The complex cardiac fiber structural organization and spatial arrangement of cardiomyocytes in laminar sheetlets contributes greatly to cardiac functional and contractile ejection patterns. This study presents the first comprehensive, ultra-high resolution, fully quantitative statistical tensor map of the fixed murine heart at isotropic resolution of 43 μm using diffusion tensor (DT) cardiovascular magnetic resonance (CMR).Imaging was completed in approximately 12 hours using a six-directional encoding scheme, in five ex vivo healthy C57BL/6 mouse hearts. The tensor map constructed from this data provides an average description of the murine fiber architecture visualized with fiber tractography, and its population variability, using the latest advances in image tensor analysis and statistics.−4 mm2/s. Moreover, average mid-ventricular helical angle distributions ranged between –41 ± 3° and +52 ± 5° and were highly correlated with transmural depth, in agreement with prior published results in humans and canines. Calculated variabilities of local myocyte orientations were 2.0° and 1.4°. Laminar sheet orientation variability was found to be less stable at 2.6°. Despite such variations, the murine heart seems to be highly structured, particularly when compared to canines and humans.Results show that non-normalized cardiac tensor maps are associated with mean fractional anisotropy of 0.25 ± 0.07 and mean diffusivity of 8.9 ± 1.6 × 10This tensor map has the potential to yield an accurate mean representation and identification of common or unique features of the cardiac myocyte architecture, to establish a baseline standard reference of DTI indices, and to improve detection of biomarkers, especially in pathological states or post-transgenetic modifications. The unique myocardial architecture, comprised of laminar sheetlets with spatially varying orientation -3 and heThe inherent cardiac tissue structural-functional associations also underline the potential significance of myocyte diffusion tensor CMR (DTCMR) tractography -11 in reWhile in vivo cardiac DTCMR tractography is still in the early stages of development for widespread pre-clinical  or cliniHistorically, some earlier studies validated the direct correlation of myocyte eigenvector orientations with conventional invasive histology, despite scale differences, in freshly excised , perfuseNevertheless, to date, no previous studies have presented a comprehensive, high-resolution, quantitative eigenvector orientation tensor map of the ex vivo murine heart. Additionally, only one prior study  targetedThis study employs 3D, microscopic, spin-echo, diffusion-weighted CMR ,37 to coThis tensor map will be useful in its potential to a) characterize electro-mechanical function, reflecting an unbiased mean of a test population, serving as a deformable template, and providing tensor-based normalization of study subjects/species; b) yield an accurate mean representation and identify common or unique features of myofiber architecture, c) establish a baseline standard reference of DTI indices, and d) improve the detection of FA, MD, and HA biomarkers, particularly in pathological states.http://www.civm.duhs.duke.edu/cardiacMRdiffusion2014 and at http://lbi-cy.com/?page_id=80.To the best of our knowledge, this is the first murine distributed eigenvector orientation map constructed at ultra-high resolution , in accordance with the American Physiological Society’s Guiding Principles for the Care and Use of Animals, European Animal Research directives, and International Guidelines for Animal Research.1 of cardiac tissue, thus allowing for short TR imaging with near complete T1 recovery between pulses. A 1.3% agarose/PBS solution was prepared and set aside. With the internal jugular venous cannula secured in place, a midline abdominal incision was made to expose the peritoneal cavity. The diaphragm was then carefully incised, dissected away from the cardiac apex, and removed. The descending thoracic aorta and inferior vena cava were exposed and isolated. The anesthetized, ventilated animals were then perfused with approximately 50 mL 0.9% NaCl over a period of 5 minutes. When perfusion began, the inferior vena cava (IVC) and descending thoracic aorta were incised at the level of diaphragmatic hiatus, allowing blood to rapidly clear from the thorax, upper extremities, and head. At the end of 5 minutes, the saline reservoir was exchanged for a 10% ProHance/formalin solution, and the animals were perfused with this solution for an additional 5 minutes, allowing for rapid fixation of the myocardium. Once perfusion fixation was complete, the animals were perfused with a heated 1.3% liquid agarose solution. Heating the solution decreases viscosity such that the solution crosses the pulmonary capillary bed and enters the left side of the heart. The animals were perfused until the gel solution could be seen emanating from the transected descending thoracic aorta. At this point, the infusion pump was switched off, and the aorta and the IVC were clamped to prevent outflow of liquid agarose from the heart. The liquid was then allowed to cool and form a semi-solid gel within the cardiac chambers, preserving anatomic atrial and ventricular shape and preventing chamber collapse. The heart was then carefully excised by transecting the great vessels and pulmonary veins, with attention to maintaining the integrity of the right and left atrial walls. The excised hearts were immersed in Fomblin® (perfluoro-polyether)  and immobilized in a specialized MR-compatible specimen tube.Male C57BL/6 mice  were anesthetized via injection of intra-peritoneal ketamine/xylazine. Endotracheal intubation was performed with trans-tracheal illumination using a 22 G angio-catheter as endotracheal tube. Mice were then maintained under general anesthesia using 1.5% isoflurane in mixed gas, delivered via a custom rodent ventilator with a tidal volume of 100 μL at a rate of 110 breaths per minute. The right internal jugular vein was surgically isolated and cannulated with a flexible catheter connected to a pre-calibrated infusion pump, loaded with both normal saline and saline mixed in 10% ProHance /formalin solutions. ProHance is a gadolinium chelate that significantly reduces T0 and six diffusion weighted image stacks were acquired  with an empirically chosen b value of 1852 s/mm2. Other imaging parameters were: Bandwidth = 62.5 kHz, FOV = 11 × 11 × 11 mm3 full-Fourier encoding, one average, single echo. All specimens were scanned in a 12 × 25 mm2 (diameter × length) solenoid radiofrequency coil.Imaging was performed at the Duke Center of In Vivo Microscopy  on a 9.4 T vertical-bore Oxford magnet equipped with a gradient system able to achieve peak values of 2000 mT/m. A 3D DW-SE pulse sequence was used to scan the samples with TE (11.8 ms) and TR (100 ms). The acquisition matrix was 256x256x256, resulting in an isotropic voxel size of 43 μm. Diffusion was encoded using a pair of half sinusoidal gradient lobes of 1600 mT/m in amplitude, 1.3 ms in width, and 6.8 ms in separation. One bEstimation-Registrations of Diffusion Tensors: The diffusion weighted MR images were imported into the Diffusion Toolkit  along with the corresponding gradient table and b–value, and the diffusion tensors for each dataset were calculated  . Additionally, ANOVA results indicate no significant variability for FA and MD in all myocardial areas, in justification of homogeneity of distribution of reported values. Such findings demonstrate that diffusion properties are similar among the normal population of studied mice.θ1,3 and σθ1,2; σθ2,3 reports the laminar structure variability. Specifically, the standard deviations exemplifying variability of rotational differences of eigenvector pairs with the third orthonormal , 1.4° , 2.6° , respectively. Local myocyte orientation variability has also been traditionally analyzed by the transmural distribution of the HA. These are reported to range between −57° and +60° with typical sectorial transmural trajectories depicted on Figure Diffusion orientation is associated with differing variability along each of the three principle directions, manifested as a measure of diffusional coherence along the three orthonormal directions ,24,27. LSignificant and extensive evidence from previous work -3 supporThe importance of quantitative DTCMR microscopy atlases and maps to the study of cardiac structure and function has been defined previously . NeverthFor these reasons, this population-based tensor map defines a crucial juncture in achieving our long-term goal of establishing a common reference for future phenotypic studies. The tensor map can be used in several ways to help identify  common local murine myocyte architectural features and population-based variabilities for quantitative  comparisons, in both pathologic and transgenetic states. Additionally, it can serve as a template reference for inter- and intra-species comparisons, addressing questions about structural-functional conservation and embryonic-adult development.Ventricular myofiber geometry and orientations were initially studied based on histological reconstructions pioneered by Nielsen et al. , with a While limited success has been evidenced thus far in in vivo animal  and humaBasic geometric LV measurements reported in this study also dismiss possible formalin-based fixation effects. They also support consistency in inducing fixation at the end-diastolic conformational state. Additionally, the adopted six-directional encoding scheme is in compliance with the realm of a proper acquisition -54, yielMethodologically the adopted data registration schemes, based on LDDMM techniques , allow p3/λ2 distributions highly agree with prior canine [λi values  are by far smaller and less variable than canine . Of course, care must be exercised in interpreting differences between human, canine, and murine data , given the disparity of acquired resolutions, field-of-views and the relative cardiac scale sizes of the three species. Regardless, in both human and canine species the pattern seems to be conserved, with the primary eigenvalue exhibiting lesser variability compared to λ2 and λ3. It is highly likely that the primary source of observed increased variability of λ2 and λ3 is attributed to the intrinsically lower signal associated with the respective diffusional processes.Similarly, patterns of eigenvalue and λr canine  and humar canine ,24 atlas3 and v2, respectively) are reported to be 2.0° and 1.4°, respectively, in comparison to 7.9° /7.7° and 13.0° /11.5° in canine and humans [Global tensor variability of 4.98 ± 1.6% compares well with reported values of 10% and 13.2% in canine  and humad humans ,24,27.2 and v3 orientation about v1) seems to be less stable at 2.6°. Such pattern is in agreement with findings in canine and humans, in support of the loosely organized laminar sheetlet structure. Nevertheless, the murine heart seems to be highly structured and stable, exceedingly so when compared to the canine (22.7°) and humans (31.1°). The smaller global tensor variabilities observed in the mouse may be physiologic, with the small-sized murine heart having evolved a less variable structure (compared to other species), but also may likely be attributed in part to the high-resolution of the acquired data. At an isotropic resolution of 43 μm3, and a typical cardiac myocyte phenotype of column-shaped cells of approximately 50–150 μm in length and approximately 20 μm in width, imaging is representative of only very few cells.Laminar sheetlet orientation variability  for HA, FA and MD are shown on Table Additionally, the HA distribution of local myocyte orientation has been studied and quantified across myocardial segments. Both the sectorial pattern of transmural helical angles (HA) range and absolute values match those of Healy et al. , as wellSheetlet dominance is confirmed at mean angles values of 62.7 (±11.8) ° and 99.5 (±11.9) °, in comparison to reports by Helm et al.  reportinQuantitative murine myocardial tractography at an isotropic resolution of 43-μm of the ex-vivo heart was accomplished in approximately 12 hours of data acquisition, sensitized to 6 diffusional directions. Fiber tractography yielded local myocyte orientation maps associated with mean fractional anisotropy (FA) of 0.25 and mean mid-ventricular HA distributions that ranged between −41° – +52°, in agreement with prior published results in humans and canines. This mouse statistical tensor map is the first of its kind in that it quantitatively estimates both normalized and non-normalized diffusion biomarkers. We believe that the tensor map will be of value in the process of phenotyping pathological and transgenetic cardiac states.CMR: Cardiovascular magnetic resonanceDTI: Diffusion tensor imagingFractional anisotropy (FA): Scalar value between zero and one that describes the degree of anisotropy of a diffusion process . A value of zero means that diffusion is isotropic, i.e. it is unrestricted  in all directions. A value of one means that diffusion occurs only along one axis and it is fully restricted along all other directions.Helix  angle (HA): The angle of obliquity of the principal eigenvector relative to the local short axis plane or relative to local circumferential direction, if necessary, projected radially onto the local wall tangent plane. Positive and negative values can be used for clockwise or anticlockwise rotation, for example as viewed from the lumen outward.Intersection angle: The angle formed between the local wall plane unit normal : The trace of the diffusion tensor; it is a scalar measure of the total diffusion within a voxel.Myocyte: Basic contractual cell unit of myocardium composed of (among others) myofibers, serially connected sarcomeres via gap-junctions.Shear layers: Fissures or interstices between adjacent sheetlets. They are thought to allow adjacent sheetlets to change imbrigation angle and shear relative to one another during contractile function.Sheetlet: Aggregate arrangements of a few cardiac myocytes in planes having microscopic thicknesses and limited spatial extent.Tractography: Visualization of distributed eigenvector orientations by plotting virtual tracts that, at all points along them, are aligned with local eigenvectors.Transmural angle: The angle of transmural obliquity, for example of the 2nd eigenvector of diffusion  relative to the local wall tangent plane, measured in the plane perpendicular to the 1st eigenvector direction .


In non-cardioembolic stroke patients, the cardiac manifestations of high blood pressure are of particular interest. Emerging data suggest that echocardiographically determined left ventricular hypertrophy is independently associated with risk of ischemic stroke.The primary objective of this study was to evaluate the frequency of different patterns of left ventricular (LV) remodeling and hypertrophy in a group of consecutive patients admitted with non-cardioembolic stroke or transient ischemic attack (TIA). In particular, we were interested in how often the relative wall thickness (RWT) was abnormal in patients with normal LV mass index (LVMI). As both abnormal RWT and LVMI indicate altered LV remodeling, the secondary objective of this research was to study whether a significant number of patients would be missing the diagnosis of LV remodeling if the RWT is not measured.All patients were referred within 48 hours after a stroke or a TIA for a clinically indicated transthoracic echocardiogram. The echocardiographic findings of consecutive patients with non-cardioembolic stroke or TIA were analyzed.P < 0.05).All necessary measurements were performed in 368 patients, who were enrolled in the study. Mean age was 63.7 ± 12.5 years, 64.4% men. Concentric remodeling carried the highest frequency, 49.2%, followed by concentric hypertrophy, 30.7%, normal pattern, 15.5%, and eccentric hypertrophy, 4.1%. The frequency of abnormal left ventricular RWT (80.4%) was significantly higher than that of abnormal LVMI (35.3%), (McNemar In this group of non-cardioembolic stroke patients, abnormal LV remodeling as assessed by relative wall thickness is very frequent. As RWT was often found without increased LV mass, the abnormal left ventricular geometry may be missed if RWT is not measured or reported. In further studies, echocardiographically detected left ventricular hypertrophy is defined to be independently associated with risk of ischemic stroke.9Arterial hypertension is one of the major risk factors for stroke. In up to 70% of patients admitted with a stroke, arterial hypertension is found.10 include a series of measurements for assessment of LV adaptation to arterial hypertension. Using measurements of LV wall thickness and LV diameter, the 3 forms of LV response to high blood pressure can be found as: concentric remodeling , concentric hypertrophy , and eccentric LV hypertrophy . This classification may provide incremental value beyond ventricular mass for further cardiovascular risk stratification.14The recommendations for chamber quantification of the American Society of Echocardiography (ASE), developed in conjunction with the European Association of Echocardiography (EAE)15Measurement of LV mass has been widely used to assess cardiac organ damage by arterial hypertension. However, cardiac damage can already be present in patients with normal LV mass. Concentric remodeling as detected by abnormal RWT but normal LV mass is an early form of cardiac adaptation to high blood pressure.16The risk of death or the composite end point of death from cardiovascular causes, reinfarction, heart failure, and stroke is lowest for patients with normal geometry, and gradually increases with concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Increased risk associated with RWT is independent of LVMI.17 In that work, it has been shown that assessment of LV mass and RWT should be included in stroke risk evaluation.There is evidence suggesting the LV geometric patterns as risk for stroke in an ethnically mixed population.The primary objective of this study was to evaluate the frequency of different patterns of left ventricular (LV) remodeling and hypertrophy in a group of consecutive patients admitted with non-cardioembolic stroke or transient ischemic attack (TIA). In particular, we were interested in how often the relative wall thickness (RWT) was abnormal in patients with normal LVMI. As both abnormal RWT and LVMI indicate altered LV geometry, the secondary objective of this research was to assess whether a significant number of patients would be missing the diagnosis of LV remodeling if the RWT is not measured or reported.The data were drawn from an audit on stroke/TIA patients at the Jeddah Heart Institute where the echocardiographic examinations are routine diagnostic measures in all patients admitted to the hospital with stroke or TIA. From 2005 to 2010, the echocardiographic findings of consecutive patients were included in a database. All patients were referred from the Department of Neurology of the Erfan&Bagedo Hospital within 48 hours after a stroke or a TIA for a clinically indicated transthoracic echocardiogram. The data were analyzed in collaboration with the Mazankowski Alberta Heart Institute. The study protocol was approved by the Jeddah Heart Institute Health Research Ethics Committee.Patients found clinically, by history or echocardiography, to have associated findings that may lead to a cardioembolic stroke including mitral stenosis, aortic stenosis, or any possible aortic source of emboli congenital heart disease, current or history of Atrial Fibrillation, and patients known to have Chronic Obstructive Pulmonary Disease .Patients who were found on computed tomography (CT) or magnetic resonance imaging (MRI) to have multiple infarcts, as this was likely to be an embolic event, even though the source could not be ascertained.Patients who had ischemic cardiac events, for example, myocardial infarction (MI) or Coronary Artery Bypass Graft surgery, as an embolic source cannot be ruled out and because the formulae used for LVMI or RWT assessment would not apply due to the lack of homogeneity of wall thickness .Patients with suboptimal acoustic windows or technically limited parasternal windows, which made echocardiographic measurements unreliable.Patients with hemorrhagic stroke.19 Diabetes mellitus (DM) was diagnosed as abnormal fasting glucose results, history of the disease, or presence of appropriate treatment.20 Obesity was defined according to WHO criteria as a body mass index21 >30 kg/m2. Serum cholesterol levels and smoking were not included into the database, as they were reported to have no impact on LV hypertrophy.22The diagnosis of TIA was made clinically as acute focal neurological deficits highly suspected by the experienced neurologist to be of vascular origin or caused by brain ischemia and resolved within 24 hours. Those patients should have either a normal brain imaging or no lesion, which could be a potential cause for the neurological symptoms. The stroke was defined clinically and confirmed by imaging. The initial brain CT was performed in all patients. In the majority of acute stroke patients, with no initial CT changes, the diagnosis was confirmed either by diffusion-weighted MRI or by repeat CT after 24 hours from time of symptoms onset. By chart review and history, all patients were reviewed for the presence of the traditional stroke risk factors: hypertension, diabetes mellitus, and obesity. The diagnosis of arterial hypertension was based on patients’ medical history, presence of treatment or blood pressure ≥140/90 mmHg.10 In end diastole, the septum wall thickness (SWTd), posterior LV wall thickness (PWTd), and the diameter of the left ventricle (LVIDd) were measured on the 2D echo recordings.Transthoracic echocardiography was performed within 48 hours after stroke or TIA using HDI 5000 ultrasound , equipped with 3 MHz transducer. Parasternal and apical 2-dimensional echocardiograms (2D) were acquired according to the ASE/EAE recommendations.LVMI was calculated using the following equations:3 – [LVID]3) + 0.6 gLV mass = 0.8  ≤0.422LVMI  <115 g/m2LVMI  <95 g/m13 Four different groups were defined: elevated RWT with increased LVMI identified as concentric hypertrophy, elevated RWT with normal LVMI as concentric remodeling, normal RWT with increased LVMI as eccentric remodeling, and normal geometry.The geometric changes of the left ventricle were classified based on left ventricular mass index and relative wall thickness.R statistic = 0.8 .All echocardiograms were performed and analyzed by an experienced cardiologist. An off-site read of randomly selected echocardiographic readings was performed at the Mazankowski Alberta Heart Institute. The reproducibility of RWT measurements was assessed in 15 randomly selected patients using interclass correlation coefficient, Data were stored and analyzed by IBM-SPSS  statistical software. The frequency of different types of LV wall abnormality was assessed using the descriptive statistics. To assess the association of the risk factors with LV remodeling, the Generalized Linear Models have been employed. The significance of the difference between abnormal RWT and LVMI was assessed using McNemar test.A total of 870 patients with stroke and TIA underwent transthoracic echocardiography in the period from January 2005 to July 2010. Four hundred ninety-one (491) of them were likely to have cardioembolic mechanism of stroke or TIA or other exclusion criteria, including old MI. Three hundred seventy-nine (379) subjects matched the inclusion and exclusion criteria. Eleven patients had suboptimal echo windows. All necessary measurements were performed in 368 patients, who were enrolled in the study. The study subjects were of a multiethnic cohort in whom Arab ethnicity was 52.4%. The rest were of North African, African, Central Asian, Indian, or Far East origins. Mean age was 63.7 ± 12.5 (SD). The sex distribution was as follows: 237 males (64.4%) and 131 females.02 (35.6%) patients.The frequencies of risk factors and abnormal RWT and LVMI based on sex distribution are presented in Table The frequencies of different patterns of LV remodeling are distributed as follows: concentric remodeling carried the highest frequency 49.2%), followed by concentric hypertrophy (30.7%), normal pattern (15.5%), and eccentric hypertrophy (4.1%). The effects of main risk factors on different types of LV remodeling are presented in Table %, followP < 0.05  was independently associated with diabetes in men, and concentric hypertrophy was associated with hypertension in women. The eccentric hypertrophy is not included in the table due to very small sample size (15 patients).23The message of our study is that LV remodeling as assessed by abnormal RWT has a significantly higher frequency than increased LVMI in non-cardioembolic stroke patients and indicates abnormal LV geometry expressed by concentric remodeling. When physicians look for cardiac remodeling, they tend to concentrate on LV mass and often neglect RWT. However, abnormal RWT was often found with normal LV mass. Abnormal RWT combined with normal LV mass (concentric remodeling) is clinically relevant, for example, in patients who present with borderline hypertension, elevated blood pressure only at the admission, and/or no known history of arterial hypertension. In these patients, antihypertensive treatment needs to be considered.16 concluded that in hypertensive subjects with DM type 2, echocardiographic RWT is a predictor of cardiovascular events independent of LVMI and other confounders.In Di Tullio's study, abnormal RWT significantly increased the stroke risk and no interaction was detected between RWT and LVMI with regard to stroke risk. In their study, Eguchi et al27 LV mass has been regarded as the best measure of LV hypertrophy and is used in many studies using echocardiography or MRI. Echocardiography is more frequently used in larger studies on hypertension because of its lower costs, but the reproducibility of echocardiographic measurements of LV mass is limited.30 Although LVMI calculation is performed using the same linear measurements as RWT, small errors in measurements have a high impact on the calculation as the equation uses squared values. In addition, as the LV diameter depends on the body mass, RWT appears to be a useful simple measurement to assess LV hypertrophy in patients with different body conditions and should not be neglected. It represents a ratio, unlike LVMI which is an absolute value; RWT may thus be less vulnerable to variability related to weight and height.LVMI has been widely used to assess LV hypertrophy as a consequence of arterial hypertension and reported as an independent risk factor for ischemic stroke.The isolated finding of abnormal RWT indicates LV remodeling, which is an early feature of hypertensive heart disease. Because of the significantly higher frequency of abnormal RWT in this study, it is important that physicians who look after patients with stroke pay attention to this value on the echocardiography reports. The detection of cardiac abnormalities such as remodeling during the acute stroke phase may result in additional diagnostics for assessment of hypertension. This is particularly important when the blood pressure is normal during admission or when the patient has no history of hypertension. In patients with elevated blood pressure, the finding of LV remodeling makes the diagnosis of chronic hypertension more likely than accidental (hypertension related to the admission). Therefore, considering RWT for medical treatment is likely to result in better care of patients. Considering the high frequency of abnormal RWT with normal LV mass in the reported group of stroke patients, outcome studies are warranted to answer the question whether patients with abnormal RWT would benefit from medical treatment as patients with increased LV mass do.31 and vary substantially. Therefore, comparison with other studies is limited.The study was conducted with emphasis on echocardiographic features of non-cardioembolic stroke patients and mainly designed to analyze the prevalence of RWT in this group. Echocardiographic criteria used to define LV hypertrophy in available studies are not uniform32 So, this shortcoming could not be avoided in our study and the reader should consider that a proportion of our study group may represent mimics.It is well known that the diagnosis of TIA is purely clinical. There is a poor agreement even between the stroke specialists in differentiating TIAs from mimics.In this group of consecutive patients with non-cardioembolic stroke, abnormal LV geometry as assessed by RWT is very frequent. As abnormal RWT was often found with normal LVMI, abnormal left ventricular geometry may be missed if RWT is not measured or reported.


However, inappropriate use of landiolol  may iatrogenically further complicate pathophysiology, and relatively higher doses of landiolol may be dangerous. We recommend that landiolol should not be routinely used to control cardiovascular responses during bronchoscopic endotracheal suctioning in the intensive care unit. Careful evaluation of factors influencing hemodynamic changes and close monitoring of the patient are mandatory following landiolol administration. Furthermore, a lower initiation dose is recommended.Supplemental landiolol administration (20 or 40 μg kg Landiolol reduces hemodynamic responses to bronchoscopy-assisted suctioning in intubated ICU patients by Tochikubo et al. with great interest [Letter to the Editor, not Original Article, we assume that authors were not able to provide sufficient data. Therefore, we would like to clarify the details of the current great literature through this letter.We read the article interest . The autWe recently reported our clinical experience with the use of landiolol hydrochloride for conservative management of blunt aortic injury (BAI) . In BAI Although details regarding the patient’s baseline characteristics remain unknown, it appeared that Tochikubo et al. . did notTochikubo et al.  mentione-1 min-1) for patients with impaired left ventricular function because the clinical safety for those who severely impaired left ventricular function has not been evaluated. Tochikubo et al. used 20 or 40 μg kg-1 min-1 landiolol to control cardiovascular responses during bronchoscopic endotracheal suctioning in the current study; therefore, we were concerned regarding the safety of landiolol use at these dosages. In fact, after bronchoscopic endotracheal suctioning, patients in the landiolol groups exhibited decreased heart rate and systolic blood pressure from baseline. Although patients with severely impaired left ventricular function appeared to be excluded in the current study, we recommend that they provide the inclusion and exclusion criteria.Moreover, additional indications of landiolol use for tachycardia in ICU patients have been recently approved by the Ministry of Health, Labour, and Welfare ; therefoIn conclusion, we recommend that landiolol should not be routinely used for control of cardiovascular responses during bronchoscopic endotracheal suctioning in the ICU patients. Careful evaluation of factors that influence hemodynamic changes and close monitoring of vital signs are mandatory during landiolol administration. In addition, a lower initiation dose is recommended.


For patients with ischaemic heart disease, remote ischaemic conditioning may offer an innovative, non‐invasive and virtually cost‐free therapy for protecting the myocardium against the detrimental effects of acute ischaemia‐reperfusion injury, preserving cardiac function and improving clinical outcomes. The intriguing phenomenon of remote ischaemic conditioning was first discovered over 20 years ago, when it was shown that the heart could be rendered resistant to acute ischaemia‐reperfusion injury by applying one or more cycles of brief ischaemia and reperfusion to an organ or tissue away from the heart – initially termed ‘cardioprotection at a distance’. Subsequent pre‐clinical and then clinical studies made the important discovery that remote ischaemic conditioning could be elicited non‐invasively, by inducing brief ischaemia and reperfusion to the upper or lower limb using a cuff. The actual mechanism underlying remote ischaemic conditioning cardioprotection remains unclear, although a neuro‐hormonal pathway has been implicated. Since its initial discovery in 1993, the first proof‐of‐concept clinical studies of remote ischaemic conditioning followed in 2006, and now multicentre clinical outcome studies are underway. In this review article, we explore the potential mechanisms underlying this academic curiosity, and assess the success of its application in the clinical setting. Cardiovascular disease remains the leading cause of death and disability worldwide, accounting for 17 million deaths in 2008, of which ischaemic heart disease (IHD) is a major contributor In this review article, we discuss the non‐invasive, virtually cost‐free strategy of remote ischaemic conditioning (RIC), which has made the leap from being an academic curiosity to a potential clinical therapy.We undertook a PubMed search using the keywords myocardial infarction, reperfusion, ischaemia, remote, preconditioning, postconditioning, perconditioning, cardiac and vascular surgery, CABG, coronary intervention, and cardiopulmonary bypass and reviewed papers retrieved using these search terms. In addition, references to papers were examined, and papers of relevance were also reviewed. Certain landmark papers have been referred to, independent of the PubMed search criteria.The endogenous cardioprotective phenomena of ischaemic preconditioning, first discovered in 1986 The first experimental study to describe this cardioprotective phenomenon was published by Przyklenk et al. in 1993 preconditioning), with subsequent experimental studies reporting efficacy with the conditioning stimulus applied at varying time points. These include 12–24 h before the index myocardial ischaemic episode (delayed remote ischaemic preconditioning); after the onset of myocardial ischaemia, but before reperfusion (remote ischaemic perconditioning); at the onset of myocardial reperfusion (remote ischaemic postconditioning); and most recently, even after 15 min of myocardial reperfusion has elapsed (delayed remote ischaemic postconditioning).One other major advantage of RIC is its ability to confer cardioprotection when applied at a number of different time points in relation to the index myocardial ischaemia‐reperfusion episode, a feature that has also facilitated its clinical application. The early experimental studies focused on applying the conditioning stimulus immediately before the index myocardial ischaemic episode  generation of the cardioprotective signal in the conditioned remote organ or tissue; (ii) the pathway that conveys the cardioprotective signal from the conditioned remote organ or tissue to the heart; and (iii) the activation of intracellular signalling pathways within the heart that mediate the cardioprotective effect Fig. . The curA number of experimental studies have implicated a blood‐borne factor(s) generated in the RIC‐treated animal as potential mediators of cardioprotection. The evidence for this is derived from the following studies. Gho et al. noted that RIC would only protect the heart if the conditioned intestine was reperfused, suggesting that reperfusion was required to wash the cardioprotective factor out of the conditioned tissue Current evidence suggests the factor is between 3.5 and 30 kDa, thermolabile and hydrophobic. Using dialysis membranes to fractionate the proteins within coronary effluent or serum according to their molecular weight, several studies demonstrated the factor to be smaller than 30 kDa Several experimental studies have suggested that the cardioprotective effect elicited by a RIC stimulus delivered in vivo was still present, even when the heart was isolated and subjected to acute MI either on a Langendorff apparatus (isolated perfused hearts) Although the identity of the blood‐borne cardioprotective mediator of RIC remains unknown, a number of candidate molecules have been suggested including opioid A number of experimental studies have suggested the involvement of a neural pathway in RIC cardioprotection. The evidence for this is summarised below. Gho et al. first noted that the ganglion blocker, hexamethonium, blocked RIC‐induced cardioprotection elicited by intestinal conditioning, thereby implicating a role for the autonomic ganglia of the sympathetic and parasympathetic nervous systems in inter‐organ protection Given the involvement of the autonomic nervous system in RIC, it is logical to hypothesise that the RIC cardioprotection is dependent on an intact sensory afferent neuronal pathway at the remote organ or tissue. Indeed, transection of the femoral nerve before application of the RIC stimulus abolishes cardioprotection The question arose, therefore, of how the brief ischaemic burden to the tissue or organ is translated to sensory afferent activation. Experimental studies have demonstrated that the application of brief ischaemia–reperfusion to a remote organ or tissue generates factors such as adenosine The final element concerns the efferent limb of the neural pathway to the heart. Initial studies demonstrated that vagal nerve stimulation Initial experimental studies had implicated a blood‐borne cardioprotective pathway, and an intact neural pathway to the conditioned organ or tissue. Recent studies have investigated the interaction between these two signalling components.It has been reported that RIC by limb ischaemia or intra‐arterial adenosine releases a dialysable blood‐borne cardioprotective factor(s), the release of which required intact sensory innervation of the limb and was blocked by pre‐treatment with the nitric oxide (NO) donor, S‐nitroso‐N‐acetylpenicillamine An important experimental study by Redington et al. demonstrated that either direct femoral nerve stimulation or topical application of capsaicin generated a dialysate that was able to reduce MI size in a naïve isolated rabbit heart, providing the first evidence that the neural pathway to the conditioned limb was required to generate the blood‐borne cardioprotective factor In an interesting clinical study, Jensen et al. found that plasma dialysate obtained from RIC‐treated diabetic patients with sensory neuropathy failed to limit MI size in an isolated naïve rabbit heart, although plasma dialysate harvested from RIC‐treated non‐diabetic and diabetic patients without sensory neuropathy was cardioprotective The concept of remote preconditioning of trauma originally arose from the observation that patients who had undergone abdominal aortic aneurysm (AAA) surgery had a greater risk for MI, a greater infarct size and increased mortality compared with those who had not undergone surgery. Indeed, Ren et al. observed that infarct size in mice increased with prior remote vascular surgery There is some evidence, although inconsistent, that a systemic inflammatory response is obtained in the setting of reperfusion injury. Reperfusion injury per se is associated with a neutrophilic infiltration within the target organ The first major step to the clinical translation of RIC was the discovery that the RIC stimulus could be delivered non‐invasively, by simply applying cycles of inflation–deflation using a standard blood pressure cuff placed on the upper arm CABG surgery, in which the heart is subjected to global ischaemic injury as the heart goes onto cardiopulmonary bypass (CPB), followed by global reperfusion injury as the heart comes off CPB. The global acute IRI that results can be detected as peri‐operative myocardial injury by measuring a rise in serum cardiac enzymes such as creatinine kinase (CK‐MB) and troponin T and I. It can also be detected as areas of late gadolinium enhancement  on cardiac magnetic resonance imaging;Major non‐cardiac vascular surgery, in which peri‐operative myocardial injury measured by a rise in serum cardiac enzymes such as CK‐MB and troponin T and I occurs in 20–30% of patients;Elective PCI. One component of the peri‐procedural myocardial injury that occurs during PCI is due to regional ischaemic injury and coronary microembolisation, the extent of which can be measured by the rise in serum cardiac enzymes;ST‐segment elevation MI (STEMI) treated by primary PCI. Patients presenting with an acute STEMI will usually have a major thrombotic occlusion in one of the major epicardial coronary arteries, resulting in acute myocardial ischaemia, the treatment for which is timely reperfusion using primary PCI. The price for restoring blood flow in the infarct‐related artery, however, is further myocardial injury and cardiomyocyte death – termed myocardial reperfusion injury Remote ischaemic conditioning has been investigated in a number of different clinical settings of acute myocardial IRI: A protocol of four cycles of 5 min ischaemia‐reperfusion of the forearm was applied to children before congenital heart surgery The biggest limitations of the clinical trials in the cardiac surgical setting lie in their study design. The vast majority of them have been single‐centre trials examining small groups of patients admitted for elective CABG surgery. This represents fewer than 50% of patients undergoing major cardiac surgery in England and Wales Two large multicentre, double‐blinded randomised controlled trials aim to address these limitations. The ERICCA  trial, run by our group, is currently recruiting at 30 centres in the UK, and aims to recruit 1610 high‐risk patients undergoing CABG, with or without valve surgery. The primary endpoints in this trial are cardiovascular death, non‐fatal MI, coronary revascularisation and stroke at one year, with various secondary endpoints, including quality of life and exercise tolerance One of the first major trials to give a negative result was conducted by Bonser's group www.clinicaltrials.gov, NCT01864252).First, the translation of RIC into the clinical setting is not straightforward. Remote ischaemic conditioning in the pre‐clinical setting was investigated in young animals that underwent myocardial IRI by direct ligature applied to the coronary artery. There was no pre‐existing disease state, and almost none of the models included any form of cardiopulmonary bypass. Direct translation into the clinical setting of this model is not feasible, as many of our patients have co‐existing morbidity. For instance, unstable angina, which is characterised by intermittent ischaemia, is a form of preconditioning, and patients with unstable angina who then have a MI often do better than patients whose first presentation is an MI Ali et al. were the first to publish on the phenomenon of RIC in the setting of major vascular surgery An early study by Iliodromitis et al. did not show any evidence of benefit from an RIC protocol administered in patients undergoing elective PCI. However, this study may have been underpowered It is important to note that an RIC intervention in the setting of an acute MI would not be a preconditioning stimulus, but a perconditioning or a postconditioning stimulus, as the onset of ischaemia is unpredictable. Primary PCI is the gold standard, and the first study to examine RIC in this setting included 33 patients in each group, but was negative −1.h−1, along the lines of the Bristol model of total intravenous anaesthesia −1.min−1 (7.2 mg.kg−1.h−1) in cardiac surgery resulted in a lower troponin levels at 24 h compared with isoflurane alone or low‐dose propofol (60 μg.kg−1.min−1) While the role of anaesthetic agents has been reviewed elsewhere in this journal −1Given this controversy, it is unclear whether anaesthetic agents enhance or block the effects of RIC. In a clinical trial involving children with congenital heart defects, anaesthesia was induced with sevoflurane and maintained with isoflurane, air and oxygen throughout the procedures. Although the exact dosages were not reported in this study, RIC proved to be cardioprotective Remote ischaemic perconditioning (RIPerC) is a strategy where multiple cycles of ischaemia‐reperfusion are applied during the lethal ischaemia phase, but before reperfusion Remote ischaemic postconditioning (RIPostC) involves the application of the remote ischaemic stimulus at the point of reperfusion. The mechanisms of RIPostC have not been fully elucidated, but there is evidence that it involves the survival activating factor enhancement (SAFE) pathway, rather than the conventional RISK pathway activated in RIPreC. Translation into the clinical arena came in the form of the trial by Hong and co‐workers. They randomly assigned 70 patients having off‐pump CABG to a combination of RIPreC and RIPostC in one group, and controls in the other. This resulted in a 48.7% reduction in peri‐operative injury, as determined by the 72‐h troponin area under the curve At this point, it is worth briefly mentioning the concept of delayed RIPostC. The basis of the concept lies in the supposition that reperfusion injury does not only occur at the point of reperfusion, but can continue for a while after reperfusion. Delayed RIPostC aims to influence protective pathways later in the reperfusion period. At the time of writing, there have been no clinical trials in humans, but pre‐clinical evidence exists that RIPostC may reduce injury in the brain and the heart Remote ischaemic conditioning is a novel strategy that has been shown to reduce myocardial reperfusion injury. While there have been both promising and disappointing results from trials, results from large multicentre randomised controlled trials such as ERICCA and RIPHeart are awaited. Anaesthetists are in the unique position of providing peri‐operative care to their patients, especially in cardiac and neurosurgery. If RIC proves to be beneficial, then anaesthetists may be at the forefront of providing peri‐operative organ protection to their patients. Even if RIC is not realised as a protective intervention, an understanding of mechanisms may lead to development of pharmacological agents that may be administered peri‐operatively by anaesthetists, in the hope of protecting vulnerable patients from myocardial injury following reperfusion. Over the years, research and development has reduced the risks of cardiac interventions and surgery dramatically. Remote ischaemic conditioning may help us reduce this even further.No external funding or competing interests declared.


Patients with repaired or palliated right heart congenital heart disease (CHD) are often left with residual lesions that progress and can result in significant morbidity. However, right ventricular-pulmonary arterial evaluation and the timing of reintvervention is still subjective. Currently, it relies on symptomology, or RV imaging-based metrics from echocardiography or MR derived parameters including right ventricular (RV) ejection fraction (EF), end-systolic pressure (ESP), and end-diastolic volume (EDV). However, the RV is coupled to the pulmonary vasculature, and they are not typically evaluated together. For example, the dysfunctional right ventricular-pulmonary circulation (RV-PC) adversely affects the RV myocardial performance resulting in decreased efficiency. Therefore, comprehensive hemodynamic assessment should incorporate changes in RV-PC and energy efficiency for CHD patients.esE), can provide a measure of RV performance. However, a detailed explanation of the relationship between RV performance and pulmonary arterial hemodynamics is lacking. More importantly, PVR is impractical for routine longitudinal evaluation in a clinical setting, because it requires invasive catheterization. As an alternative, analytical methods and computational fluid dynamics (CFD) have been used to compute energy endpoints, such as power loss or energy dissipation, in abnormal physiologies.The ventricular pressure-volume relationship (PVR) and other energy-based endpoints derived from PVR, such as stroke work (SW) and ventricular elastance (In this review, we review the causes of RV-PA failure and the limitation of current clinical parameters to quantify RV-PC dysfunction. Then, we describe the advantage of currently available energy-based endpoints and emerging energy endpoints, such as energy loss in the Pas or kinetic energy, obtained from a new non-invasive imaging technique, i.e. 4D phase contrast MRI. Congenital heart diseases (CHDs) often lead to critical conditions causing morbidity, mortality, and increased healthcare cost for patients during their treatment period, which often begins from childhood. The recently reported incidence of CHD in the United States is approximately 8 per 1000 live births , rangingRecent advances in diagnosis and surgical treatments for CHD patients significantly reduce (less than 2%) the early postoperative mortality rate . HoweverIn the clinical setting, cardiac magnetic resonance imaging (MRI), including 2D phase contrast MR imaging, and catheterization have been used as gold standards to assess systolic and diastolic ventricular volumes, flow, and pressure. However, these techniques are limited by the fact that 1) 2D phase contrast MRI allows only the 1D axial flow information through a prospectively chosen plane and 2) catheterization is invasive and is not considered as a routine evaluation modality for longitudinal follow-up.To circumvent these obstacles, energy-based endpoints have been proposed. Such end-points will be discussed in the following sections. Energy-based endpoints are believed to be superior indicators in assessing the status of ventricular hemodynamic status over current techniques, including echocardiography, cardiac MRI, and catheterization, when used independently ,15. EnerThe functional assessment of right heart including the pulmonary vasculature has been less intensively studied since the result of right heart failure was thought to be less important for patient outcomes. Also, the RV operates at lower pressures compared to the left ventricle (LV) and the systemic arteries. The lower working pressure of the RV is a result of a pulmonary vascular resistance that is lower than the systemic vascular resistance because the pulmonary system has larger peripheral vessels with shorter and relatively more distensible arteries and veins.In this review, we first describe the cause of RV-PC dysfunction followed by the importance of its long-term patient care. Secondly, we examine the advantages and limitations of current clinical diagnostic parameters in assessing abnormal hemodynamics in CHD patients. Thirdly, we discuss existing energy-based endpoints Table  for evalThe RV-PC dysfunction is a post-operative sequela of repaired CHD that patients are confronted with aging. Typically, it involves one or more of the following: 1) pulmonary regurgitation due to an absent of incompetent pulmonary valve, 2) pulmonic stenosis, 3) RV outflow tract obstruction within the RV chamber, and 4) pulmonary artery stenosis. It leads to increased RV work to maintain sufficient pulmonary circulation, resulting in the RV and PA dilatation, and progressive RV dysfunction -18. Pulmvolume-based indices obtained from cardiac MRI, such as RV ejection fraction (EF), end-diastolic and end-systolic volumes , RV mass, and peak ejection and filling rate, have been used to assess the status of RV and pulmonary vasculature . Wi. WiEes) iography ,44. HoweSuga et al. ,42 intro, Baxley  used the, Baxley  and show2/ml was 2.059 kg.m. Further, De Tombe et al. [In the above equation, LV stroke work (SW) was calculated by multiplying stroke volume (SV) and mean LV pressure. The total e et al.  confirme11C-clearance curve recorded during myocardial washout. They modified Eq. 1 to compute mechanical efficiency of the LV as shown in Eq. 2.Further refinement of the efficiency calculation requires a more accurate measure of myocardial metabolism. A non-invasive measurement of myocardial metabolism can be made using positron emission tomography (PET) imaging. Porenta et al.  used C-1where MAP = the mean arterial pressure, HR = heart rate, and LVM = LV mass. They found that mechanical efficiency in 11 normal subjects was not significantly different between at the rest and stress conditions (29 ± 6% at rest and 32 ± 6% during dobutamine stress). However, external work efficiency was significantly lower at rest (16 ± 6%) compared to dobutamine stress condition (21 ± 4%).As discussed above, most studies on the ventricular SW and the efficiency were performed for the LV, and only a few studies have described the RV SW and the efficiency ,15,48-50MPAe), using non-simultaneously acquired RV pressure, volume, and blood flow data, as follows. RV SW was calculated from RV pressure and volume synchronized by ECG gating (Eq. 3):Recently, Das et al.  proposedP is RV pressure, V is RV volume. The rate of energy transfer at the main PA (MPA) was computed using Eq. 4:where m pis the MPA pressure, m Ais MPA area. Finally, energy transfer ratio (MPAe) was obtained by a ratio of net energy transfer at the MPA (netE) to RV SW (Eq. 5):where MPA efor the patient was considerably lower than that for the control (patient: 0.56 vs. control: 1.06). Further, Lee et al. [MPA eof the patient group was significantly lower than that of the control group , despite the fact that the patient group had significantly higher RV SWI (RV SW indexed to body surface area), than the control group  and mean flow (OQ), and the oscillatory component term  has provided valuable insight into ventricular contractility and its relationship to different pressure and volume loading conditions. However, invasive catheterization is required for accurate pressure measurement. In recent years, therefore, analytical and computer fluid dynamics (CFD) techniques have been used as alternatives to obtain hemodynamics in the ventricles and large arteries, including pulmonary arteries, and aorta.As mentioned earlier, however, most studies were performed with the left heart disease such as Fontan and aortic stenosis. Ascuitto et al.  used an ρ is blood density, Q : mean flow rate, A Ais aortic cross-sectional area, S is geometrical shape factor, and where MPAe) at the PAs (as described earlier) using CFD to obtain energy transfer ratio between the RV and MPA.Meanwhile, Hunter et al.  used bipMany recent studies have investigated the Fontan physiology that involves the total cavopulmonary connection (TCPC) between the venae cava and the PA while bypassing the RV. Soerensen et al.  performewhere d et al.  reported4D phase contrast MRI, three dimensional and directional velocity data over the cardiac cycle, can be performed for ventricular chambers and large vessels -67. ThisConsidering the complex nature of 3D blood flow in CHD patients, the irregularity and fluctuation of flow characteristics are important aspects of energy-based analysis -69. 4D pvox Nis total number of voxels in the ventricle, ρ is the density of a voxel which is assumed to be 1.05 g/ml, and u is the blood velocity in the voxel. They found that the average KE in both the ventricles was related to EDV, ESV, and SV. The computed KE for the LV and RV accounted for less than 1% and 3% of the external work done by the LV and RV at rest, respectively. However, it increased up to 3% and 24% for the LV and RV during peak exercise.where Dyverfeldt et al. ,69 demonwhere ure loss . Lantz eure loss  showed aFurther, Lee et al. ,75 used They showed that the total energy loss in the branch PAs for the patients with PA pathophysiology was an order of magnitude larger than the control subjects. More importantly, the total energy loss varied significantly among patients who had the different levels of RV-PC dysfunction Figure  and 12. 3) which limits its applicability to compute hemodynamics near or at the vessel wall, and 3) requirement for complex data post-processing. New approaches are being developed to address many of these problems. For example, fast imaging techniques, such as k-space undersampling  [Although 4D phase contrast MRI is a validated technique to measure blood velocity, it has limitations including 1) relatively long scan time (10~20 minutes depending on the acquisition volume), 2) moderate spatial resolution (2.0~2.5 mmand etc) ,77 and mand etc) ,79, haveand etc)  proposedand etc) -84. TogeThe computation of energy-based endpoints, such as ventricular pressure-volume relationships, stroke work, and efficiency, traditionally requires cardiac catheterization. Computation fluid dynamics (CFD) utilizing data from ultrasound or phase contrast MRI (and pressure data from catheterization) can be used to estimate energy-based endpoints. Recently, non-invasive 4D phase contrast MRI has become available to compute energy-based endpoints avoiding catheterization, and consequently reducing risks for patients while decreasing costs. Therefore, we believe that non-invasive methodologies, such as 4D phase contrast MRI, can be used to calculate energy-based endpoints to follow longitudinally CHD patients and help with interventional planning.The RV-PC dysfunction is a common chronic disease in post-operative CHD patients that poses a threat to the patient's lives over time unless it is timely treated. The status of RV-PC dysfunction needs a careful evaluation during routine follow-up for a patient because of its adverse effect on RV-PA hemodynamics. The RV pressure-volume relationship (PVR) is the gold standard for detailed ventricular function throughout the cardiac cycle independent of loading conditions. Energy-based endpoints derived from PVR, such as RV SW, the ventricular efficiency, and energy transfer ratio between the RV and the MPA, have also been useful means to characterize the RV performance. However, these approaches are not widely applicable in clinical settings since they require invasive catheterization and involve simultaneously measured RV pressure and volume. Therefore, the new energy endpoints, for instance, energy dissipation, energy loss in the PAs, kinetic energy loss, or turbulence kinetic energy, computed using non-invasive methodologies, 4D phase contrast MRI and CFD, are emerging, and may be useful surrogates. As described in this review, energy-based endpoints are capable of better delineating and quantifying comprehensive hemodynamics and associated energy changes caused by RV-PC dysfunction. Therefore, energy-based endpoints can be useful measures in helping clinicians to make better clinical decisions for patients with abnormal RV-PA physiology.es E: ventricular end-systolic elastance; CFD: computational fluid dynamics; MRI: magnetic resonance imaging; EDV: end-diasystolic volume; ESV: end-systolic volume; EDVI: EDV indexed by body surface area; LV: left ventricle; SV: stroke volume; mA: MPA area; netE: net energy transfer at the MPA; T: cardiac cycle; OP: mean pressure; OQ: mean flow; N: the total number of harmonics; n: harmonic number; nZ: PA impedance modulus at the funda-mental frequency of pressure wave; nθ: impedance phase at that frequency; PAH: pulmonary arterial hypertension; TCPC: the total cavopulmonary connection; CEDI: circulation energy dissipation index; AV-EDI: aortic valve energy dissipation index; TCPC-EDI: total TCPC energy dissipation index; ρ: the density of a blood ; AA: aortic cross-sectional area; S: geometrical shape fact; HR: heart rate; LVM: left ventricular mass; MPA e: energy transfer ratio at the MPA; P: RV pressure; V : RV volume; mp: MPA pressure; ε: the mean energy dissipation at TCPC; vox N: total number of voxels in the ventricle; U: the blood velocity; TKE: turbulent kinetic energy; CHD: congenital heart disease; RV: right ventricle; EF: ejection fraction; ESP: end-systolic pressure; RV-PC: RV-PA circulation; EDV: end-diastolic volume; PA: pulmonary artery; PVR: pressure-volume relationship; SW: stroke work; The authors declare that they have no competing interests.NL carried out the review and drafted the manuscript. RB and MT reviewed the final manuscript.


For the 25th time in a row the Interuniversity Cardiology Institute of the Netherlands (ICIN-Netherlands Heart Institute) and the Netherlands Society of Cardiology (NVVC) supported the competition for the best three cardiovascular PhD theses, published in the year 2013 . The dissertation prize carries the name of one of the greatest Dutchmen in the history of cardiovascular medicine, Willem Einthoven, who in 1902 for the first time recorded the human ECG, for which he received the Nobel Prize in 1924.This time the jury received a total of 33 PhD dissertations published in 2013. The jury members were very much impressed by the high scientific quality of the PhD fellows. The ultimate selection was based on a combination of several parameters: the curriculum vitae of the candidate, the scientific originality of the PhD thesis and its relevance for the cardiovascular field. In addition, several objective bibliometric parameters were used: 1) the number of articles in first-rate journals both in PubMed and the Web of Science (WOS), 2) the number of citations in WOS, 3) the Hirsch Index, and 4) the contribution as a first author (or shared first author). Based on a combination of these results, the jury finally selected three nominees: Dr. Peter Damman , Dr. Loek van Heerebeek , and Dr. Rutger-Jan Nuis .The members of the jury were: J.W. Deckers (Director CVOI), A. Mosterd (Chairman WCN), M.J. Schalij (Chairman Concilium NVVC), V.A. Umans (President NVVC), and E.E. van der Wall (Director ICIN).The three candidates presented their PhD theses at the annual Spring Congress of the NVVC at the RAI Congress Centre, in Amsterdam, on Friday 4 April 2014. The ultimate winners of the first (Loek van Heerebeek), second (Peter Damman) and third prize (Rutger-Jan Nuis) were chosen by the audience. Summaries of the three nominated PhD theses are given below.Address of correspondence:Ernst E. van der Wall, MDInteruniversity Cardiology Institute of the Netherlands (ICIN) - Netherlands Heart Institute, Catherijnesingel 52, PO Box 19258, 3501 DG Utrecht, the Netherlandsernst.van.der.wall@icin.nle-mail: Victor A.W.M. Umans, MDDepartment of Cardiology, Medical Center Alkmaar, Wilhelminalaan 12, 1815 JD Alkmaar, the Netherlandse-mail: v.a.w.m.umans@mca.nlpassive). Cardiomyocyte Fpassive is mainly determined by the elastic sarcomeric protein titin through shifts in expression of its stiff (N2B) and compliant (N2BA) isoforms and isoform phosphorylation. Whether DHF and HF with reduced EF (HFrEF) or systolic HF (SHF) represent distinct HF phenotypes is still debated.Background: Heart failure with preserved ejection fraction (HFpEF), or diastolic HF (DHF) is widely prevalent and has a poor prognosis. Its pathophysiology is incompletely understood and therapeutic strategies remain uncertain. Characteristic for DHF is high diastolic left ventricular (LV) stiffness, which is attributed to myocardial fibrosis and elevated cardiomyocyte stiffness . In addition, the importance of metabolic risk factors, such as diabetes mellitus type II (DMII), for diastolic LV dysfunction was investigated.n = 36) and SHF (n = 43) patients and perioperatively in AS patients (n = 67). Biopsies showed no evidence of infiltrative or inflammatory myocardial disease. Biopsies were analysed for structural and biochemical characteristics using histomorphometry, electron microscopy, immunohistochemistry and gel electrophoresis, respectively. Single cardiomyocytes were isolated from the biopsies, permeabilised and stretched to 2.2 μm sarcomere length for force measurements, including cardiomyocyte Fpassive.Methods: All patients were free from obstructive coronary disease. We used a translational ‘bed-to-bench’ approach, relating clinical parameters to structural, functional and biochemical characteristics of the myocardium and cardiomyocytes through procurement of LV endomyocardial biopsies, performed transvascularly in DHF  acutely lowered cardiomyocyte Fpassive, through phosphorylation of titin N2B. The larger fall in Fpassive after PKA and PKG administration in DHF implies a relative phosphorylation deficit of titin N2B in DHF. Indeed, myocardial cyclic guanosine monophosphate (cGMP) expression and PKG activity were profoundly lower in DHF than in SHF and AS, which related to higher myocardial nitrosative/oxidative stress in DHF. In DHF, downregulation of nitric oxide-cGMP-PKG signalling with subsequent hypophosphorylation of titin and increased cardiomyocyte stiffness could represent a novel mechanism contributing to elevated diastolic LV stiffness in DHF, possibly associated with the high prevalence of metabolic risk factors in DHF.Results: DHF patients had a higher prevalence of obesity and more frequently had hypertension (compared with SHF) and DMII (compared with AS). Concentric LV remodelling and hypertrophy were observed in both DHF and AS patients with similarly increased cardiomyocyte diameter, in contrast to eccentric remodelling in SHF. Cardiomyocyte filamentary density was higher in DHF than in SHF, whereas interstitial myocardial fibrosis was similar in DHF and SHF, but increased in AS. Diabetes increased diastolic LV stiffness in all groups through distinct mechanisms with increased fibrosis and advanced glycation endproduct deposition contributing relatively more in SHF and increased cardiomyocyte FConclusion: DHF and SHF are distinct HF phenotypes because of unequal myocardial structure and function.Loek van Heerebeek.Department of Physiology, VUMCE-mail: l.vanheerebeek@vumc.nlThe first part of the thesis concerns treatment strategies for acute coronary syndromes (ACS).For patients presenting with non-ST-elevation (NSTE)-ACS, two treatment strategies have been compared extensively in the past decade: a routine invasive strategy (routine angiography and revascularisation) and a selective invasive or conservative strategy .One chapter includes the long-term outcomes of the ‘Invasive versus Conservative Treatment in Unstable coronary Syndromes’ (ICTUS) trial in which these strategies were compared. At 5-year follow-up, we could not demonstrate a benefit of a routine invasive strategy in reducing death or myocardial infarction (MI) in patients with NSTE-ACS and elevated troponin T, irrespective of the patients’ baseline risk profile.These data were pooled with two other large clinical trials in which these two strategies were compared: FRISC-II and RITA-3. In the patient-pooled data of these trials (the FRISC II-ICTUS-RITA-3: FIR collaboration), we showed that a routine invasive strategy reduces long-term cardiovascular death or MI and the largest absolute effect was seen in higher-risk patients. The discrepancy between the above results is probably explained by the intensity of revascularisation in the treatment arms. A high intensity of revascularisation was observed in the selective treatment arm in ICTUS, while a relatively low intensity was observed in the selective treatment arm in FIR.After the publication of these results, the routine invasive strategy was endorsed the highest level of recommendation for high-risk patients in European and American clinical guidelines.Using the Swedish national SWEDEHEART database to assess trends in the implementation of these treatment strategies, we observed an increase in the use of a routine invasive strategy in NSTE-ACS patients over a 12-year course.An important point in the discussion on treatment strategies is the ‘early hazard’ of the routine invasive strategy, composed of procedure-related MIs. Using the FIR database and a critical appraisal of literature, we described that these procedure-related MIs probably do not have large clinical consequences, in contrast to spontaneously occurring MI.The second part of the thesis concerns risk stratification in acute coronary syndromes.In patients with NSTE-ACS, we have shown the prognostic value of qualitative assessment of the baseline electrocardiogram. Furthermore, the prognostic value of the novel biomarker growth-differentiation factor 15 (GDF-15) for long-term outcomes is described.In patients with ST-elevation MI (STEMI), we describe that the combination of different biomarkers  improves prognostication. Furthermore, the use of a simple risk score based on these biomarkers identifies a high-risk subgroup for mortality. The simple risk score was validated in an independent database from Groningen, the Netherlands. In order to further explore the association between the risk score and higher mortality risk, we assessed the association between this score and several cardiovascular mechanistic markers of outcomes. The multimarker risk score was associated with angiographic, electrocardiographic and cardiac magnetic resonance mechanistic markers of outcomes, and our data show the ability to identify patients at high-risk of sub-optimal reperfusion and cardiac magnetic resonance outcomes who might benefit most from adjuvant treatments in STEMI.P. DammanDepartment of Cardiology, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands, e-mail:P.Damman@amc.uva.nlAortic stenosis is a common valvular heart problem of which its prevalence increases with age. Advanced age and associated comorbidities often render these patients less amenable to surgical aortic valve replacement (AVR). In the quest for development of less invasive therapies for high-risk patients with cardiac valve disease, catheter-based aortic valve implantation (TAVI) via a peripheral blood vessel was introduced in 2004 as a novel treatment modality. Despite its advantages, TAVI remains an invasive procedure used in high-risk patients which is invariably associated with substantial risks as demonstrated in this thesis.Our studies show that TAVI is associated with ≥1 (non)cardiovascular and/or permanent pacemaker implantation in 59 % of the patients while TAVI is truly uncomplicated in 41 %. Nevertheless, complication rates declined as a result of experience, and improvements in technique and technology  and, eventually the use of filters placed in the cerebral arteries that capture embolic debris that is liberated during the procedure.Acute kidney injury (AKI) occurred in 21 % of the patients following TAVI of whom 2 % needed temporary haemodialysis. Blood transfusion therapy was the strongest predictor of AKI while both transfusion and AKI predicted early and late mortality. Interestingly, patients with baseline anaemia (57 % of the cohort) had less blood loss but received more blood transfusions in comparison with patients without anaemia before TAVI, suggesting either an unconscious or better control of haemostasis during TAVI in patients with baseline anaemia and/or a lower threshold for administering transfusion during TAVI in such patients. Therefore, TAVI outcomes may be improved by a more restrictive use of transfusions, which should be directed by more strict guidelines for blood transfusion therapy in addition to optimisation of haemoglobin levels before TAVI.The ongoing cycle of iterations in design, increase in clinical experience and ongoing clinical research assessing the role of TAVI relative to AVR but also observational cohort research in large series of patients who are more close to most patients seen in clinical practice will lead to ongoing improvements in outcome. Critical assessment in accordance with clinical and scientific principles will boost the future of TAVI to the benefit of care of patients with valvular heart disease. The technique will not be restricted to the aortic valve.R-J. NuisDepartment of Cardiology, Erasmus MC, Rotterdam, the Netherlands, e-mail:r.nuis@erasmusmc.nlReferences1. van der Wall EE, Schalij MJ, Umans V, van Gilst WH. Einthoven dissertation prizes 2011. Neth Heart J. 2012;20:240–4. doi: 10.1007/s12471-012-0280-z.2. van der Wall EE, van Gilst WH, Schalij MJ, Umans V. Einthoven dissertation prizes 2012. Neth Heart J. 2013;21:256–61. doi: 10.1007/s12471-013-0404-0.


Non-invasive quantification of the pulmonary blood volume (PBV) by cardiovascular magnetic resonance imaging (CMR) is a novel method which may provide a measure of pulmonary congestion and backward failure in heart disease. The aims were to prospectively evaluate the factors contributing to PBV by CMR, and determine whether PBV is higher in patients with left ventricular (LV) measures outside normal limits.1.5T CMR was performed in 119 subjects . A subgroup of patients  were identified by LV measures outside normal limits  index > 100 ml/m2, LV ejection fraction (LVEF) < 58%). PBV was measured as the product of the pulmonary transit time for an intravenous contrast bolus and cardiac output from CMR phase contrast flow measurement.For all subjects, PBV correlated with height , LVEDV , lung volume  and age , but not with LVEF . Compared to controls , the subgroup  had a higher PBV  but no difference in PBV indexed to lung volume , height (p = 0.41) or lung volume (p = 0.10).In a clinical population, only 44% of the variation in PBV could be explained by height, LVEDV, lung volume and age. Hence, quantification of PBV by CMR is a novel and feasible tool for clinical assessment of patients with heart disease and appears to provide additional information compared to conventional anthropometric and cardiac pumping measures. A subgroup of patients outside LV normal limits had a higher PBV but PBVI was not increased. Prospective evaluation of PBV in patients with congestive heart failure would be of value.Swedish Research Council, Swedish Heart and Lung Foundation, Stockholm County Council, Karolinska Institutet, Swedish Medical Assocation, Swedish Society of Medical Research, and The Kleberg, Osterman, Wiberg, Erling-Persson, and Grönberg Foundations.


The prevalence of LV systolic dysfunction, defined as fractional shortening < 27%, LV ejection fraction (LVEF) < 55%, and global longitudinal strain (GLS) ≤ 16%, was 5.2%, 6.0%, and 23.1%, respectively. Abnormal GLS was observed in 24 (18%) patients despite a normal LVEF. Indices of LV systolic function were similar regardless of anthracycline dose. However, GLS was worse  and prevalence of abnormal GLS was higher  in patients treated with mediastinal radiotherapy. Mediastinal radiotherapy was associated with reduced GLS (p = 0.040) after adjusting for sex, age, and cumulative anthracycline dose. In adult survivors of childhood, adolescent, and young adult cancer, 2DSTE frequently detects LV systolic dysfunction despite a normal LVEF and may be useful for the long-term cardiac surveillance of adult cancer survivors. Two-dimensional speckle tracking echocardiography (2DSTE) provides a sensitive measure of left ventricular (LV) systolic function and may aid in the diagnosis of cardiotoxicity. 2DSTE was performed in a cross-sectional study of 134 patients  previously treated with anthracyclines (mean cumulative dose: 320 ± 124 mg/m Strategies in cancer diagnostics and therapeutics have improved dramatically over the last several decades, leading to a growing number of adult survivors of childhood, adolescent, and young adult cancer. The 5-year survival rate for all cancers diagnosed before age of 45 exceeds 80% . As of 2Late cardiac effects due to anthracycline chemotherapy and mediastinal radiotherapy in adult cancer survivors are well recognized , and subTwo-dimensional speckle tracking echocardiography (2DSTE) is a novel method that has potential advantages over LVEF or FS measurement in the early detection of LV systolic dysfunction among both children , 21 and A total of 134 consecutively referred adult survivors of childhood, adolescent, and young adult cancer followed up in the Adult Long-Term Follow-Up Program at Memorial Sloan Kettering Cancer Center, a program for high-risk cancer survivors, were included in this study. Screening echocardiograms were performed between July 1, 2010, and December 31, 2012. As per COG and NCCN recommendations, screening echocardiograms were performed annually or biennially , 16. AllE-wave) and late (A-wave) diastolic filling velocities were measured and their ratio  was calculated. Doppler tissue imaging of the mitral annulus was performed with measurement of the early (e′) diastolic velocity at the septal annulus. Diastolic function assessment was based on mitral E/A ratio and tissue Doppler (e′) velocity only.Conventional 2D and Doppler echocardiography was performed using a commercially available standard ultrasound scanner , according to the standardized American Society Echocardiography (ASE) protocol . LVEF waThree apical views were used to measure peak systolic global longitudinal strain (GLS) and strain rate using dedicated automated software . Three points were manually placed at the endocardial border  in each of the apical views, allowing the software to automatically track myocardial movement throughout the cardiac cycle. After careful inspection, manual correction was performed if the automatic detection was suboptimal. Each view was divided into 6 segments, for a total of 18 segments representing the entire left ventricle. In the case of unsatisfactory tracking due to inadequate image quality, that segment was eliminated from analysis. The timing of aortic valve closure in the apical 3-chamber view was used to define end-systole. Longitudinal strain and strain rate curves were generated for each segment. Strain data were expressed in absolute values (|%|). Global radial (GRS) and circumferential (GCS) strain were calculated by averaging the peak systolic strain values in all 6 segments of the parasternal short-axis view at the papillary muscle. Abnormal LV systolic function was defined as GLS ≤ |16|%. This is a conservative estimate of the lower limit of normal that was derived from studies performed in several healthy cohorts using the mean GLS minus two standard deviations , 26, 27.Interobserver variability was assessed by comparing the original GLS, GRS, and GCS calculation with that calculated by a blinded second observer in 20 randomly selected patients. Intraobserver variability was calculated by repeated measurements in 20 patients by the primary reviewer 3 weeks after the initial measurement.2) and by mediastinal radiotherapy (yes versus no) for the comparison of the 2D echocardiographic and strain indices, and by-group comparisons were tested using Fisher's exact test when categorical and Kruskal-Wallis test when continuous. The prevalence of abnormal GLS and abnormal FS and LVEF was compared using an exact McNemar's test. Dependent variables considered in multivariable linear regression analysis included FS, LVEF, LV mass/BSA, GLS, mitral E/A ratio, and septal e′ velocity. GLS ≤ |16|% was considered the dependent variable in a multivariable logistic regression model. There were too few events to consider FS < 27% or EF < 55% as outcomes in multivariable analysis. Each multivariable regression model incorporated sex, age at echocardiogram, mediastinal radiotherapy (yes or no), and cumulative anthracycline dose (continuous) as independent variables. Interobserver and intraobserver variability were assessed using the intraclass correlation coefficient (ICC). Bland-Altman plots were constructed by plotting the average of the two readings on the x-axis versus the difference between the two readings on the y-axis. The mean and standard deviation of the differences were calculated. Because of the small sample size, the t-distribution was used as the reference distribution to calculate the 95% limits of agreement. A p value of less than 0.05 was considered statistically significant. All statistical analyses were performed using either SAS software version 9.2  or R software version 2.13.1 .Continuous measures were summarized as median and interquartile range (IQR) whereas categorical measures were summarized as frequency and percent. Patients were stratified based on cumulative anthracycline dose , Hodgkin lymphoma (n = 29), and acute leukemia (n = 31) were the most common diagnoses. All patients were treated with anthracycline chemotherapy, and the median cumulative anthracycline dose was 300 mg/m2 . Less than half of patients (39%) received mediastinal radiotherapy as part of their cancer treatment, with a median dose of 35 Gy . The overall prevalence of cardiac risk factors such as hypertension and diabetes was low . Patients who received mediastinal radiotherapy as part of their cancer treatment regimen (n = 52) had a lower cumulative anthracycline dose exposure  compared to those who were treated with anthracycline chemotherapy alone.A total of 134 survivors of childhood, adolescent, and young adult cancer were included in this study. Demographic and treatment characteristics are provided in p < 0.001) or LVEF (p < 0.001) , 61.1% , and 18.0% . LV systolic dysfunction was detected by FS < 27% in 5.2% and LVEF < 55% in 6.0%. However, the prevalence of abnormal GLS ≤ |16|% was 23.1%, significantly higher than abnormal FS (< 0.001) . In the p = 0.003) and the prevalence of patients with GLS ≤ |16|% was more than two times greater in the radiotherapy group . However, there was no difference in FS  or LVEF  between the groups with and without mediastinal radiotherapy. Although GCS for the whole study group was significantly lower than the normative reference value  based on a recent meta-analysis of normal ranges [p = 0.203) or GRS  between the groups with and without mediastinal radiotherapy.Echocardiographic parameters of LV systolic function, stratified by mediastinal radiotherapy exposure, are shown in l ranges , there wp = 0.040) after adjusting for sex, age at echocardiogram, and cumulative anthracycline dose. Mediastinal radiotherapy was also associated with decreased indices of diastolic function, including lower transmitral E/A ratio  and medial septal tissue Doppler e′ velocity . There was a trend towards increased LV mass index with higher doses of anthracycline chemotherapy  and decreased LV mass index with mediastinal radiotherapy , but neither association reached statistical significance.In multivariable linear regression analysis, mediastinal radiotherapy was associated with reduced GLS  and the ICC for intraobserver agreement was 0.822 (95% CI 0.610 to 0.925), reflecting substantial agreement for measurement of GLS. The Bland-Altman plots indicate that, for interobserver agreement, we expect 95% of measurements from two different readers to differ by between −1.86% and 2.28% whereas, for intraobserver agreement, we expect 95% of measurements taken by the same reader at two times to differ by between −0.84% and 2.35% . For GCSThe principle finding of this study is that a significant proportion of adult survivors of childhood, adolescent, and young adult cancer have abnormal LV systolic function detected by 2DSTE despite having a normal LVEF. While an abnormal GLS (≤|16|%) was observed in nearly one-quarter of study participants, a corresponding reduction in FS of <27% or LVEF of <55% was observed in only 5.2% and 6.0% of participants, respectively. These observations suggest that the prevalence of LV systolic dysfunction among long-term cancer survivors may be significantly underestimated using LVEF alone as compared to GLS by 2DSTE.In the current study, there was no association between cumulative anthracycline dose and conventional or strain indices of LV systolic function. However, this may be attributable to the heterogeneity of the study population and the limited sample size. Indices of diastolic function were significantly lower among patients treated with mediastinal radiotherapy (median dose 35 Gy). This is consistent with a study by Heidenreich et al. in which a high prevalence of diastolic dysfunction was observed among Hodgkin lymphoma survivors treated with at least 35 Gy of mediastinal radiotherapy . InteresAlthough LVEF by 2D echocardiography is the current standard method for monitoring LV systolic function in cancer survivors, myocardial strain by 2DSTE has several important advantages as a screening tool for cardiotoxicity. First, myocardial strain can identify subclinical LV systolic dysfunction prior to a decrement of LVEF. Poterucha et al. found that a reduction in GLS preceded a decrease in LVEF among adolescents receiving anthracycline chemotherapy . SimilarFindings from several prior studies support the utility of myocardial strain assessment in cancer survivors –35. CheuLess than 10% of the patients were treated with cardioprotective medications, which may confound the association between mediastinal radiotherapy and GLS. However the results of our analysis were not substantively different when these patients were excluded. While radiation increases the cardiotoxicity of anthracyclines via different mechanisms of injury, it is unclear whether this relationship is additive or synergistic.Overall, 24 of 134 patients (18%) in the current study had abnormal GLS despite a normal LVEF. This is consistent with findings from the St. Jude Lifetime Cohort Study, in which abnormal GLS was more prevalent than a reduction in LVEF among adult survivors of childhood cancer and was associated with both chest-directed radiotherapy and anthracycline exposure . Althoug2) exposure. Lipshultz et al. also demonstrated that parameters of LV function progressively declined as many as 15 years after diagnosis among childhood cancer survivors treated with doxorubicin [The findings of this study reinforce the importance of continued routine cardiac surveillance for adult survivors of childhood, adolescent, and young adult cancer many years beyond their initial treatment. Consistent with prior reports, LV systolic dysfunction was detected 15 years after successful treatment in this study, despite only modest doses of anthracycline (median 300 mg/morubicin . Given tThis study has several limitations. The prognostic significance of abnormal GLS was not evaluated, and long-term follow-up is currently underway to determine whether abnormal GLS is predictive of subsequent LVEF decline or symptomatic heart failure in this population. Given the limitations of a retrospective cross-sectional study, we assessed LV function at one point in time and cannot comment on longitudinal changes that may have occurred. An analysis of serial echocardiograms is currently underway to investigate the natural history of GLS and LVEF impairment in this at-risk patient population. Although the study did not include a healthy control group, we used reference normative strain data that have been published in several healthy cohorts. Blood pressures were not measured at the time of the echocardiogram which can cause fluctuation in the GLS, but the majority of the patients were normotensive. Finally, our study pools together a heterogeneous study population with multiple cancer types from a single cancer referral center, which may limit the generalizability of the results.LV systolic dysfunction is significantly more prevalent when assessed by GLS than by 2D LVEF among adult survivors of childhood, adolescent, and young adult cancer. 2DSTE may be useful for the long-term follow-up in this high risk population to identify patients with subclinical LV systolic dysfunction despite a normal LVEF. Mediastinal radiotherapy appears to be an independent risk factor for the development of LV systolic dysfunction in patients treated with anthracycline chemotherapy, and additional studies are needed to further explore the effect of possible confounders. Whether early identification of subclinical LV systolic dysfunction using 2DSTE will translate into long-term cardiovascular benefits warrants further investigation.


Chagas' heart disease (CHD) is a common cause of non-ischemic cardiomyopathy in Latin America. In CHD, male gender has been shown to have worse clinical prognosis, but the reasons for that remain unclear. Cardiovascular magnetic resonance (CMR) imaging is able to assess the extent of myocardial fibrosis (MF), which correlates to left ventricle ejection fraction (LVEF), and is a marker of disease severity. Our objective was to investigate whether male gender is associated to greater myocardial injury, assessed by CMR as myocardial fibrosis and dysfunction.2, Fisher exact tests, t test and Mann-Whitney test when appropriate and for correlation Spearman test, were performed using Stata 12.We retrospectively analyzed 139 patients with CHD of 3 previous CMR studies from 2 different sites. Patients had CMR examination on 1.5 T MRI systems with cine-MR with SSFP sequence for left ventricle function evaluation and late gadolinium enhancement for myocardial fibrosis detection. LV volumes and function were measured by Simpson's method. All analyses were performed using CVi42 software . χLVD was present in 45.3% of patients and was more frequent in male than in female . The presence of MF was greater in male than in female group . Quantified MF was significantly higher in males . Functional class (FC-NYHA) was also significantly greater in males (Table In our group of 139 CHD patients, male gender was associated with higher degree of myocardial fibrosis and left ventricle dysfunction measured by CMR. Moreover, gender and myocardial fibrosis were independent predictors of myocardial dysfunction. This is the first demonstration that myocardial injury assessed by CMR as myocardial fibrosis and dysfunction is greater in male gender, which parallels the epidemiological data indicating worse clinical prognosis in males. Further studies are necessary to investigate the pathophysiology behind these findings in humans.N/A.


Myocardial infarction results in myocardial scarring which can have an impact on left ventricular (LV) stiffness and contractile function, ultimately leading to reduced LV systolic function and LV remodelling, However controversy remains about the relation between scar extension and segmental wall motion contractility global systolic function, and LV remodelling.To elucidate the relationship between scar extension, wall motion score index (WMSI), LV dimensions and systolic function in a group of patients with previous myocardial infarction by cardiac magnetic resonance (CMR).133 patients with previous (>6 month) myocardial infarction were retrospectively enrolled in the study. Indexed end-systolic volume (ESVi), indexed end-diastolic volume (EDVi), LV ejection fraction (EF), stroke volume (SV), left ventricular mass, WMSI and sum scar score (SSS) were measured using cardiac magnetic resonance.A total of 2261 segments were studied: regional wall motion abnormalities were present in 1032 segments (45 %) and 724 (32 %) showed presence of myocardial infarction  and segments. WMSI correlated significantly with EF (r=-0.87 p<0.0001) in all patients; both in patients with EF ≥40% (r=-0.77 p<0.0001) than in patients with EF<40% (r=-0.68 p<0.0001). WMSI also correlated significantly with SSS . However, correlation between WMSI and SSS was more significant in patients with transmural myocardial infarction  than non transmural myocardial infarction . Significant correlation was found between EF and SSS (r=-0.55 and p<0.0001) and between SSS and LV indexed volumes .Patients with transmural MI demonstrated a more impaired global and regional systolic function together with increased LV dimension. Beyond transmurality, scar extension evidenced even more relation with both segmental and global wall motion abnormalities as well as systolic dysfunction. This emphasised the importance of CMR to evaluate all at once scar dimensions, segmental wall motion and subsequent LV remodelling.This research was supported by NIHR Bristol Cardiovascular Biomedical Research Unit.