WB-MRA, all datasets were analysed once by each of a team of four radiologist observers in order to derive interobserver variation. Again the datasets were divided into four groups of n = 12, and one group was assigned to each radiologist observer for further segmentation, resulting in four independent assessments of intra-observer variation. Dataset randomization was performed by an independent support statistician (P.R.). Repeat analysis was separated by at least 1 month in order to eliminate “learning effects” by observers.For CMR, all datasets . Region of interest (ROI) contours were placed around endocardial and epicardial LV borders on all CMR image sections at end-diastole and end-systole that contained 50% or more full-thickness myocardium. Quantitative measurements of EF and LVM (at end-diastole) were derived. Papillary muscles were included in the LVM if indistinguishable from the myocardial wall, but otherwise assigned to the left ventricular blood pool.WB-MRA analysis was performed using a diagnostic PACS radiological workstation  on the post-contrast TurboFLASH source images, with MIP and MPR images for further interpretation. Analysis was performed on 31 arterial segments per dataset . Radiolow)0.5, where Sw is the within-subject standard deviation. One-way analysis of variance (ANOVA) was implemented (with 95% confidence limits) in order to highlight any significant differences between the means of the EF and LVM parameters both within and between observers. A minor variation to the standard Bland–Altman plot was used to illustrate interobserver variation for EF and LVM.k) for interobserver measures. Variability in whole-body atheroma scoring was assessed using the Kruskal–Wallis test for multiple observations and the Wilcoxon signed rank test was used to test for observational pairs of data. Statistical analysis was performed using IBM SPSS, version 21 .For the CMR LV function data, intra- and interobserver coefficients of repeatability (CoR) for EF and LVM were calculated as 2.77× was deemed non-interpretable and excluded from further analysis. An example image dataset highlighting CMR (LV short axis) and the corresponding WB-MRA is illustrated in n = 4 medical physics observers) for EF ranged from 65.3 ± 5.1% to 71.1 ± 4.7%, with a consensus mean of 67.3 ± 4.8% (for n = 48 patients). For LVM, mean values ranged from 92.8 ± 22.1 g to 105.3 ± 22 g, with a consensus mean of 100.3 ± 22.8 g . There were no cases of myocardial LGE identified by the radiologist observers.For CMR, mean values (derived by p < 0.05). However, when EF data derived by the remaining observers were evaluated, there was no statistical difference detected between their means. The single-measure interobserver CoR for EF was 8.1%, and for each individual observer the test-retest intra-observer CoR for EF was 4.7% (observer 1), 2.1% (observer 2), 2.7% (observer 3) and 3% (observer 4). For LVM, observer 1 tended to generate values that were smaller than those from the other observers (p < 0.05). Again, when LVM data derived by the remaining observers were considered there was no statistical significance detected between their means. The single-measure interobserver CoR for LVM was 19.1 g, and for each individual observer the test-retest intra-observer CoR for LVM was 9 g (observer 1), 10.2 g (observer 2), 10.1 g (observer 3) and 12 g (observer 4).Data plots for multiple observers are presented in n = 29 volunteers. Details of the arterial segments where disease was noted by consensus are highlighted in For WB-MRA, of the 1488 arterial segments evaluated  there was evidence of vessel luminal narrowing or stenosis in 53 (3.6%) segments, involving The greatest frequency of luminal narrowing was noted at the coeliac axis, where a stenosis score of grade 1 or more was noted in 18 of the volunteers. This was followed by the abdominal aorta (10 cases), and the right and left iliac arteries (four cases each). At all other segments, luminal narrowing was only ever noted in two (or less) of the 48 volunteers.k = 0.66) and best case agreement was found at the innominate and left popliteal arteries (k = 1.00).Independent single assessments of all datasets by each radiologist observer resulted in identical scoring between all four radiologist observers in 1277 (85.8%) of the 1488 arterial segments evaluated. Of those not scored identically, clear consensus agreement between three out of four radiologist observers was recorded for 162 (10.9%) of the segments. Radiological opinion was divided at the remaining 49 segments, i.e., 3.3% of the total reviewed. Fleiss' kappa values are listed for each of the arterial segments under investigation as a measure of interobserver agreement . Worst cn = 12 volunteers) resulted in radiologist observers 1 and 2 achieving consistent scoring in 356 (95.7%) of 372 arterial segments. For radiologist observers 3 and 4, consistent scoring was achieved in 346 (93%) and 350 (94.1%) of the segments respectively.Intra-observer repeatability . Further, a subset of n = 12 volunteers were evaluated by each radiologist observer for a second time and when the SAS scores were compared on a per-radiologist basis (using the Wilcoxon signed rank test), there was no significant difference between the means of the first and second assessments .The median SAS score equation  by conseIn the present study, a hybrid cardiovascular clinical MRI protocol was implemented from existing clinical sequences in order to acquire CE-MRA images of the human vascular tree together with assessment of heart structure, function, and LGE within a single examination. The data analysis methods are repeatable and all techniques are available on commercial systems, which allows for use at other centres.The CMR arm of the protocol was implemented using recent recommendations.There are certain limitations associated with the CMR work reported here. The segmentation repeatability was optimized by consensus choice of basal section inclusion between observers. This approach was taken since any study involving the assessment of LVM using CMR  would normally account for consistency within the section ranges included. Therefore, the consensus choice resulted in a CoR that was representative of boundary contour placements. Even with this additional step included, the interobserver repeatability of 19.1 g was still quite variable but this is very much consistent with findings described in detail elsewhere where “real world” LVM inconsistencies of typically 28% may be expected for a large cohort.For WB-MRA, the two-injection “standard dose” approach was chosen for three reasons. Firstly, the use of two stations per injection allowed for more sensitive control of bolus timing, and therefore, reliable arterial phase images. A single-injection approach was considered, but it was felt that this would require the use of less widely available time-resolved MRA techniques in order to ensure arterial phase data across the entire arterial tree. Secondly, the use of a contrast agent “standard dose” approach has been previously described on a similar cohort,For WB-MRA, a similar data analysis approach was adopted to those reported elsewhere.Recent published work indicates that radiological scoring of stenoses at the coeliac axis can result in false-positive assessments with MRI.The development of a whole-body atheroma score based on the accumulation of individual vessel segment scores has been reported previously.In conclusion, the present study reported a dual-faceted MRI protocol applied to a cohort of healthy volunteers with low to medium risk of CVD. The protocol provides a comprehensive cardiovascular MRI examination of WB-MRA together with cardiac structure, function, and myocardial LGE with a mean examination time of 51 min. All MRI sequences are commercially available, and the analysis methods are repeatable between single and multiple observers. The technique is potentially suitable for future radiological investigation of patients with systemic CVD, and may also enable the effectiveness of targeted treatments to be monitored via individual, longitudinal, or multi-centre investigations.


Systemic sclerosis (SSc) is characterised by vascular dysfunction and multi-organ fibrosis, with the heart commonly involved. Cardiovascular disease (CVD) in SSc may be direct or indirect, but often remains subclinical. SSc patients with apparent cardiovascular clinical features are at greater risk of deterioration and premature cardiovascular death, often from complications of myocardial ischaemia. CMR first-pass perfusion detects myocardial ischaemia with great accuracy. We hypothesised that CMR first-pass perfusion would be able to differentiate between segmental  and non-segmental subendocardial (indicating microvascular dysfunction) perfusion defects in patients with SSc; and that microvascular dysfunction  was more frequent in SSc.17 SSc patients  and 17 matched controls  were enrolled. All patients with known cardiovascular disease were excluded. Study participants underwent CMR at 1.5T and the assessments included cine, tagging, T1 mapping, T2-weighted, perfusion, late gadolinium imaging (0.15mmol/kg gadoderic acid - Dotarem®) and ECV quantification. Comorbid status, disease activity index (VDAI score) and duration of disease were recorded for each subject.Myocardial perfusion reserve index was 1.5 ± 0.3 and 2.0 ± 0.4 (p<0.001) in SSc and controls, respectively. Non-segmental  subendocardial perfusion defects were seen in 41% of SSc and none (p<0.001) of controls studied. There was no significant difference in LV size, mass and ejection fraction between SSc patients and controls. Peak systolic circumferential strain and peak diastolic strain rate were impaired in patients. Impaired MPRI correlated with peak systolic strain  and peak diastolic strain rate  in SSc. Furthermore, abnormal MPRI correlated with VDAI  and ECV  in SSc.Myocardial perfusion is impaired in asymptomatic SSc patients with apparently normal hearts. Abnormal perfusion correlates with strain, strain rate, disease activity and ECV in SSc. CMR can detect subclinical cardiovascular involvement in SSc.This study was funded by investigator-led grants from Guerbet and GlaxoSmithKline.


Either decreased renal function or increased systolic time interval is associated with cardiac hypertrophy and poor cardiac outcome. The aim of this study was to evaluate combination of renal function and brachial systolic time intervals were associated with increased left ventricular mass index (LVMI) and left ventricular hypertrophy (LVH).2 and bPEP/bET < 0.38 (group 1), eGFR ≥ 45 ml/min/1.73 m2 and bPEP/bET ≥ 0.38 (group 2), eGFR < 45 mL/min/1.73 m2 and bPEP/bET < 0.38 (group 3), and eGFR < 45 mL/min/1.73 m2 and bPEP/bET ≥ 0.38 (group 4), respectively. Patients in groups 1 and 4 had the lowest and highest LVMI among 4 groups, respectively (P < 0.001). In multivariable analyses, increased LVMI and LVH were significantly associated with patients in groups 2, 3 and 4 (vs group 1) (P ≤ 0.019).In total of 990 patients were consecutively included in this study from January 2011 to December 2012. All study participants were further classified into 4 groups by the values of estimated glomerular filtration rate (eGFR) and ratio of brachial preejection period (bPEP) to brachial ejection time (bET). The classification of 4 groups were eGFR ≥ 45 mL/min/1.73 mOur study demonstrated that joined parameter of renal function and systolic time intervals, in terms of eGFR and bPEP/bET, might be an alternative method in risk stratification for increased LVMI and LVH. Either cardiac volume or pressure overload triggers several biological signal cascades leading to cardiac hypertrophy.2 Meanwhile, either arterial pressure or fluid volume overload are common noted in patients with chronic kidney disease (CKD), which can contribute to abnormal cardiac geometry and function in these patients. In epidemiological studies, advanced CKD patients had a high prevalence of LVH.6 The prevalence of LVH is inversely proportional to the value of eGFR.5 CKD patients, who either have reduced estimated glomerular filtration rate (eGFR) or renal damage, frequently have volume retention and electrolyte imbalance which may cause abnormal cardiac function, increased left ventricular mass index (LVMI), and adverse cardiac events. Prior studies demonstrated that reduced eGFR was the important factor affecting not only the progression of renal disease but also abnormal left ventricular geometry.8Abnormal cardiac and vascular structure and function are increased the risk of cardiovascular mobility and mortality.9 The relationship between renal and cardiac disease is close and bidirection.10 Parameters of cardiac systolic function can be measured from echocardiography and peripheral arterial Doppler waveform.13 Systolic time intervals, including preejection period and ejection time, are a well-known indicator for global cardiac systolic function.14 Brachial preejection period (bPEP) and brachial ejection time (bET) calculated from waveform of brachial arterial pressure, electrocardiogram and phonocardiogram were alternative parameters for evaluation of left ventricular systolic function.14 In our previous studies, prolonged bPEP, short bET, and high bPEP/bET were associated with cardiac systolic dysfunction.15 Furthermore, bPEP/bET can serve as a useful parameter in prediction of LVH and cardiac death in patients with CKD and hemodialysis.17On the opposite hand, preexisting cardiac disease is also associated with renal damage and rapid deterioration of eGFR.Although deterioration of renal function and brachial systolic time internals, in terms of decreased of eGFR and high bPEP/bET, have significant associated with LVH, there was no study investigated LVH from combining these 2 important indicators. We hypothesized that mixed parameters of renal function and brachial systolic time intervals were useful tools in the risk classification for LVH. The goal of our study was to evaluate the role of joined with eGFR and bPEP/bET in risk categorization for increased LVMI and LVH.Study participants were enrolled for echocardiographic survey in a regional hospital in Taiwan owing to suspected cardiovascular disease from January 2011 to December 2012 . From standard transthoracic view, we measured left ventricular internal diameter (LVID), interventricular septal wall thickness (IVST), and left ventricular posterior wall thickness (LVPWT) in the end left ventricular diastolic phase. The Doppler and tissue Doppler parameters, such as transmitral E wave velocity (E), E-wave deceleration time, transmitral A wave velocity, and early diastolic mitral velocity (Ea), were measured from standard apical four-chamber view.18 We calculated left ventricular ejection fraction (LVEF) and Left ventricular mass by the modified Simpson method and the Devereux-modified method, respectively.19 LVMI was calculated by dividing left ventricular mass by body surface area. In the present study, we defined LVH as LVMI more than 115 g/m2 in men and more than 95 g/m2 in women.18 All echocardiographic parameters were acquired from 3 continued beats and measured from offline EchoPAC software by a single experienced cardiologist.All study patients were received echocardiographic examination by a standard protocol.20All blood pressures, bPEP, and bET measurements were obtained after echocardiographic examination. The bPEP, bET, and ratio of bPEP/bET were calculated from an ABI-form device (VP1000) by a standard measurement.21Baseline medication, personal characteristic, and laboratory data were collected from medical records. The value of eGFR was calculated by the equation of Modification of Diet in Renal Disease study.2 and bPEP/bET < 0.38 (group 1), eGFR ≥ 45 mL/min/1.73 m2 and bPEP/bET ≥ 0.38 (group 2), eGFR < 45 mL/min/1.73 m2 and bPEP/bET < 0.38 (group 3), and eGFR < 45 mL/min/1.73 m2 and bPEP/bET ≥0.38 (group 4).12The study participants were divided into 4 groups by the values of eGFR and bPEP/bET. Patients were classified into 4 groups when their eGFR ≥ 45 mL/min/1.73 mP-value < 0.05.Statistical analysis was calculated by SPSS 18.0 . The baseline, laboratory, and echocardiographic data were presented as percentage or mean ± standard deviation. Four study groups were analyses by 1-way analysis of variance and Bonferroni post hoc test. Among study groups, group 1 was taken as reference category. Variables which were significance in univariate analysis were selected into multivariable linear and logistic analyses for determinants of LVMI and LVH, respectively. The statistical difference was considered when the 2, LVH = 69.8%), patients in group 2 , group 3 , and group 4  had a higher LVMI (P < 0.001) and higher prevalence of LVH (P ≤ 0.041). Table P = 0.001), group 3  and group 4 . Table P = 0.017), group 3 , and group 4 .A total of 990 patients were divided into 541, 236, 142, and 71 patients in groups 1, 2, 3, and 4, respectively. The differences of clinical data and echocardiographic parameters among four study groups are shown in Tables In the present study, we demonstrated that combination of eGFR and bPEP/bET were useful in risk stratification for increased LVMI and LVH. Patients in group 1 (higher eGFR and lower bPEP/bET) and patients in group 4 (lower eGFR and higher bPEP/bET) had the lowest and highest LVMI among 4 groups, respectively. In addition, compared to patients in group 1, the other groups were associated with a higher LVMI and higher prevalence of LVH in the multivariate analysis.22 showed significantly correlation between the ratio of systolic time intervals and LVMI in patients with hypertension. Our previous studies had demonstrated that bPEP/bET was a significant parameter in prediction of decreased LVEF and increased LVMI.23 The main aim of the present study was to compare LVMI and LVH among 4 groups divided by eGFR and bPEP/bET. Compared with reference group (group 1), we found patients with higher bPEP/bET and/or lower eGFR had an increased LVMI and high prevalence of LVH. These results might suggest patients with relatively normal cardiorenal function had a low LVMI and LVH, but patients with cardiorenal dysfunction had a high LVMI and LVH. Hence, classification of patients into 4 groups using eGFR and bPEP/bET might be useful in recognizing patients with increased LVMI and LVH.Boudoulas et al24 Mechanisms of cardiorenal interaction may include impaired endothelial function, anemia, systemic inflammation, increased active oxygen species or activation of adrenergic nervous system and rennin–angiotensin system.25 Pressure and volume overload are frequently noted in CKD patients, which can contribute to LVH and abnormal left ventricular function in these patients. In fact, CKD patients have a high prevalence of increased LVMI and LVH.26Cardiac and renal failure may interact each other and influence cardiac and renal outcomes.27 High arterial pressure and atherosclerotic process serve important roles in cardiac hypertrophy and its sequentially adverse cardiac events.28 Recently, several studies showed genetic factors of hypertension were associated with poor cardiovascular outcome. Lanni et al29 showed the glycoprotein IIIa protein with platelet antigen 2 (GPIIIA PlA2) isoform was increased in hypertensive patient with stroke and could serve as a genetic determinant of ischemic stroke among high risk patients. Furthermore, Santulli et al showed the GPIIIA PlA2 polymorphism was an independent predictor for cardiac death (odds ratio = 9.594) in patients with atherosclerotic coronary artery diseases.30 Some possible molecular mechanisms, including vascular endothelial dysfunction, sympathetic nervous activation, G-protein-coupled receptor kinase (GRK) expression, and calcium/calmodulin-dependent kinase (CaMK) regulation, were associated with high arterial pressure.31 The GRKs family, especially GRK2, played an important role in essential hypertension.31 In bench studies, different G-protein-coupled receptors, such as β-adrenergic receptor and angiotensin II type 1A receptor, were regulated by GRK2.33 Recently, both in vivo and in vitro studies, Sorriento and Cipolletta et al and Ersilia et al demonstrated that GRK2 mediated cardiac hypertrophy through nuclear factor-κB (NFκB) and extracellular regulated kinase pathway, respectively.35 Besides GRK2, GRK5 also regulated cardiac hypertrophy from NFκB signal transduction.36 Additionally, the family of CaMKs and their genes were associated with hypertension and cardiac hypertrophy. Santulli et al demonstrated that CaMK4 gene deletion was an important role in regulation of vascular pressure through inactivation of endothelial nitric oxide synthase.37The causes of cardiac hypertrophy were multifactors. Growth of myocardial mass was influenced by various neurohormones, growth factors, and circulatory cytokines.There were several limitations to our study. First, our study was a cross-sectional design, was performed only in 1 regional hospital and lacked follow up, which limited our study strength. Second, there was no validation of bPEP/bET in patients with atrial fibrillation and valvular heart diseases. Therefore, our results could not be applied in these patients. Finally, we did not check gene polymorphisms in our patients. Hence, the genetic consideration and molecular signal transduction about cardiac hypertrophy were lack in this study.In conclusion, separating patients into four groups using eGFR and bPEP/bET might be an alternative method in risk stratification for increased LVMI and LVH.


Blood entering the left ventricle (LV) through the left atrio-ventricular valve (LAVV) and exiting through the aorta is assumed to follow the most energy efficient pathway. In patients with a corrected atrio-ventricular septal defect (AVSD), this intra-cardiac blood flow pathway may be altered, due to the restricted opening of the LAVV. This might affect optimal LV function. Particle tracing in 4DFlow MRI data enables quantitative evaluation of the temporal distribution of blood particles in the LV. We aimed to compare the LV intra-cardiac blood flow pathway in corrected AVSD patients with that of healthy subjects, using 4DFlow MRI and particle tracing in the standard 16 segment model of the American Heart Association (AHA).Twenty five patients with a history of corrected AVSD (mean age 23 ± 10 years) and 25 healthy subjects (21 ± 11 years) were included. Whole-heart 4DFlow MRI was performed at 3T  with free breathing, three-directional velocity encoding of 150 cm/s in all, spatial resolution 2.3 × 2.3 × 3.0-4.2 mm 3 and 30 phases reconstructed over one cardiac cycle. Particles, evenly distributed within the left atrium (LA), were released at the end-systole and then followed over one cardiac cycle using forward particle tracing  project number 11626.


Despite advances in the pharmacologic and interventional treatment of coronary artery disease (CAD), atherosclerosis remains the leading cause of death in Western societies. X-ray coronary angiography has been the modality of choice for diagnosing the presence and extent of CAD. However, this technique is invasive and provides limited information on the composition of atherosclerotic plaque. Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) have emerged as promising non-invasive techniques for the clinical imaging of CAD. Hereby, CCTA allows for visualization of coronary calcification, lumen narrowing and atherosclerotic plaque composition. In this regard, data from the CONFIRM Registry recently demonstrated that both atherosclerotic plaque burden and lumen narrowing exhibit incremental value for the prediction of future cardiac events. However, due to technical limitations with CCTA, resulting in false positive or negative results in the presence of severe calcification or motion artifacts, this technique cannot entirely replace invasive angiography at the present time. CMR on the other hand, provides accurate assessment of the myocardial function due to its high spatial and temporal resolution and intrinsic blood-to-tissue contrast. Hereby, regional wall motion and perfusion abnormalities, during dobutamine or vasodilator stress, precede the development of ST-segment depression and anginal symptoms enabling the detection of functionally significant CAD. While CT generally offers better spatial resolution, the versatility of CMR can provide information on myocardial function, perfusion, and viability, all without ionizing radiation for the patients. Technical developments with these 2 non-invasive imaging tools and their current implementation in the clinical imaging of CAD will be presented and discussed herein. Despite major advances in the treatment of coronary artery disease (CAD), it still remains one of the leading causes of death in Western societies   can provide non-invasive imaging with sub-millimeter spatial resolution and high blood-to-tissue contrast  resolution for the assessment of cardiac function. The latter is almost 10-fold higher compared to competing nuclear scintigraphy techniques. Although earlier CMR studies had limitations, such as poor slice coverage and low temporal resolution, limiting the detection of CAD, subsequent data demonstrated that CMR compares favorably to SPECT for the detection of myocardial ischemia  and spatial , 86%  and of 91%  and 81% , respectively were reported Tables . In thisAn example of a patient with inducible wall motion abnormality of the anterior-septal apical wall during peak dobutamine stress CMR is illustrated in Figures p < 0.05) for the detection of obstructive CAD  in at least one myocardial segment, which persists for ≥5 consecutive image frames, is considered as indicative of inducible ischemia  is an established method for the assessment of infarct size and for the risk stratification of patients after acute myocardial infarction and with chronic ischemic heart disease . More than 10,000 have already been enrolled in this study and first results are expected in 2015.Ongoing clinical trials such as the PROMISE study now aim at comparing functional stress tests such as CMR and echocardiography with anatomical modalities such as CCTA in order to determine which might be better at finding out who has heart disease and will require more testing and treatment (Cardiac Computed Tomography Angiography (CCTA) can provide non-invasive imaging of moving coronary arteries with sub-millimeter spatial resolution and high signal-to-noise ratio. This technique has seen rapid progress in its utility for the assessment of CAD in the last years and can provide delineation of both vessel lumen and coronary vessel wall. The latter enables the assessment of atherosclerotic plaque composition, which seems to be of great importance not only for the diagnostic classification but also for the estimation of future cardiac events in patients with suspected CAD. In contrast to CMR, the administration of iodine contrast agents is necessary with CCTA for the visualization of cardiac structures and coronary arteries.In addition CCTA is associated with radiation exposure for the patients, which limits its serial applicability, particularly in younger patients  compared to those without proximal coronary stenosis. In this regard, the number of proximal segments with stenosis >50% and the number of proximal segments with mixed or calcified plaque were identified as the best predictors of outcome surpassing the value provided by standard clinical variables, including the Framingham and the Morise score. In addition, the value of risk assessment in patients with CAD using a CCTA-based semi-automated plaque assessment has been recently shown . In this regard, cardiac troponins were shown to aid the diagnostic classification and risk stratification of such patients  on the other hand, was previously proposed as a central mediator in atherosclerotic plaque development and vascular inflammation  to non-invasively visualize moving coronary vessels with high spatial resolution, excluding significant CAD with high precision and (2) to assess the composition of atherosclerotic plaque components. Its main limitation is the resultant radiation exposure for the patients, which limits its serial applicability particularly in younger patients. However, scientist, clinicians, and manufacturers managed significant reductions of radiation exposure in this field within the last 5 years. The strength of CMR on the other hand, is its ability to assess inducible wall motion abnormalities and perfusion defects during stress testing aiding the detection of functionally significant CAD. Thus, it represents the optimal technique for the risk stratification of patients with suspected CAD and for guiding revascularization procedures in patients with diagnosed CAD by CCTA or invasive angiography. Current guidelines encourage the liberal use of both CCTA and CMR as first choice modalities for the diagnostic work-up of patients with low and intermediate likelihood for CAD in experienced centers.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Free intracellular taurine and principal α-amino acids  are abundant in human heart. They are cellular regulators and their concentration can change in response to disease and cardiac insults and have been shown to differ between hypertrophic left ventricle (LV) and the relatively “normal” right ventricle (RV) in patients with aortic valve stenosis (AVS). This difference has not been shown for coronary artery disease (CAD) and there are no studies that have simultaneously compared amino acid content in LV and RV from different pathologies. In this study we investigated the effect of disease on taurine and principal amino acids in both LV and RV, measured in myocardial biopsies collected from patients with either AVS (n = 22) or CAD (n = 36). Amino acids were extracted and measured using HPLC. Intra- and inter-group analysis was performed as well as subgroup analysis focusing on gender in AVS and type 2 diabetes in CAD. LV of both groups has significantly higher levels of taurine compared to RV. This difference disappears in both diabetic CAD patients and in male AVS patients. Alanine was the only α-amino acid to be altered by diabetes. LV of female AVS patients had significantly more glutamate, aspartate and asparagine than corresponding RV, whilst no difference was seen between LV and RV in males. LV of females has higher glutamate and glutamine and less metabolic stress than LV of males. This work shows that in contrast to LV, RV responds differently to disease which can be modulated by gender and diabetes. Exclusions included patients who had undergone previous surgery, were having combined coronary and valve surgery, an emergency or salvage operation, were already participating in another clinical trial, or those with chronic renal failure requiring dialysis, current congestive heart failure or poor left ventricular function.The investigation conforms to the principles outlined in the Declaration of Helsinki. Ethical approval by the NHS Research Ethics Committee (ISRCTN84968882) as well as patient consent were obtained. Patients with coronary artery disease  were analyzed for the effect of type 2 diabetes whilst patients with aortic valve disease (included only one diabetic patient) were analyzed for the effect of gender. Patients’ characteristics are shown in Table Patients were anesthetized in the routine manner used in our institute, and then cardiopulmonary bypass was initiated. Immediately following the institution of cardiopulmonary bypass, myocardial tissue biopsy specimens were collected from the apex of LV and RV using a 14 Ga. TW’11.4 cm cannula Trucut needle . Each specimen was immediately snap frozen (less than 5 s) in liquid nitrogen and stored at -80°C until processing for amino acid extraction and quantification.Free amino acids were measured in all biopsies collected. Amino acids were determined using HPLC according to the Pico-Tag method of Water as reported earlier . Comparison between continuous variables was made using non-parametric tests for paired or unpaired samples (tested using Mann–Whitney or Wilcoxon’s signed rank). All statistical analyses mentioned were performed with the aid of a computerized software package, Statview for Windows .There was no difference in the cardiac α-amino acids, glutamate, glutamine, aspartate, asparagine and alanine between LV and RV of CAD patients Figure A-B. HoweBoth taurine and alanine were significantly lower in RV compared to LV in non-diabetic patients  . On the other hand taurine levels were similar for both left and right ventricles of male patients (~1.1). The relatively lower level of taurine in the right ventricle of female patients with aortic valve stenosis is similar to the finding for non-diabetic right ventricle of coronary artery disease patients (see above).There was no intra- or inter-disease differences in any of the principal α-amino acids Figure . Our earThere was no difference in levels of amino acids between left and right ventricles in the male patients Figure . The two+ levels as a result of the increased Na-glutamine symport activity. Glutamine is also metabolically active and acts as a nitrogen donor for the biosynthesis of a number of compounds such as nucleotides and amino acids including glutamate . This is more complicated when it comes to α-amino acids. Although it can be argued that higher glutamine, glutamate and aspartate in tissues is also beneficial, higher alanine can be considered as an indicator of increased vulnerability.The differences in amino acids between LV and RV could have implications for the extent of ischemia and reperfusion injury during open heart surgery. This of course will depend on the pathology and the amino acid in question. For example higher taurine levels in the LV of CAD non-diabetics and AVS females compared to corresponding RV suggests improved ability to cope with NaThe observed differences between the left and right ventricles of patients with either valve stenosis or coronary artery disease and between ventricles of the two pathologies clearly indicate that designing a cardio-protective strategy should take into account these differences. Myocardial protection techniques are largely aimed at preventing (reducing) the cellular changes in metabolites and ions. However, having two different ventricles with two different starting points would require a more thorough consideration of the formulation of cardioplegia. Diabetes in coronary artery disease and gender in aortic valve stenosis are important determinants or remodeling in amino acid content with potential impact on vulnerability to ischemia and reperfusion injury during open heart surgery.


Although magnetic resonance angiography is well established and deliver highly sensitive diagnosis of aneurismatic disease of aorta in patients with extensive atherosclerosis, the routine imaging of aortal wall with contrast-enhanced (CE) MRI itself is not well developed and not in routine clinical use.The patients population comprised 33 patients  with extensive atherosclerosis and old transmural acute myocardial infarction (AMI) of the left ventricle. All pts underwent cardiac CE MRI before coronary artery bypass surgery. As a control group eight patients with tumor pathology of the chest without evidence of clinically significant atherosclerosis were employed (aged 53±8 years). In addition to the CE MRI of the heart, the CE MRI of atherosclerotic lesions of the aorta was carried out. Before and in 15-20 minutes after the injection of paramagnetic contrast agent T1-weighted spin-echo images  were acquired. Geometric diameter and wall thickness of the aorta at the level of uptaken of contrast-paramagnetic agent to the wall, and index of enhancement (IE) were also measured.In the control group no significant accumulation of contrast paramagnetic material in the aortic wall was observed, IE did not exceed 1.04(mean 1.01±0.06), the diameter and the wall thickness at the accumulation of contrast are 2.1±0.24 cm and 0.34±0.05 cm, respectively. In 25 (76%) patients with extensive atherosclerosis and old AMI, IE of the atherosclerotic lesions in the aortic wall in all cases was over 1.14 (mean 1.17±0.13), far the over increase of intensity in the control group. In eight patients (24%) the lack of accumulation of contrast-paramagnetic material in the aortic wall was observed. Accumulation types of contrast paramagnetic were assigned to a local (Figure MRI CE technique of atherosclerotic lesions of the aorta can be suggested as additional independent research technique in atherosclerosis prospective studies of both surgical and medical methods of anti-atherosclerotic therapy. At the moment a study of the risk of delamination, aneurysmal rupture of atherosclerotic lesions is in progress, aimed at developing additional criteria to their surgical management.


The assumption of the presence of diffuse myocardial fibrosis in long standing cyanotic congenital heart disease (CHD) inspired us to noninvasively determine the myocardial extracellular volume (ECV) using contrast CMR (T1 mapping).T1 maps were measured pre and 3-10 minutes after the infusion of 0.15 mmol/kg of gadolinium on 25 subjects. Seven adult patients with longstanding cyanotic CHD and no previous surgical history (aged 16-53 yrs and oxygen saturations of 69-90%), nine normal subjects (aged 14-49 yrs), and nine patients with previously cyanotic CHD after total repair during which a heart lung machine was used (aged 2 months-58 yrs). Images were obtained in a mid-ventricular short axis plane. Late gadolinium enhancement using the phase sensitive inversion recovery (PSIR) sequence was performed to exclude scar areas. The T1 values were measured in two areas of the myocardium, in the septum and in the left ventricular posterior or inferior wall, such that same areas were assessed in every patient in the pre and post contrast T1 scan. ECV was calculated according to (1-hematocrit)*(ΔR1 myocardium/ΔR1 blood).Patients with cyanosis had significantly lower ECV percentage than the previously cyanotic patients after total repair . No significant differences were found between patients with cyanosis and normal controls . ECV values were significantly different between the three groups in both septum and LV wall .Long standing cyanosis in congenital heart disease without cardiac surgery does not cause diffuse myocardial fibrosis or expansion of the myocardial extra cellular volume.All authors have no conflict of interest.


The aim of this study is to assess the accuracy and feasibility of left ventricular systolic function determined by four-dimensional echocardiography (4DE).Latex balloons were sewn into the left ventricle (LV) of 20 freshly harvested pig hearts which were then passively driven by a pulsatile pump apparatus. Global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS) and left ventricular ejection fraction (LVEF) derived from 4DEand two-dimensional echocardiography (2DE)-derived LVEF were quantified at different stroke volumes (SV) 30–70 ml and correlated with sonomicrometry data.In all comparisons, GLS, GCS, GAS, 2DE-LVEF, and 4DE-LVEF demonstrated strong correlations with sonomicrometry data . Bland-Altman analyses showed slight overestimations of echo-derived GLS, GCS, 2DE-LVEF and 3DE-LVEF over sonomicrometry values . Furthermore, there is better agreement between GCS, 4D LVEF and sonomicrometry values compared with GLS and 2D LVEF.Four-dimensional echocardiography accurately assesses LV function. GCS derived by 4DE is a potential alternative parameter to quantify LV systolic function. Left ventricular (LV) systolic function is an important predictor of cardiac mortality and morbidity and often is used to select patients for surgical and pharmacological treatment ,2. LV ejStrain is a useful index for determining LV regional and global systolic function in research and clinical settings. Two-dimensional (2D) speckle-tracking echocardiography (STE), a novel technique to quantify the complex cardiac motion based on frame-to-frame tracking of acoustic speckles in grayscale 2D images, has been shown to be superior to LVEF in the quantification of LV segmental wall motion and LV global function. However, 2D STE is limited by its geometric assumptions, while myocardial mechanics of LV function are complex, involving multidirectional axes of motion. 2D STE is unable to quantify one of the three components of the local displacement vectors. The newly developed 3D speckle tracking program is the most direct and simple way of acquiring 4D cardiac data. 4DE overcomes the 2D limitations because it allows the acquisition of a full 3D volumetric data set with simultaneous evaluation of multidirectional wall motion. Yu et al  demonstrPrevious studies demonstrated the improved accuracy and reproducibility of LV functional quantification using real time three-dimensional echocardiography (RT3DE) or 4DE compared to those generated via 2D acquisition –11. RT3DThe Toshiba Aplio Artida ultrasound system with a matrix array PST-25SX 2.5 MHz transducer is capable of acquiring 4D volumes, and offline analysis software allows analysis of 4DE datasets to provide quantification of strain and LVEF. The aim of our study was to validate 4D echocardiography as an alternative quantifier of LV function by comparing the accuracy of three different components of global strain: global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS) and LVEF with sonomicrometry values as a gold standard. Area strain is a relatively new parameter, which integrates both longitudinal and circumferential deformation, and is suggested as a sensitive and reproducible parameter to detect early and subtle LV systolic dysfunction, showing greater feasibility than other conventional strain parameters .A closed-circuit pulsatile harvested pig heart model was designed for this study. Pig hearts were purchased from Carlton Farms , which processes pork for commercial sale and is licensed to provide organs for in vitro research. OHSU does not require IACUC approval for in vitro projects.A latex balloon was sewn into the mitral valve annulus of the LV in twenty freshly harvested pig hearts with atria and major vessels removed. The aortic outlet was sutured closed to prevent the inflated balloon from exiting the LV. The base of the heart was mounted on a plastic ring to minimize global movement during the simulated cardiac cycle while remaining outside of the imaging window to reduce artifacts. A calibrated pulsatile pump  was connected using two plastic tubes to a Y-shape connector, which was connected to a latex balloon. The balloon was filled with water until the passive resistance of the LV cardiac muscle was sufficient to oppose the gravitation force of the water before all of the air bubbles were removed. This apparatus and a transducer were fixed inside a water tank. The distance between LV apex and the transducer was adjusted to obtain the best image quality. The pump defined stroke volume (SV) ranged from 30 to 70 ml.Four sonomicrometry crystals were sewn into the myocardium through the epicardium. Crystals 1 and 2 were placed in the base of LV anterior wall and in the apex of LV, respectively. Crystals 1–2 were longitudinally oriented along the long axis of the LV to determine longitudinal strain (LS) and long axis dimensions. Crystals 3 and 4 were sewed at the middle of LV interventricular septum and lateral wall. Crystals 3–4 were perpendicular to the line of crystals 1–2 to calculate circumferential strain (CS) and short axis dimensions.LV = (π/6) ·Dlong·Dshort·Dshort, . Ejection Fraction (EF) was calculated from the difference between the maximum LV volume (EDV) and the minimum LV volume (ESV), using formula: [(EDV—ESV) / EDV] x 100 = EF (%).Signals from the sonomicrometry crystals were acquired using SonoSoft software  as a reference standard for EF and echo-derived stain. The LV volumes were calculated as a modified ellipsoid model with the use of the following formula VFull 4D volumes were acquired with Toshiba Aplio Artida ultrasound system  with a matrix array PST-25SX 2.5 MHz transducer. Gain was determined for the best endocardial border definition. Depth and scanning angle were adjusted to include the entire LV and maximize temporal resolution. In this study, SV ranged from 30 to 70 mL at an increment of 10 mL with a constant end-systolic volume maintained.Full 4D images were analyzed by a three-dimensional speckle tracking program in which the endocardial and epicardial border can be automatically generated and then manually adjusted to refine the tracing at the following five views: (1) the apical four-chamber view; (2) the apical two chamber view and the three short-axis views; (3) the apex of the LV; (4) the midlevel of the LV; and (5) the basal level of the LV. Thus, the software was able to perform all deformation parameters including global longitudinal strain (GLS), global area strain (GAS), and global CS (GCS) throughout the entire cardiac cycle. Meanwhile, left ventricular ejection fractions (LVEF) were observed automatically .To test intraobserver reproducibility, a single observer analyzed the data twice on occasions separated by an interval of 1 month for the measurement of GLS, GCS, GAS and LVEF from 4DE and sonomicrometry in 10 subjects. To test interobserver variability, a second observer analyzed the data in 10 subjects without knowledge of the first observer’s measurements.All statistical analyses were performed using SPSS version 16.0software . Linear regression analysis was applied between strain values derived by 3D speckle tracking program and different SV. Pearson’s correlation analysis was performed between sonomicrometry data and echo-strain values, and also applied between sonomicrometry data and LVEF derived by 2D and 4D echocardiography. The agreements of sonomicrometry data against strain value and LVEF derived by 2D and 4D echocardiography were assessed by Bland-Altman analysis. Intra-observer variability and inter-observer reliability was assessed using the intraclass correlation coefficient (ICC) along with absolute differences, expressed as the mean percentages error.Linear regression analysis and Bland-Altman analysis showed excellent correlations and strong agreements between 2D LVEF, 4D LVEF and EF derived by sonomicrometry data. Furthermore, the correlation coefficient between 4D LVEF and sonomicrometry demonstrated better linear correlation than that of 2D LVEF and sonomicrometry data . Bland-Altman analysis also displayed higher overestimation of 2D LVEF (3.37) than 3D LVEF (2.78) when compared with sonomicrometry .Strain values from 4DE and sonomicrometry data also demonstrated good correlations. The strongest correlate for EF obtained by sonomicrometry was with 3D GCS . The correlation result for 3D GAS was r = 0.79, P< 0.001. The weakest correlation for EF was with 3D GLS . Strong 3D GLS, GCS and GAS derived by 3D speckle tracking program continuously increased with the increment of SV. Linear regression analysis indicated the highest regression coefficient appeared between 3D GCS and SV  . GLS wasGood reproducibility was shown for both intraobserver and interobserver reliability , with ICAccurate quantification of LV systolic function has important prognostic implications and is helpful to determine treatment decisions for a variety of therapies. 2D LVEF is the most commonly used echocardiographic parameter to evaluate the LV function in clinical practice. However, measurement of LVEF is limited by geometric structure, image quality, load dependence and poor reproducibility . Therefo2D STE has been validated by cardiac MRI and 3D echocardiography as an effective method to assess LV function . Many pr4D echocardiographic techniques including real-time 3D speckle tracking program and 3D echocardiography allow volumetric analysis and simultaneous measurement of multidirectional components of strain in a single data set. The acquisition of the entire LV within a single data set allows global assessment of LV longitudinal, circumferential and radial functions across all myocardial segments. Zhu et al  demonstrdistance between piezoelectric crystals based on the speed of acoustic signals through the medium they are embedded in. An electrical signal sent to either crystal will be transformed in to sound, which passes through the medium, eventually reaching the other crystal, which converts the sound into electricity, detected by a receiver. From the time taken for sound to move between the crystals and the speed of sound in the medium, the distance between them was calculated. Sonomicrometry is a well-established technique to study pressure-volume loops in animals. They are most commonly implanted within cardiac muscle tissue to track changes in distance and to estimate left ventricular volume according to a geometric algorithm. Several studies have documented accuracy of this method of studying LV volumes [In previously published literature, there is strong correlation between LVEF and volumetric assessment obtained by 3D STE and magnetic resonance imaging (MRI) . Jenkins volumes ,11,30–33 volumes . This stOur results showed GLS, GCS, and GAS from 4DE increased by the increment of SV (30ml to 70ml). In other words, GLS, GCS, and GAS could increase by the increment of LVEF. And they were all correlated well with LVEF obtained by the gold standard of sonomicrometry. Especially, there was a stronger correlation between GCS and LVEF than GLS and GCS. Therefore, GCS is an alternative parameter to quantify LV systolic function. It is postulated that circumferential fibers play a more important role in LV myocardial function than that of longitudinal fibers because circumferential fibers, which are over longitudinal fibers within the myocardial wall, exist in greater proportion in the basal segments compared with the apex. This result was similar as a study by Luis et al , which dThe results in this study also showed strong agreement between strain values and sonomicrometry strain data and there was better agreement between GCS and sonomicrometry than between GLS and sonomicrometry. Seo et al  assessedIn our results, Bland-Altman analyses demonstrated a slight overestimation between 3D strain values and sonomicrometry strain data, which is similar to our previous studies ,11. The Although the harvested pig heart model could model the unique imaging properties of cardiac tissue at a similar size to the human heart, the model itself is not a perfect replica in terms of chamber shape, contractility, and cardiac mechanics. The limitation of 4DE is related to the relative low temporal resolution, which is still inferior to that of 2DE. Technological advances increasing the temporal resolution of 4DE would improve the accuracy of LV quantification.A recent study demonstrated the strain parameters follow a shape function correlation to EF, not necessarily linear , which w4DE is a feasible modality that has the ability to accurately assess the LVEF and multidirectional components of strain of the LV.GCS derived by 4DE is a potential alternative marker to quantify LV systolic function.