Cardiac magnetic resonance imaging (CMR) has an important emerging role in the evaluation and management of patients who present with symptoms concerning for acute coronary syndrome (ACS). This paper discusses the role of CMR in the emergency department setting, where CMR can aid in the early and accurate diagnosis of non-ST elevation ACS in low and intermediate risk patients. For those with confirmed myocardial infarction (MI), CMR provides comprehensive prognostic information and can readily diagnose structural complications related to MI. Furthermore, the pattern of late gadolinium enhancement (LGE) seen on CMR can help determine the etiology of cardiac injury in the subset of patients presenting with ACS who do not have obstructive coronary artery disease by angiography. Currently, more than a third of the 5.5 million people who present to the emergency department (ED) annually in the United States with a chief complaint of chest pain are admitted to the hospital, while only about a third of those admitted are eventually given the diagnosis of acute coronary syndrome (ACS) , 2. ThusT2-weighted imaging due to the increased water content of the myocardium. Edematous tissues with higher water content have longer T2 relaxation times, leading to a brighter signal on T2-weighted images. First-pass myocardial perfusion is assessed using saturation-recovery gradient echo techniques during intravenous injection of gadolinium contrast agents. This can be performed during pharmacologic stress using adenosine or dobutamine infusion providing an assessment of myocardial ischemia. Myocardial scar is assessed by late gadolinium-enhanced (LGE) imaging, the pattern of which can help differentiate infarction from nonischemic processes. Regions with myocardial scar have a higher concentration of contrast agent and, thus, appear bright in these images. Conversely, areas of microvascular obstruction, thrombus, and myocardial hemorrhage appear dark on LGE imaging. A complete CMR protocol can be performed in less than 45 minutes providing a rapid comprehensive assessment of the heart.CMR is capable of performing a rapid and comprehensive evaluation of cardiac anatomy, function, and myocardial perfusion at rest and/or during stress. CMR can accurately identify the presence of infarction, myocardial edema, microvascular obstruction, and intramyocardial hemorrhage. The sequence of a typical CMR exam for ACS usually begins with anatomic images of the chest, which can often provide clues about other pathologies that may be causing the patient's chest pain. Cine steady-state free precession imaging provides an assessment of myocardial and valvular function and enables accurate assessment of left ventricular ejection fraction (LVEF) and ventricular volumes. CMR can assess myocardial edema and inflammation using T2-weighted imaging and LV wall thickness quantification to distinguish acute events [T2-weighted imaging enables visualization of edema associated with acute, but not chronic, myocardial infarction [T2-weighted imaging accurately identified all acute MI cases, often before cardiac biomarkers became elevated. Compared with conventional CMR, the addition of T2-weighted edema imaging and wall thickness quantification increased specificity from 84% to 96%, positive predictive value from 55% to 85%, and overall accuracy from 84% to 93%; respectively, while sensitivity remained unchanged at 85% [CMR has been shown to improve both the diagnostic accuracy and time to diagnosis of ACS in the emergency department setting. This was demonstrated in a study of 161 patients presenting to the ED within 12 hours of onset of symptoms concerning for ACS, but without ST elevation on ECG . The CMRfarction . In thisA large proportion of low- and intermediate-risk patients presenting to the ED with symptoms concerning for ACS without evidence of MI undergo additional functional or anatomic imaging on either an inpatient or outpatient basis. CMR has been shown to compare favorably to other non-invasive cardiac imaging modalities for diagnosing ischemia. In a study by Nagel et al., 208 patients with suspected CAD underwent both dobutamine stress echo and dobutamine stress CMR prior to cardiac catheterization . The senThe costeffectiveness of using stress CMR to evaluate intermediate- and high-risk patients in the ED setting was evaluated in a study of 110 patients with chest pain, negative ECG, and negative initial biomarkers, being admitted to the hospital to rule out MI . These pFor those patients who present early after symptom onset with ST elevation MI (STEMI) or without ST elevation, but with elevated cardiac biomarkers , an early invasive strategy with cardiac catheterization is generally recommended . In thesLeft ventricular function has long been known to predict outcomes after MI. Impaired LV systolic function and an elevated LV end-systolic volume (ESV) are both powerful independent predictors of increased mortality –24. CMR CMR-based assessment of infarct size using late gadolinium enhancement (LGE) is well validated and has been shown to be highly predictive of cardiac events at followup. Yokota et al. evaluated 86 patients with prior MI by CMR and found that infarct size by LGE was a better predictor of cardiac events than LVEF, LVESV or LVEDV, at 20 month follow up . Cheong Microvascular obstruction (MO) refers to severe capillary and endothelial damage induced by prolonged ischemia, which prevents blood flow into the infarcted core after reperfusion. The extent of MO usually peaks between 2 hours to 2 days after reperfusion occurs –33, afteCMR has become the gold standard for assessment of MO, due to its excellent spatial resolution and tissue characterization ability. MO can be assessed by CMR using two separate techniques. Early MO is visualized early after contrast injection using first-pass perfusion. Typical protocols using this method define MO as hypoenhancement of the myocardium persisting longer than 1 to 2 minutes after initial contrast injection. The second technique collects late LGE images 10 to 15 minutes after contrast injection, and MO appears as an area or areas of hypoenhancement encompassed within a core of enhanced infarcted myocardium, often extending from the subendocardium. This latter method in the literature is sometimes termed persistent or late MO. Both methods of MO assessment have been validated, and there is not yet a clear consensus as to which method should be the preferred technique. Early MO has been shown to be predictive of long-term infarct size, infarct transmurality, LV function, and LV remodeling and is also a powerful independent long-term prognostic indicator of hard cardiac events even after controlling for infarct size , 35; howT2-weighted CMR, correlates very well to the area at risk determined histologically with fluorescein staining [T2-weighted in vivo CMR measurement of the area at risk 2 days following MI showed excellent correlation to the area at risk determined by fluorescent microspheres at the time of coronary occlusion [The region of ischemic myocardium within the perfusion bed of an occluded coronary artery is the “area at risk” of infarction and is potentially salvageable with appropriate and timely intervention. The area at risk, as measured by staining . Similarcclusion . P < 0.001) [T2-weighted CMR to detect myocardial salvage and predict adverse events, it may become an extremely valuable surrogate measure of outcome in studies of reperfusion therapy. Accurate assessment of both infarct size and the area at risk allows noninvasive measurement of a potentially clinically important parameter: the amount of myocardial salvage. The myocardial salvage index (MSI) is a measure of the myocardium that has been spared infarction, presumably due to a given procedure or treatment, and has important prognostic significance. CMR trials of STEMI patients undergoing PCI have repeatedly shown that an increase in the time from symptom onset to PCI leads to a significant incremental increase in infarct size and microvascular obstruction, with a corresponding decrease in myocardial salvage, while the extent of myocardial edema, or area at risk, remains unchanged , 41. A t< 0.001) . MSI wasAnother prognostic indicator after MI is the presence of right ventricular (RV) infarction. RV infarction has been associated with an increased risk of cardiogenic shock, atrioventricular conduction block, and rupture of the interventricular septum . In-hospDue to CMR's unique tissue characterization abilities and spatial resolution, it is an ideal imaging modality for assessing complications arising after MI. CMR is widely considered the gold standard for analyzing both regional and global ventricular function after MI  and can T2-weighted CMR, can help differentiate acute from chronic episodes of both ischemic and nonischemic events, and has been found to be present in acute episodes of Tako-Tsubo's cardiomyopathy [An estimated 9–14% of patients who are diagnosed with STEMI will be found to have normal coronary arteries at cardiac catheterization . These pmyopathy , 62, myomyopathy , cardiacmyopathy , pulmonamyopathy , acute tmyopathy , and recIn the current era of cost awareness, there is an appropriate focus on the ability of an imaging modality to improve cost and real patient outcomes when compared with other available diagnostic strategies. As already discussed, there is a relatively large body of evidence demonstrating that CMR offers excellent diagnostic and prognostic data in ACS patients and that it compares favourably to other imaging modalities. It has also been found to be cost effective in a selected population of patients presenting to the ED with suspected ACS . CMR canT2-weighted imaging of edema and late gadolinium enhancement have the ability to detect infarction and severe ischemia early in the course of MI, even before cardiac biomarkers become elevated, and can differentiate acute from chronic infarction. Importantly, adding CMR to the emergency physician's tool belt has been shown to improve diagnostic accuracy compared to current standards of care and to be cost effective in certain populations. Taken together, CMR provides a wealth of meaningful diagnostic and prognostic data for a wide range of patient populations with suspected or confirmed acute coronary syndrome.CMR has emerged as a robust diagnostic imaging modality capable of providing a comprehensive cardiac evaluation for patients with ACS. CMR is widely regarded as the reference standard for assessment of cardiac structure and function. In patients with acute myocardial infarction, CMR provides powerful diagnostic and prognostic information, allowing evaluation of cardiac function, infarct size and location, infarct complications, the extent of edema or area at risk, the amount of myocardial salvage, and the status of the microvasculature—all in a single scan. CMR has been shown to be safe, even immediately after PCI in STEMI patients , 19, and


Aortic stenosis (AS) and systemic hypertension (HT) are associated with increased interstitial myocardial fibrosis (IMF). T1-mapping-derived extracellular volume fractions (Ve) have been shown to correlate with IMF in AS patients after infusion of gadolinium. We hypothesized that interstitial expansion could be detected after bolus gadolinium administration in patients with HT or severe AS when compared to healthy controls; and that these measures would correlate with both histological assessment of fibrosis from LV biopsies and abnormal myocardial strain.A Modified Look-Locker Inversion Recovery (MOLLI) sequence was used to generate 11 T1-weighted images in 3 groups of subjects: 1) Healthy Volunteers , 2) Severe AS, 3)Patients with significant but controlled hypertension. Myocardial and blood pool T1 values were derived by fitting a signal intensity-time curve using CMR42®. The λ was determined by plotting (1/T1myo vs. 1/T1blood pool) at various time points once contrast equilibrium was reached. Ve was derived accounting for hematocrit. Multiple short- and long-axis T1 maps were acquired at 1.5T  before and 1,2,5,8,15,20,25 and 30 minutes after contrast. Myocardial tagging was acquired using single- and multiple-breath-hold CSPAMM sequences in multiple planes and analyzed with inTag® . Histological validation was performed by biopsy of the LV septal and free walls during AV replacement surgery.Sixty-three subjects  were recruited to the study. Subjects with HT and severe AS displayed higher Ve when compared to healthy controls (p<0.01), with AS patients demonstrating higher Ve than those with HT (p=0.008, Figure Multi-slice T1-mapping-derived Ve is significantly elevated in patients with AS and also in those with systemic hypertension compared to healthy controls and correlates well with histology and indices of reduced myocardial performance. Multi-slice T1-mapping Ve measurement after bolus gadolinium administration is clinically practical and holds promise for the detection of IMF in pressure-overload hypertrophy.This project was supported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust, the British Heart Foundation, and CORDA. Dr. Jabbour was supported by a Postdoctoral.Research Fellowship from the National Health and Medical Research Council of Australia, a Vincent Fairfax Family Foundation Research Fellowship from the Royal Australasian College of Physicians, the St. Vincent’s Clinic Foundation, and the Victor Chang Cardiac Research Institute.


The amount and location of left ventricular (LV) mechanical dyssynchrony affects an individual’s ability to respond positively to cardiac resynchronization therapy (CRT) [Bax et al JACC 2005]. By using high temporal resolution short-axis cines, it is possible to derive radial motion curves throughout the LV. These radial motion curves can be used to create maps showing dyssynchronous regions in patients enrolled for CRT.The objective of this study was to characterize the size and location of areas of mechanical dyssynchrony in patients scheduled for CRT by comparing their radial wall motion curves to radial motion curves from normal subjects.CMR was performed in 5 normal subjects with no presence of dyssynchrony (QRS<120ms) and 13 patients scheduled for CRT that met current inclusion criteria .reference curve was generated for each patient by averaging all curves with a similar trajectory using quality threshold (QT) clustering. The temporal delay between the radial motion curves at each location relative to the reference was determined using cross-correlation analysis. By repeating this analysis at all locations throughout the LV, a mechanical dyssynchrony map was generated and projected onto an AHA 17-segment bullseye.Endocardial borders were traced in normal subjects and patients on high-temporal resolution SSFP short-axis cines (60 frames per cardiac cycle). Radial shortening at 100 locations around the contour relative to the center of mass of the LV was determined for each slice. A The mean and standard deviation of delay times throughout the LV were determined in the normal subjects. A “normal file” was defined using a 95% confidence interval based on these subjects. By comparing patients to this normal file, we could identify 1) the most dyssynchronous region and 2) the size of this dyssynchronous region.In the normal subjects, the normal range of delay times was -49 to 47 ms.The most dyssynchronous region was posterolateral in 6 patients, anterolateral in 4 patients, and septal in 4 patients. The CRT patients had an average of 8.6±1.9dyssynchronous segments which comprised 48.9±12.1 % of the LV, figure Using cross-correlation analysis of radial displacement curves from high temporal resolution cine CMR images, regional mechanical dyssynchrony maps can be generated. By comparing patients to a “normal file”, the size and location of dyssynchronous regions in the LV can be determined. These maps could be used for CRT LV lead placement planning.This research was funded by the National Science Foundation Graduate Research Fellowship and the American Heart Association.


Fibroblasts comprise the largest cell population in the myocardium. In heart disease, the number of fibroblasts is increased either by replication of the resident myocardial fibroblasts, migration and transformation of circulating bone marrow cells, or by transformation of endothelial/epithelial cells into fibroblasts and myofibroblasts. The primary function of fibroblasts is to produce structural proteins that comprise the extracellular matrix (ECM). This can be a constructive process; however, hyperactivity of cardiac fibroblasts can result in excess production and deposition of ECM proteins in the myocardium, known as fibrosis, with adverse effects on cardiac structure and function. In addition to being the primary source of ECM proteins, fibroblasts produce a number of cytokines, peptides, and enzymes among which matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), directly impact the ECM turnover and homeostasis. Function of fibroblasts can also in turn be regulated by MMPs and TIMPs. In this review article, we will focus on the function of cardiac fibroblasts in the context of ECM formation, homeostasis and remodeling in the heart. We will discuss the origins and multiple roles of cardiac fibroblasts in myocardial remodeling in different types of heart disease in patients and in animal models. We will further provide an overview of what we have learned from experimental animal models and genetically modified mice with altered expression of ECM regulatory proteins, MMPs and TIMPs. Myocardium is comprised of a number of cell types, cardiomyocytes, cardiofibroblasts, endothelial cells and smooth muscle cells. Cardiac fibroblasts (CFBs) have the highest cell population in the myocardium, accounting for about two-thirds of the cells, while cardiomyocytes constitute about two-thirds of the myocardial tissue volume , althougA number of cell surface markers have been identified for FBs and CFBs, but over time their specificity to these cells has been challenged. Vimentin, a protein that is present in the intermediate filaments of FBs, has been the most widely used FB marker – and although it is also expressed in other cell types such as endothelial cells  and myoeIn response to appropriate stimuli, most commonly myocardial injury, CFBs can differentiate into myofibroblasts (myoFBs), which are more mobile and contractile with a greater synthetic ability to produce ECM proteins . MyoFBs,In vitro, αSMA expression levels in cultured CFBs are increased by passaging, and after the third passage CFBs are believed to become myoFBs [Cardiac injury triggers CFBs to be differentiated to myoFBs, which have a stronger ability to produce ECM proteins. MyoFB have been demonstrated to play a key role in reparative fibrosis in the infarcted heart , and to e myoFBs  with elee myoFBs . TransfoCFBs are derived from mesenchymal cells. During heart development, epicardial cells formed by migration of proepicardial cells over the embryonic heart undergo epithelial-to-mesenchymal transformation and subsequently differentiate into FBs . This trInjury to the heart can trigger amplification of resident CFBs, transformation of endothelial or epithelial cells to FBs, or recruitment of hematopoietic cells originating from the bone marrow to the site of injury and their transformation into CFBs and myoFBs Figure . Myocardin vitro[Bone marrow-derived cells and circulating blood cells such as monocytes and fibrocytes are another source of CFBs in response to injury . Monocytin vitro, but thein vitro. In summCFBs are involved in many aspects of cardiac functions, such as homeostasis and remodeling of the cardiac ECM, cell–cell communication with cardiomyocytes, electrical activity, production of growth factors and cytokines, and intercellular signaling with other CFBs, endothelial or smooth muscle cells that can impact cellular events such as angiogenesis, cell proliferation, cardiomyocyte hypertrophy or apoptosis Figure . FBs canOne of the primary functions of CFBs is maintaining the integrity of the cardiac ECM, a network structure that in addition to providing structural and functional integrity to the heart, also contains a number of cytokines and growth factors that can impact cardiac function and the fate of cardiac cells. Cardiac ECM is critical in mediating the mechanical connection among the cardiomyocytes, CFBs and the blood vessels within the myocardium. The ECM also transmits extracellular mechanical signals to the cardiomyocytes. The ECM is mainly comprised of fibrillar collagen types I and III, as well as less abundant collagen types IV, V and VI. The ECM also includes fibronectin, laminin, elastin and fibrillin, proteoglycans and glycoproteins. CFBs are the primary source of all of these ECM proteins , which c2+-activated proteases that are synthesized as inactive zymogens (pro-MMPs), and can be activated by removal of an amino-terminal propeptide domain and exposure of the catalytic domain. Among the 26 MMPs cloned and characterized in vertebrates, the MMPs so far identified to be involved in myocardial remodeling are as follows: MMP1, MMP3, MMP8, MMP13, MMP2, MMP9, MMP12, MMP28 and the membrane-type MMPs (MT1-MMP/MMP14) [In addition to producing ECM proteins, CFBs also produce ECM-regulatory proteins – matrix metalloproteinases (MMPs), which can degrade ECM proteins – and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). A well-controlled balance between the function of MMPs and TIMPs is critical in maintaining ECM homeostasis . MMPs arP/MMP14) -69, althP/MMP14) -73. AlthP/MMP14) . RodentsP/MMP14) , primariP/MMP14) . The proP/MMP14) . Four TIP/MMP14) , among wP/MMP14) ,78-80. TP/MMP14) . AlthougP/MMP14) ,82.−/−, MMP8−/−, MMP2−/−, MMP9−/−, MMP14−/− (or MT1-MMP−/−) and MMP16−/− (or MT3-MMP−/−)), Sabeh and colleagues demonstrated that only the membrane-anchored MMP14 is required for focal collagen invasion required for FB migration through the stroma, compared with bulk collagenolysis by the soluble MMPs [CFBs can produce a number of MMPs and TIMPs -86 whereble MMPs .While CFBs are the main source of ECM regulatory proteins, MMPs and TIMPs, these molecules can also impact on CFB function. MT1-MMP can cleave a number of ECM proteins including fibronectin, laminin-1 and fibrillar collagen type I -73, and Remodeling of the ECM is a key component of cardiac remodeling that occurs in disease. Disruption of the ECM network structure interrupts the connection between the myocardial cells and blood vessels, thereby compromising the structural integrity and function of the heart. On the other hand, excess production and accumulation of ECM structural proteins, or fibrosis, results in enhanced stiffness of the myocardium and impedes ventricular contraction and relaxation, leading to distorted architecture and function of the heart. Excess collagen deposition and fibrosis has been clearly linked to myocardial stiffness, diastolic and systolic dysfunction . FibrosiFibrillar collagen types I and III are the predominant components of cardiac ECM. These collagens are produced as pro-collagens that are then processed into mature collagen molecules upon cleavage of their pro-peptide domain by procollagen peptidase. Assembly and cross-linking of mature collagen molecules gives rise to collagen fibrils and collagen fibers. During physiological ECM turnover or pathological ECM remodeling, collagen fibers are degraded and the telopeptides in the amino-terminals or carboxy-terminals of collagen molecules are cleaved Figure . The proDifferent reports have been made with respect to collagen turnover in hypertensive patients. Reduced serum CITP, a marker of collagen type I degradation, was suggested to explain collagen deposition and fibrosis in hypertensive patients , whereasIn patients with coronary artery disease but no MI, serum levels of PIIINP, but not PINP, correlated well with the number of diseased vessels and severity of coronary artery disease . In addiIn using plasma biomarkers for ECM remodeling in patients with heart disease, it is important to keep in mind that collagen type I is the most abundant collagen in the human body and is ubiquitously expressed in almost all organs and tissues in the body. Although collagen type III shows a relatively more tissue-specific expression pattern, it is also highly expressed in the skin, lungs and the vasculature. Hence, development of more cardiac-specific plasma biomarkers would provide more accurate insight into ECM alterations in the myocardium.Alterations in MMPs and TIMPs levels have been studied in different types of heart disease as a surrogate measure of myocardial ECM remodeling. In patients with end-stage dilated cardiomyopathy, analysis of LV myocardial tissue showed decreased MMP1, increased MMP3, MMP9, TIMP1 and TIMP2, and no changes in MMP2 levels . Picard In patients with MI and unstable angina, serum levels of MMP2 and MMP9 (but not MMP1), TIMP1, TNFα and IL-6 were significantly elevated compared with healthy controls, suggesting that these MMPs, TIMP1 and proinflammatory cytokines could play an important role in the pathophysiology of acute coronary syndrome . MeasureMI results from occlusion of a coronary artery, subjecting the downstream myocardial tissue to hypoxia and ischemia. The remodeling process consists of a series of timed molecular events that include recruitment of inflammatory cells, proliferation of CFBs or recruitment of circulating bone-marrow-derived cells and their differentiation to myoFBs, and formation of the fibrotic scar tissue. Experimental models of myocardial ischemic injury can be generated in different species by permanent or temporary ligation of the left anterior descending coronary artery resulting in MI or ischemia–reperfusion, respectively. Ischemia–reperfusion results in greater inflammatory cell influx and prolonged inflammatory response compared with MI, whereas in the MI model a greater number of CFBs are detected at the injury site, which correlates well with greater degree of fibrosis and ECM remodeling in the MI compared with the ischemia–reperfusion model . CFBs arIn hypertensive heart disease, reactive myocardial fibrosis increases myocardial stiffness and reduces compliance. Roles of MMPs and TIMPs have been indicated in the myocardial fibrosis in a number of hypertensive animal models. Deoxycorticosterone acetate salt-hypertensive rats showed higher collagen deposition through endothelin-1-mediated TGFβ expression . This waWhile TGFβ is well known to activate the Smad signaling pathway in CFBs, thereby mediating FB activation and collagen production, a recent study by Koitabashi and colleagues demonstrated that the TGFβ signaling pathway in the cardiomyocytes via TGFβ-receptor 2 plays a critical role in myocardial fibrosis following pressure overload . Cardiomin vitro [−/−), resulted in hypertension, cardiac hypertrophy, congestive heart failure and sudden death at 6 months of age [Atrial natriuretic peptide and BNP have been shown to inhibit FB proliferation, collagen synthesis and MMP release via activation of the cGMP pathway , and to in vitro ,126. Thein vitro . Deletios of age ,129. Eles of age . Atrial s of age ,132 as ws of age ,134, ands of age . Taken tAs discussed earlier, a tightly controlled balance between the function of MMPs and TIMPs is critical in maintaining the ECM integrity. A number of experimental animal models have been developed in order to determine the contribution of MMPs and TIMPs in ECM remodeling in heart disease, and genetically modified mice have provided valuable tools in examining the causal role of MMPs and TIMPs in this process.−/− mice, MI led to greater LV dilation and increased LV end-diastolic volume compared with parallel wildtype mice [−/− and TIMP4−/− impaired ECM remodeling in these mice. Second harmonic generation imaging further revealed reduced density and greater disarray of fibrillar collagens in the infarct myocardium of TIMP3−/− and TIMP4−/−, consistent with the increased rate of LV rupture in these mice [Targeted deletion of MMP2 improved post-MI survival by hindering macrophage infiltration and reducing the rate of LV rupture . MMP7 haype mice . In miceype mice . Lack ofype mice , whereasype mice . While lese mice ,141. The+/−) [Mice overexpressing MT1-MMP showed lower survival and ejection fraction post MI compared with parallel wildtype mice, whereas these parameters were improved in mice with reduced MT1-MMP levels (MT1-MMP+/−) . Overexp+/−)  and rat +/−)  models o+/−) .−/− mice exhibit greater LV dilation and dysfunction, with non-homogeneous ECM remodeling which was characterized by areas of disrupted ECM network adjacent to regions of fibrotic lesions [−/− hearts was not due to increased expression of collagen type I and/or type III, however, but due to elevated levels of SPARC (secreted protein acidic and rich in cysteine) and enhanced post-translational stabilization of collagen fibers [−/− mice exhibited comparable cardiac remodeling, dysfunction and myocardial fibrosis compared with the parallel wildtype mice [Pressure overload exerts a mechanical stress on the ventricles and can trigger cardiac hypertrophy and fibrosis. In this model of heart disease, the excessive biomechanical stress is transmitted to ECM and cell–ECM connections that can lead to adverse remodeling of the ECM, and can further activate the intracellular signaling pathways leading to cardiac hypertrophy, fibrosis and cell death. MMP2-deficient mice showed reduced myocardial hypertrophy and fibrosis , while M lesions . Myocardn fibers . Cardiacn fibers , and to n fibers . The exan fibers , while mn fibers . Interesype mice .The ECM is an integral component of the myocardium, and the factors that influence the integrity of the ECM structure also impact cardiac structure and function. Cardiac FBs play a central role in the physiological turnover of the ECM as well as its pathological remodeling. Although cardiac FBs are often associated with cardiac fibrosis and adverse outcomes, it is important to note that the primary function of FBs is tissue repair  – which in cases such as MI is in fact beneficial, and its interruption would have undesirable outcomes. In addition, MMPs are traditionally known for degrading the ECM proteins, and TIMPs to inhibit this process. However, MMPs can also promote ECM production (and fibrosis) by regulating the activity of FBs, and similarly TIMPs can influence FB behavior and ECM production in a MMP-independent fashion. Hence, it is critical to understand the diverse functions of MMPs, TIMPs and FBs towards developing effective therapies to control harmful myocardial fibrosis.AMI, acute myocardial infarction; αSMA, alpha smooth muscle actin; BNP, brain natriuretic peptide; CFB, cardiac fibroblast; CITP, carboxy-terminal telopeptide of collagen type I; CIIITP, carboxy-terminal telopeptide of collagen type III; DDR, discoidin domain receptor; ECM, extracellular matrix; FB, fibroblast; IL, interleukin; LV, left ventricular; MI, myocardial infarction; miRNA, microRNA; MMP, matrix metalloproteinase; MT-MMP, membrane-type matrix metalloproteinase; myoFB, myofibroblast; NITP, amino-terminal telopeptide of collagen type I; NIIITP, amino-terminal telopeptide of collagen type III; PICP, carboxy-terminal propeptides of collagen type I ; PINP, amino-terminal propeptides of collagen type I ; PIIICP, carboxy-terminal propeptides of collagen type III ; PIIINP, amino-terminal propeptides of collagen type III ; TIMP, tissue inhibitor of metalloproteinase; TGFβ, transforming growth factor beta; TNF, tumor necrosis factor.The authors declare that they have no competing interests.DF and ZK conceived the original concept of the review. DF contributed to 50%, and AT and JL each contributed to 25% of the first draft. All authors read and approved the final manuscript.


Camelus dromedarius).Echocardiography and intra-cardiac dimensions have not previously been reported in adult camels despite its potential application for medical purpose. The aim of this study was to describe the results of a prospective study, aiming to report normal cardiac appearance and normal chamber dimensions in adult camels , the caudal long-axis four-chamber view of the ventricles, atria, and the interventricular septum was obtained. Placing the probe slightly more cranially in the 4th ICS, the caudal long-axis four-chamber view and the caudal long-axis view of the left ventricular outflow tract (LVOT) were imaged. In 7 camels, a hybrid view between a “four-chamber” and “LVOT view” was imaged from the same position. The short-axis view of the ventricles was obtained in the 4th ICS where the transducer was rotated between 0° and 25°. Placement of the transducer in the 3rd ICS allowed visualisation of the right ventricular outflow tract (RVOT). On the left side, when the probe was placed in the 5th or 4th ICS, a four-chamber view was obtained. The LVOT is imaged in the 4th ICS and the RVOT was seen from the 3rd ICS.On the right side, when the probe was placed in the 5This study showed that it is possible to obtain good-quality echocardiograms in adult camels and provide normal cardiac dimensions. This study could be used as a reference for further studies concerning camels with cardiac diseases. The dromedary camel is important species in Africa, Middle-East and Australia. Despite their valuable use as draft animals, it is also used for milk and meat production. In the northern hemisphere, it is mainly kept as a companion animal or found in the circus or zoological collections, and can therefore have a worldwide veterinary importance due to the relatively high value . In the The heart diseases listed above are mostly diagnosed at slaughterhouses or incidentally discovered at postmortem examination , showingEchocardiography is a good ancillary tool to assess the heart in other ruminant species. It is a non-invasive, straightforward method for assessment of the bovine heart . It has In camel practice, ultrasonography has been used mainly for examination of the reproductive tract -16. The Camelus dromedarius) (age: 8.8 ± 3.8 years) were examined at the Veterinary Teaching Hospital, Qassim University, Saudi Arabia. Of the 22 camels, 2 (9%) were males and 5 (25%) were 2–3 month pregnant females, whilst the others were non-pregnant and non-lactating females. Their BCS ranged from 3.0 to 3.75 and weighed 514 ± 69 kg. All camels received a full clinical examination [Laboratory Animal Control Guidelines of Qassim University, which basically conform to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health in the USA . The experimental protocol has been approved by the Animal Ethical Committee, Deanship for Scientific Research, Qassim University.Twenty-two adult camels (mination  includinmination . All camrd to 6th) on both sides of the thorax were clipped, shaved and swabbed with alcohol to remove excess oil, and coupling gel was applied. The third, fourth and fifth intercostal spaces in the cardiac region were examined ultrasonographically on the right and then the left sides of the thorax. The thoracic limbs were moved cranially to facilitate better contact between the probe and the intercostal space. In the cardiac area, the heart, valves and major blood vessels were imaged.First, the forelimb of each camel was bent and tied with a rope on the carpal joint. The head was then held and the animal was pushed until it was positioned in a sternal recumbency. The fore-and-hind limbs were then tied by a rope near the carpal and hock joints, respectively. All echocardiographic examinations were performed in the recumbent animal. Camels were sedated using xylazine (0.02 mg/kg IV) . Echocardiographic examinations were performed using an ultrasound machine with a 3.5 MHz sector transducer . In preparation for the echocardiography, the intercostal spaces , a caudal short-axis view of the ventricles and a cranial long-axis view of the right ventricular outflow tract (RVOT). On the left side, a caudal long-axis view of the heart (four-chamber view), a caudal long-axis view of the LVOT and a cranial long axis-view of the RVOT were obtained. The intercostal space and probe orientation used to obtain each image was recorded at the end of each examination.The cardiac views obtained in this study are adaptation of those described for cattle ,9,17. Foth intercostal space (ICS) with a slight clockwise rotation or perpendicular in the 4th ICS. Left ventricular diameter in systole (LVs) diastole (LVd), left atrium diameter in systole (LAs) and diastole (LAd), left ventricular wall thickness in systole (LVWs) and diastole (LVWd) and mitral valve diameter in systole (MVDs) were measured from the left parasternal view with the transducer positioned in the 5th or 4th ICS and directed slightly caudodorsally. Aortic diameter in diastole (AOd) was measured from the left parasternal view with the transducer placed in the 4th ICS turned slightly more cranially and rotated slightly counter clockwise. Pulmonary artery diameter in diastole (PAd) was measured from the left parasternal view with the transducer placed obliquely in the 3rd ICS. Systolic measurements were measured during closure of the atrioventricular valves and opening of the semilunar valves, whilst diastolic measurements were measured during opening of the atrioventricular valves and closure of the semilunar valves. Ventricular measurements were measured at the level of the papillary muscles close to the chordae tendinae, whilst atrial measurements were measured at the widest part of the atria. Data are expressed as mean ± SD. At the end of the study, all the camels were slaughtered and their hearts were examined macroscopically.Echocardiographic measurements were performed using the electronic ultrasound calipers. Echocardiographic examinations were performed in the camels by the same operator (M.T.). Three non-consecutive cardiac cycles were measured and later measurements were averaged in order to eliminate some of the measurement errors. Eighteen measurements were recorded from the 2-D images. Right ventricular diameter in systole (RVs) and diastole (RVd), right atrial diameter in systole (RAs) and diastole (RAd), right ventricular wall thickness in systole (RVWs) and diastole (RVWd), interventricular septal thickness in systole (IVSs) and diastole (IVSd) and tricuspid valve diameter in systole (TVDs) were measured from the right parasternal caudal long-axis four-chamber view with the probe placed in the 5The camels in this study had no history or evidence of cardiac dysfunction. No abnormalities were detected on clinical examination of the cardiothoracic systems of any of the animal and no murmurs or dysrhythmia were detected by cardiac auscultation. On clinical evaluation, mean rectal temperature was 36.6 ±0.6 °C , mean heart rate was 36 ± 8 bpm  and mean respiratory rate of 10 ± 4 bpm . Postmortem examination of the camels’ hearts revealed no epicardial, myocardial or endocardial anomalies.th intercostal space with a slight clockwise rotation or perpendicular in the 4th ICS, the caudal long-axis four-chamber view of the ventricles, atria, and the interventricular septum was imaged  were imaged in 17 camels . The RVOT was seen from the 3rd intercostal space . Although the clinical significance of the αThe data presented in this paper demonstrates that it is possible to obtain good quality echocardiograms in adult camels and provide normal cardiac dimensions to compare against diseased animals. This study is thus relevant for the diagnosis of early manifestations of cardiac disease in adult camels. The technique is relatively straightforward but does require some physical strength. Application of the normal ranges generated in this study has the potential to confirm or deny the presence of cardiac diseases in camel patients with cardiovascular disease. In addition, echocardiographic measurements in the healthy camels may be used as prognostic values in sick camels with heart diseases. In this regard, echocardiographic findings should be compared with the normal reference ranges described in this study.MT and SB initiated and planned the study. MT, FA and AA carried out the ultrasonographic and postmortem examinations. MT wrote the manuscript and made the figures. SB read and revised the manuscript. All authors have read and approved the manuscript.MT: DVM, MSc, PhD, Associate professor, Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Saudi Arabia. Permanent address: Department of Animal Medicine, Faculty of Veterinary Medicine, Zagazig University, Egypt. FA: DVM, MSc, PhD, Professor, Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Saudi Arabia. AA: DVM, MSc, PhD, Professor, Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Saudi Arabia. SB: Dr Vét, DÉS, MSc, DACVIM, Associate professor, Clinique ambulatoire bovine/Bovine ambulatory clinic, Faculté de médecine Vétérinaire, Université de Montréal, CP 5000, St-Hyacinthe, J2S 7 C6, Québec, Canada, Tel/Phone 450 773 8521 ext 8675, Fax 450 778 8120.


Our study demonstrates that diabetic patients have increased myocardial edema in the infarct segment at an early time point post acute myocardial infarction which persists till the subacute phase. This may lead to deleterious left ventricular remodeling and worse outcome in these patients.Diabetes is associated with worse left ventricular remodeling and poor prognosis in patients post acute myocardial infarction (AMI). The impact of diabetes on microvascular injury parameters including myocardial edema and hemorrhage post AMI is unknown. Our objective was to characterize the evolution of myocardial edema and hemorrhage post AMI in patients with and without diabetes.Sixty patients were enrolled post AMI and underwent cardiac magnetic resonance on a GE Signa Excite, 1.5T scanner with a 8-channel receive coil at 48 hours and 3 weeks. T2 maps were computed from a previously validated cardiac-gated spiral imaging sequence with T2 preparations yielding TEs=2.9,24.3,88.2,184.2ms to assess myocardial edema. The T2* sequence was a multiecho acquisition with 8 echoes (between 1.4 and 12.7ms) acquired at TR=14.6ms. Delayed hyperenhancement was also performed. We retrospectively reviewed and stratified patients into those that did and did not have diabetes (type 1 or type 2).We compared 15 diabetics versus 45 non-diabetics . At this time interval, the mean T2* was equivalent in the IS of both patient groups .Our study demonstrates that diabetic patients have increased myocardial edema in the IS at an early time point post AMI which persists till the subacute phase (3 weeks). The degree of myocardial hemorrhage does not appear to be influenced by diabetes status. Diabetes increases the area at risk during AMI which may lead to deleterious left ventricular remodeling and worse outcome in these patients.Dr. Connelly is supported by a Heart and Stroke Foundation of Canada Phase 1 Clinician Scientist Award. Dr. Wright receives research funding from GE Healthcare. Dr. Dick is supported by the Heart and Stroke Foundation of Canada. This work was supported in part by a Canadian Institutes of Health Research (CIHR) operating grant and the Ontario Research Fund.


Heart failure is associated with high mortality, and diagnosis lacks reliable quantitative measures. Therefore, new measures of heart failure are needed. Vortex formation ratio (VFR)  is a metEight healthy volunteers and 14 heart failure patients (dilated cardiomyopathy. DCM) underwent cardiac MRI using a 1.5T scanner . Healthy volunteers were examined at rest and during physical exercise using an ergometer. LV end-systolic volume (ESV) and the blood volume before atrial contraction  were measured by manual delineation. E-wave volume (EWV) was defined as EWV=DV-ESV. The mean mitral valve diameter (Dm) was defined as the mean between two measurements taken from the 3-chamber long-axis view (D1) and the short-axis view of the LV D2). The formula for calculating VFR was derived from earlier studies [. The forVFR=4/π×EWV/Dm^3VFR was significantly lower in DCM compared to healthy volunteers at rest (figure This study is the first to assess VFR using MRI, and to study VFR during physical exercise. DCM patients has, as a group, a significantly lower VFR than healthy volunteers which suggests that VFR can be used as a measure of heart failure. During exercise in this preliminary study, VFR did not change significantly, suggesting that optimal vortex formation is maintained at higher cardiac output.The Swedish Research Council; the Medical Faculty at Lund University, Sweden; the Region of Scania, Sweden; and the Swedish Heart-Lung Foundation.


Heart failure represents an end-stage phenotype of a number of cardiovascular diseases and is generally associated with a poor prognosis. A number of organized battles fought over the last two to three decades have resulted in considerable advances in treatment including the use of drugs that interfere with neurohormonal activation and device-based therapies such as implantable cardioverter defibrillators and cardiac resynchronization therapy. Despite this, the prevalence of heart failure continues to rise related to both the aging population and better survival in patients with cardiovascular disease. Registries have identified treatment gaps and variation in the application of evidenced-based practice, including the use of echocardiography and prescribing of disease-modifying drugs. Quality initiatives often coupled with multidisciplinary, heart failure disease management promote self-care and minimize variation in the application of evidenced-based practice leading to better long-term clinical outcomes. However, to address the rising prevalence of heart failure and win the war, we must also turn our attention to disease prevention. A combined approach is required that includes public health measures applied at a population level and screening strategies to identify individuals at high risk of developing heart failure in the future. Heart failure is a clinical syndrome that represents the end-stage phenotype of a number of different cardiovascular diseases. However, regardless of the underlying cause, the prognosis is generally poor once a patient develops symptoms or signs of heart failure. There has been considerable progress in management including the use of drugs that interfere with neurohormonal activation, device therapy in selected patients, and multidisciplinary disease management. This at least partly explains the reductions in heart failure mortality seen in population-based studies over the last two decades; however, the overall epidemiological impact has been modest. This paper will provide an overview of the epidemiology of heart failure and outline our continued efforts to fight the battle focusing on management strategies that have been shown to modify disease progression. I will then consider whether or not we are winning the war and suggest that efforts to minimize variation in care should continue coupled with increasing emphasis on heart failure prevention.Heart failure is one of the few cardiovascular diseases whose prevalence continues to rise, largely related to the aging population accompanied by improved survival in patients with heart failure and following myocardial infarction , 2. InciThe prognosis of patients with heart failure is generally poor with frequent admissions to hospital throughout the disease trajectory and median survivals of 3–5 years , 23–28. Despite heart failure representing an end-stage phenotype of different cardiovascular diseases, numerous large-scale, randomized, and placebo-controlled studies have extended our mechanistic understanding of this syndrome. Most of these studies have been conducted in patients with moderate to severe LVSD regardless of the underlying cause. Broadly speaking, the therapeutic approaches can be divided into pharmacological therapies, device-based therapies, and coordinated disease management –51.Treatments primarily focused on managing congestion and hemodynamic derangements play an important role in treating decompensated heart failure with loop diuretics remaining the most effective pharmacological approach to manage congestion. However, these approaches have a limited effect on long-term clinical outcomes. Over the last three decades, a number of multicenter studies conducted in patients with symptomatic and asymptomatic LVSD have highlighted the role of neurohormonal activation on disease progression see  21, 52––52–65. Angiotensin converting enzyme (ACE) inhibitors improve symptoms, reduce hospitalization, and prolong survival in patients with symptomatic heart failure associated with moderate to severe LVSD both early following myocardial infarction and in the setting of chronic heart failure regardless of the underlying etiology , 58, 65.However, despite the well-established benefit from blockade of the renin-angiotensin system, the long-term cumulative mortality rates remained high reflecting ongoing disease progression, often associated with progressive adverse LV remodeling. Subsequent large, placebo-controlled studies emphasized the need for a combined approach to neurohormonal blockade. The addition of a beta blocker reduced mortality by 34-35% and decreased heart failure hospitalization in chronic heart failure patients with underlying moderate to severe LVSD on top of standard therapy which included an ACE inhibitor and diuretic in the majority of patients –61.http://www.fda.gov/drugs/drugsafety/ucm300889.htm). Furthermore, a population-based study conducted in Canada reported increased hospitalizations and deaths related to hyperkalemia, associated with increased rates of prescribing spironolactone to heart failure patients treated with ACE inhibitors following the publication of the Randomized Aldactone Evaluation Study (RALES) , 7978, 7Approximately 20–30% of patients with heart failure due to LVSD have abnormal intraventricular conduction manifested by a prolonged QRS duration on the 12-lead electrocardiogram . Short-tThe management of chronic heart failure includes lifestyle adjustment, initiation and uptitration of medical therapy, and selective consideration of device therapy. These cases are often diagnosed following an acute episode of decompensation with 25–40% of patients admitted to hospital with acute decompensated heart failure having no prior documented history of heart failure –98. The A large body of evidence supports the use of coordinated, multidisciplinary models of care usually led by heart failure nurses to support the transition of care from the acute hospital setting to community health providers. These services have been shown to prolong survival, reduce hospitalizations, and improve quality of life –105. FurWhilst there is a rich body of evidence supporting the safety and clinical efficacy of pharmacological and device-based therapies in heart failure, the key question is whether this translates to clinical effectiveness in a real-world population. Recent registries and population-based cohorts of patients admitted to hospital with acute decompensated heart failure have highlighted treatment gaps and considerable variation in the quality of care provided in different hospitals , 109–115Whilst the rates of prescribing disease modifying agents in patients admitted to hospital with heart failure have improved over the last decade, recent registries conducted in Europe, the Asia-Pacific region, and the USA still report discharge prescription rates of 63–80% for ACE inhibitors or angiotensin receptor blockers, 41–74% for beta blockers, and 20–48% for aldosterone antagonists , 122. FuReasons for the gaps in treatment provided in real-world practice compared to clinical trials may include the limitation of using administrative datasets to code heart failure patients, the different populations being treated, the limitation of assessing treatment in hospital following an acute decompensation, and the level of care provided.Administrative datasets rely on appropriate documentation by the treating clinicians and accurate coding by administrative staff. A number of studies have evaluated the accuracy of administrative coding demonstrating high positive predictive accuracy compared with independent chart abstraction or objective scoring systems such as the Boston score criteria –143. WhiPatients treated in clinical trials are on average over a decade younger than the patients we see in our clinical practice. Furthermore, the clinical trials which guide our practice either exclusively or largely enrolled patients with moderate to severe LVSD; yet up to half the patients enrolled in heart failure registries and population-based cohorts have preserved LVEF , 144–147http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx). However, few patients will have new therapies commenced in the first few months following hospital discharge [Hospital-based registries generally report in-hospital metrics to measure quality performance. Whilst performance of echocardiography and discharge prescription of ACE inhibitors or angiotensin receptor blockers are well-accepted inpatient quality measures of healthcare, discharge prescription of beta blockers was not included in the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) heart failure performance indicators . Our local experience matches that seen in most studies that report prescribing patterns in clinical practice see  124–137137, 155,The role of supplementary monitoring strategies to guide therapy and support disease management including telemonitoring and biomarkers remains the active area of investigation. Noninvasive telemonitoring has shown promise , 160; hoFinally, most of the therapeutic gains made with drugs and device therapy have been in heart failure due to LVSD. Studies conducted in patients with preserved LVEF have been disappointing, which probably at least partly relates to the difficulty in clearly defining this population –178. FurWhilst efforts to improve the quality of care and clinical outcomes of heart failure patients should continue, this will have a limited epidemiological impact on the human and economic burden imposed by heart failure in our society. Unless we also focus on early disease detection and prevention, we are in effect chipping away at the tip of the iceberg as incident cases of heart failure continue to emerge. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) staging classification emphasizes the need for disease prevention akin to the approach applied in cancer prevention . This clTo address the presymptomatic phase of heart failure, a combined approach is required that encompasses both public health measures applied at a population level and identification and management of individuals at high risk of developing heart failure in the future. Public health measures should focus on environmental contributors with the ultimate aim being to encourage and facilitate healthy lifestyles through education, legislation, and urban planning . SmokingThe best example of this is asymptomatic LVSD which is associated with a five-fold increased risk of developing heart failure with over half dying (most from cardiovascular causes) before they present with clinical heart failure . This reIf we can accurately detect LVSD, it would seem reasonable to link this with the evidence from treatment efficacy studies conducted in subjects with asymptomatic LVSD to infer the clinical effectiveness of a screening strategy, provided the subjects detected through screening represent the same spectrum of disease as the patients enrolled in the clinical trials see  140, 18. HoweverRather than limiting a screening strategy to identify asymptomatic LVSD, another approach is to screen for a number of structural cardiovascular derangements that are associated with an increased risk of developing heart failure including left atrial dilatation, LV diastolic dysfunction, LV hypertrophy, valvular heart disease, and aortic stiffness , 214–218Despite considerable advances in the treatment of heart failure over the last two to three decades, its prevalence continues to rise. Registries and population-based cohorts have revealed substantial gaps and variation in care. Multidisciplinary disease management brings us closer to the models of care that were applied in the randomized, controlled trials that guide our practice. More importantly, these programs improve quality of care, decrease mortality, and are cost effective in reducing hospitalizations in high-risk patients. However, to win the war, we also need to focus on disease prevention to reduce the human and economic burden imposed by heart failure. These strategies include addressing cardiovascular risk factors at a population level and screening for structural cardiovascular derangements such as asymptomatic LVSD.


Myocardial dysfunction is a recognized toxicity of anthracycline (A) and herceptin (H) chemotherapy. Whilst there is much current focus on the incidence and magnitude of myocardial dysfunction following the A/H regimen, whether these changes are mediated by reversible or irreversible myocardial injury remains unknown . We sought to determine rates of persistent LV dysfunction at 12 months (as defined by left ventricular ejection fraction (LVEF) decrease by 10% or below lower limits of normal) following A/H and explore the mechanism of myocardial dysfunction using advance cardiac imaging.Thirty six chemonaive patients  with breast cancer, underwent serial CMR imaging  and advanced echocardiography for global longitudinal strain (GLS) in addition to standard measurements of LV diastolic function. All tests were conducted at baseline, 1, 3 and 12 months (21 patients). Six normal volunteers underwent the same CMR protocol. For edema imaging, short-TI inversion recovery was used in 3 short-axis views of the LV. Myocardial edema was assessed using Lake Louis criteria [In the study patients, the mean CMR LV end-systolic volume index (LVESVI) increased from baseline of 17.4 ± 6.1 to 26.4 ± 9.6; p value <0.001 at 12 months (Table Our data suggest that the subtle functional changes in the LV myocardium early post breast cancer chemotherapy persist into 12 months in a significant number of patients. These changes are likely mediated by myocardial inflammation, and despite absence of irreversible myocardial injury, continue to 12 months post therapy. These findings warrant caution and suggest ongoing regular follow-up of patients following chemotherapy is required.nil


Arrhythmogenic right ventricular Dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited cardiomyopathy associated with ventricular arrhythmia, heart failure and sudden death. Genetic studies have demonstrated the central role of desmosomal proteins in this disease, where 50% of patients harbor a mutation in a desmosmal gene. However, clinical diagnosis of the disease remains difficult and molecular mechanisms appears heterogeneous and poorly understood. The aim of this study was to characterize the expression profile of desmosomal proteins in explanted ARVD/C heart samples, in order to identify common features of the disease.We examined plakophilin-2, desmoglein-2, desmocollin-2, plakoglobin and β-catenin protein expression levels from seven independent ARVD/C heart samples compared to two ischemic, five dilated cardiomyopathy and one healthy heart sample as controls. Ventricular and septum sections were examined by immunoblot analysis of total heart protein extracts and by immunostaining.DSG2 and DSC2 mRNA transcript levels, suggesting increased protein turn-over rather than transcriptional down regulation.Immunoblots indicated significant decreases in desmoglein-2 and desmocollin-2, independent of any known underlying mutations, whereas immune-histochemical analysis showed normal localization of all desmosomal proteins. Quantitative RT-PCR revealed normal Reduced cardiac desmoglein-2 and desmocollin-2 levels appear to be specifically associated with ARVD/C, independent of underlying mutations. These findings highlight a key role of desmosomal cadherins in the pathophysiology of ARVD/C. Whether these reductions could be considered as specific markers for ARVD/C requires replication analysis. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare inherited cardiomyopathy characterized by progressive sub-epicardial fibro-fatty replacement of myocardial tissue, mostly in the right ventricle ,2,3. TheJUP and DSP, associating ARVD/C with palmoplantar keratosis and woolly hair . Ad. Ad21]. Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) on behalf of the PHRC .All patients have signed a written informed consent form enabling the use of their tissue for this study. This project was given the approval number 35-06 by the CCPPRB (Cardiac tissue samples were collected between 2006 and 2009 from patients with confirmed ARVD/C (referred to as: ARVD/C 1 to 7) according to validated diagnostic criteria , and whoPKP2 (NM_004572.3), DSG2 (NM_001943.3), DSC2 (NM_024422.3), DSP (NM_004415.2) and PG (NM_021991.2) was performed in all ARVD/C patients as previously described T method .p value < 0.05 was considered as statistically significant. Data are expressed as the mean value ± standard error (SEM).Differences between the two groups (ARVD/C and controls) were analyzed using the non-parametric Mann-Whitney Rank Sum test. A DSG2 mutations as previously described  and 84.9 in the normal heart sample. Decreased DSG2 was observed for all patients  and 122.8 in the normal heart sample  compared to controls. The ratio of DSC2 to ACTN2 was 38.7 ± 13.8 in ARVD/C, 68.1 ± 12.9 in controls samples  and in six septum samples  by quantitative RT-PCR. ACTN2 expression was used to standardize for cardiomyocyte specific mRNA input. As shown in DSG2 and DSC2 mRNA transcript level in ARVD/C compared to DCM control samples. This indicated that reduced levels of DSG2 and DSC2 in ARVD/C are not a consequence of mRNA down-regulation, but rather suggest an increased degradation or translation defect.The decrease in desmosomal cadherins observed in ARVD/C samples could either be the consequence of transcriptional down-regulation or increased protein turnover. To answer this question, we studied We characterized desmosomal protein expression in heart tissue samples from end-stage ARVD/C patients with or without mutations in desmosomal protein genes. We observed a significant decrease in DSG2 and DSC2 protein levels in all ARVD/C samples, regardless of the genetic status, but no mislocalization of desmosomal proteins, in comparison to the seven controls.PKP2, DSG2, DSC2, DSP and JUP) in four ARVD/C cases, suggesting that the observed desmosomal cadherin decrease is an indicator of ARVD/C which is independent of the causative mutation. Nevertheless, it still remains unexplained why DSG2 from transplanted ARVD/C subjects seems more frequently mutated in our patients (three of seven) compared to that which has been reported in previous ARVD/C screens , andound 30% ). It maypatients . ConfirmDSG2 and DSC2 were the only desmosomal proteins shown to be significantly reduced by immunoblot in our study. This result suggests that desmosomal cadherin decrease is a specific feature of late-stage ARVD/C, rather than a general marker of cardiomyopathy-induced cardiac remodeling. None of the desmosomal proteins appeared altered by immunohistochemistry, suggesting no abnormal relocalization of them.Although it was not our intention to quantify the signal on tissue immunostaining, we did not observe systematic decreased intensity of any specific desmosomal protein in all ARVD/C patients compared to controls. In order to increase our sensitivity to detect a decreased signal specific for DSG2 we applied a dilution protocol for the antibody directed against DSG2 as proposed by Asimaki et al. . At maxiDSC2 and DSG2, showing decreased DSG2 expression with unchanged plakoglobin and PKP2 [We also observed that among the desmosomal proteins tested, only cadherins were specifically decreased. This result is partly supported by another study performed on an isolated case with compound heterozygous mutations in and PKP2 . Compareand PKP2 .DSG2 or other undetected mutations. It remains to be determined if the desmosomal cadherins decrease, particularly of DSG2, is also observed in patients with mutations in genes encoding desmosomal proteins other than cadherin, and if this reduction is discernible in earlier forms of ARVD/C.We studied samples with advanced forms of ARVD/C from patients carrying DSG2 and DSC2 transcripts were similar to those measured in controls. Normal levels of cadherin mRNA in the right ventricle of ARVD/C patients has also been previously reported [Desmosomal cadherin decrease is likely due to increased protein degradation or to translational defects, as the levels of reported . This isreported ,30,34 whreported ,35.Altogether, our results suggest that a key aspect of ARVD/C pathophysiology could be increased degradation of cardiac cadherins, leading to desmosomal disorganization and disrupted cardiomyocyte junctions, and which may be a marker of ARVD/C. In order to gain insight into ARVD/C physiopathology, further studies are required to confirm this finding and identify the downstream pathways affected by desmosomal cadherin loss.Decreased cadherin expression is observed in all end-stage ARVD/C patient heart samples and not in the normal heart or dilated cardiomyopathy samples. We had access to seven heart tissue samples from ARVD/C patients and only one normal heart, low numbers which weaken our conclusions. Additionally, mutations in desmosomal genes have been recently reported in 5% of DCM cases , and we DSG2 and DSC2, or mutations in unknown genes which could affect DSC2 and DSG2 expression.Finally, we cannot exclude that patients with no identified mutations, may carry undetected genetic abnormalities such as large deletions in Figure S1Representative histology images of right ventricles from ARVD/C1-4.Hematoxylin and eosin-stained section of the right ventricular myocardium showing mostly fatty replacement in all ARVD/C patients. Two magnifications are represented (2X and 10X).(TIF)Click here for additional data file.Figure S2Representative histology images of right ventricles from ARVD/C5-7.Hematoxylin and eosin-stained section of the right ventricular myocardium showing mostly fatty replacement in all ARVD/C patients. Two magnifications are represented (2X and 10X).(TIF)Click here for additional data file.Figure S3Quantitative immunoblotting of desmoglein-2 in all ARVD/C and control patients.Representative images of western blots obtained for desmoglein-2 in the right, left ventricle and septum for each patient. Bar graphs indicate the mean ± SEM following normalization to the cardiac protein α-actinin-2 (ACTN2).(TIF)Click here for additional data file.Figure S4Representative images of immunofluorescent staining in ARVD/C and control patients after maximum dilution of anti-desmoglein-2 antibody.Immunofluorescent staining of desmoglein-2 (DSG2) was performed in all ARVD/C and control samples as described in the material and methods section of the manuscript. We used the maximum dilution  of anti-DSG2 antibody (1/300). The labeling of three samples, ARVD/C1, 5 and 6, appeared reduced compare to the others . These three samples match the samples for which the immunoblot based quantification of DSG2 appeared lower (ed lower .(TIF)Click here for additional data file.Table S1Primary antibodies used in study.(DOC)Click here for additional data file.


Left ventricular (LV) rotation is increasingly examined in those with heart disease. The available evidence measuring LV rotation in those with heart diseases has not been systematically reviewed.To review systematically the evidence measuring LV rotational changes in various heart diseases compared to healthy controls, literature searches were conducted for appropriate articles using several electronic databases . All randomized-controlled trials, prospective cohort and case–controlled studies that assessed LV rotation in relation to various heart conditions were included. Three independent reviewers evaluated each investigation’s quality using validated scales. Results were tabulated and levels of evidence assigned.A total of 1,782 studies were found through the systematic literature search. Upon review of the articles, 47 were included. The articles were separated into those investigating changes in LV rotation in participants with: aortic stenosis, myocardial infarction, hypertrophic cardiomyopathy, dilated cardiomyopathy, non-compaction, restrictive cardiomyopathy/ constrictive pericarditis, heart failure, diastolic dysfunction, heart transplant, implanted pacemaker, coronary artery disease and cardiovascular disease risk factors. Evidence showing changes in LV rotation due to various types of heart disease was supported by evidence with limited to moderate methodological quality.Despite a relatively low quality and volume of evidence, the literature consistently shows that heart disease leads to marked changes in LV rotation, while rotational systolic-diastolic coupling is preserved. No prognostic information exists on the potential value of rotational measures of LV function. The literature suggests that measures of LV rotation may aid in diagnosing subclinical aortic stenosis and diastolic dysfunction. In recent years, there has been increased interest in quantifying left ventricular (LV) rotation.-6 Using In young healthy individuals, systole of the LV is associated with counterclockwise rotation of the apical level while the basal level rotates clockwise (when viewed from the apex). Rotational motion, according to mathematical models, depends disproportionately on fibers arranged in a helical manner around the LV . It has heart disease, cardiovascular disease, heart failure, heart transplant, valve stenosis, aortic stenosis, cardiomyopathy, myocardial infarction, transplant – and rotational function keywords – rotation, twisting, untwisting, recoil, twist, torsion, torsional – as well as ventricular anatomy phrases – ventricular, ventricle, heart, cardiac, and myocardial - were paired by permutation  and confirmed by a third reviewer with expertise in systematic reviews (DW) using the Downs and Black (D&B) tool for non-RCTs . The higOperational definitions were developed to streamline comparisons of primary outcome variables between studies. Rotation was defined as the rotary motion (in degrees) of either the apex, base, or mid-ventricle. Also, as viewed from the apex of the heart, counterclockwise rotation is denoted by a positive angle (degrees) while clockwise rotation is marked by a negative angle (degrees).,30 Twistabsolute amplitude. For example, a percent reduction in both a negative rotation at the base and a positive rotation at the apex are both reported as negative values.Where two or more articles reported mean differences between a given cardiovascular disorder, the average and standard deviation of the percent difference was calculated. These values are presented graphically in a series of figures throughout this article. Percent differences between groups are reported as the difference relative to healthy controls in The articles selected were categorized into thirteen groups according to heart disease. Within the text we have provided a summary table where the overall findings from the moderate to strong articles within each heart disease may be found Table . In ordeAortic Stenosis   to report on LV rotation in those with aortic stenosis, six papers showed agreement that LV twist is elevated  is associated with an average 75% increase in systolic apical rotation but very little change  in basal rotation. It is less clear how diastolic rotation is related to aortic stenosis. It is interesting however that time to peak diastolic untwist was prolonged in aortic stenosis. This may be due to a greater time requirement for peak passive force generation from compressed cardiac spring proteins; owing to greater compression during systole.Six published articles investigated LV rotation in those with MI as compared to healthy controls ,24,49-52low EF sub-group only [Five papers reported a reduction in LV twist ,49,51,52oup only , whereasoup only ,51,52. Aoup only . For exaThree moderate strength articles which reported on LV rotation in diastole suggest that both untwisting rate and timing are negatively affected by MI. Specifically, two articles showed an increased time to peak untwisting velocity in those with prior MI  that rotation characteristics in both systole and diastole are altered in those with prior MI. Specifically, there is agreement in the literature that twist and apical rotation are reduced in MI, however  infarct .Eleven published articles investigated LV rotation in those with HCM as compared to healthy controls ,35,53-56Those with HCM were widely reported to have no difference in apical rotation ,31,32,56A total of seven articles reported on basal rotation in HCM, however two did not report statistics and/or had a small sample size  while aA total of nine articles reported on LV twist in those with HCM Again, the same four papers were methodologically sound and comparable, two of which showed no change in twist, while the same two articles to show no change in basal rotation reported no change in twist ,56. We aDiastolic LV rotation was shown to be impaired in those with HCM through consistent reports of decreased early untwist rate ,55,56. TThere is substantial disagreement within the literature examining systolic LV rotation in HCM. It is likely that differences in methodological techniques as well as subtle differences between study populations are the cause of variability in this section, given the extremely heterogeneous nature of HCM phenotypic expression. It appears the disagreement is not due to methodological strength, as even the four strongest articles from this section reported opposite LV twist findings. With such substantial disagreement regarding LV rotation in those with HCM we feel it is not possible, until more work is completed, to comment on overall trends arising from the literature. Diastolic parameters of LV rotation were consistently shown to be impaired in those with HCM.Nine articles examined LV rotation in those with dilated cardiomyopathy as compared to healthy controls -36,58-61restrictive LV filling (not a criteria in the other articles) [Nine articles examined systolic LV rotation in those with dilated cardiomyopathy -36,58-61rticles) . Of the rticles) ,30,58.All articles which reported on diastolic LV rotational parameters in those with dilated cardiomyopathy were in agreement that average and peak untwisting velocity was significantly decreased ,35,59,60There is broad agreement, according to level three evidence (somewhat reliable), that systolic and diastolic ventricular rotation characteristics are reduced in those with dilated cardiomyopathy. Also there was agreement in all three articles where it was reported, implying that the LV rotates similar to a rotating pipe, instead of twisting sponge, in those with dilated cardiomyopathy.Two articles investigated LV rotational parameters in those with non-compaction cardiomyopathy as compared to healthy controls and received D&B scores of 17  and 19   that systolic LV rotational parameters are reduced in those with non-compaction cardiomyopathy ,62. The Five articles investigated LV rotation in those with SHF as compared to matched controls ,43,63-65The three articles that reported on systolic apical and basal rotation were in agreement showing a reduction in both regions in SHF ,64,65  that systolic LV rotation is altered in those with SHF. There is also level three evidence (somewhat reliable) that diastolic apical untwisting is altered in those with SHF. It appears that apical and basal rotation occurs in unison in a high proportion of those with SHF. More work is needed to clarify diastolic rotational motion of the LV in those with SHF.Heart failure normal ejection (HFnEF) fraction describes a significant reduction in LV filling during diastole (diastolic dysfunction), with a preserved EF. Diastolic dysfunction is described by four categories of increasing intensity, with HFnEF considered grades three and four as long as EF is preserved . Left veThe five articles to report on systolic LV rotation in those with diastolic dysfunction have considerable disagreement between studies. Work by Park and colleagues reported a significant increase in apical rotation, basal rotation, twist and twist rate in those with grade one diastolic dysfunction (impaired relaxation), while those with more severe diastolic dysfunction were not different from controls . SimilarP = 0.07) and twist (P = 0.18), with no difference in the more severe diastolic dysfunction group.[These disagreements can likely be explained by systolic LV rotation differing across the spectrum of diastolic dysfunction, as EF was preserved in all articles. Park and colleagues as well as Mizuguchi et al. only reported significant differences between the control group and those with the mildest form of diastolic dysfunction (impaired relaxation) whereas the two more severe categories were not different from those of controls regarding systolic LV rotation. In support of this contention, the only other article to look at an intermediate diastolic dysfunction group showed borderline significant increases in apical rotation  that LV rotation in both systole and diastole is increased in those with mild diastolic dysfunction , it appears that aortic stenosis as well as SHF and dilated cardiomyopathy lead to the most profound changes in LV systolic rotation as compared to healthy controls. According to the same criteria, in diastole, MI, HCM and dilated cardiomyopathy have the largest reductions in LV rotational parameters. Interestingly, aortic stenosis has considerable support showing systolic rotation is increased as compared to healthy controls. It is also worth note that there are no trends in the literature suggesting systolic-diastolic rotational uncoupling in heart disease.In an effort to provide clinical meaning, it appears from the literature that heart disease with heterogeneous characterization such as MI and HCM show less agreement in relationship to parameters of LV rotation. To our knowledge no literature exists regarding the prognostic value of LV rotation. In light of the reports found in this article, there may be clinical value in monitoring LV rotation in those at the highest risk for aortic stenosis with no other clinical markers of LV dysfunction, as well as untwist in those with suspected diastolic dysfunction.Several studies did not utilize relevant control groups, matched on known cardiovascular confounding factors such as age  appear to follow their own disease-dependent pattern.The authors declare that they have no competing interest.AAP conceptualized the topic, performed the literature search, drafted the manuscript and edited the manuscript. ATC independently performed the literature search and edited the manuscript. SSDB conceptualized the topic and edited the manuscript. DERW conceptualized the topic and edited the manuscript. All authors read and approved the final manuscript.This research was supported by funding from the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation and the BC Knowledge Development Fund. AA Phillips was supported by funding from Natural Sciences and Engineering Research Council and the Mathematics of Information and Complex Systems. DER Warburton was supported by salary awards from the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/46/prepub


We hypothesized that clinical factors other than glycemic control may influence abnormal cardiac function in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the independent factors for abnormal cardiac function among clinical factors in T2DM.We studied 148 asymptomatic patients with T2DM without overt heart disease. Echocardiographic findings were compared between diabetic patients and 68 age-matched healthy subjects. Early (E) and late (A) diastolic mitral flow velocity and early diastolic mitral annular velocity (e’) were measured for assessing left ventricular (LV) diastolic function. We evaluated insulin resistance, non-esterified fatty acid, high-sensitive CRP, estimated glomerular filtration rate, waist/hip ratio, abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and other clinical characteristics in addition to glycemic control. VAT and SAT were quantified by computed tomography.In T2DM, E/A and e’ were significantly lower, and E/e’, left atrial volume and LV mass were significantly greater than in control subjects. In multivariate liner regression analysis, VAT was an independent determinant of left atrial volume , E/A , e’  and E/e’ . Age was also an independent determinant, whereas fasting plasma glucose and hemoglobin A1c levels were not. In addition to systolic blood pressure, waist-hip ratio  and VAT/SAT ratio  were independent determinants of LV mass.Excessive visceral fat accompanied by adipocyte dysfunction may play a greater role than glycemic control in the development of diastolic dysfunction and LV hypertrophy in T2DM. Diabetes mellitus may cause myocardial injury even in the absence of coronary artery disease, hypertension or valvular disease . This caRecently, visceral fat accumulation has gained attention as playing an important role in the development and pathophysiology of type 2 diabetes mellitus (T2DM) ,21. ExceThe aims of our study were the following: (1) to clarify if diastolic dysfunction and LV hypertrophy are characteristics of abnormal cardiac function and structure in T2DM in comparison with age-matched healthy controls; and (2) to investigate the independent factors for diastolic dysfunction and LV hypertrophy among clinical factors including glycemic control, blood pressure, insulin resistance, fatty acid and visceral fat.A total of 148 consecutive asymptomatic patients with T2DM and without cardiovascular disease, who were admitted to our institution  for diabetic educational program between January 2010 and May 2012, were prospectively enrolled in this study. Patients were included if they met the following inclusion criteria: no symptoms and history of heart disease, LV ejection fraction (LVEF) > 50%, absence of regional LV wall motion abnormalities, and clinically stable. Exclusion criteria were coronary artery disease, congenital heart disease, atrial fibrillation, significant heart valve disease, renal failure (serum creatinine > 2.0 mg/dl) and type 1 diabetes mellitus. In addition, 68 age-matched healthy controls without hypertension, dyslipidemia or diabetes mellitus served as a control group. The study protocol was approved by the Institutional Review Board of Juntendo University Hospital.This study was a prospective cohort study. The diagnoses of hypertension, dyslipidemia, coronary artery disease and cerebrovascular accident were assessed by the treating physician. Standard comprehensive two-dimensional and Doppler echocardiographic examinations were performed using commercially available systems. As indicators of obesity, body mass index was calculated from height and weight and the waist-hip ratio was calculated from the waist and hip circumference.In all patients and control subjects, cardiac chamber quantification by 2D echocardiography was performed according to guidelines provided by the American Society of Echocardiography . LV diamFor assessing conventional diastolic pmeters, left atrial volume was measured by Simpson’s biplane method (indexed to body surface area), and mitral inflow velocities were determined by pulsed Doppler and tissue Doppler imaging. The peak early (E) and late (A) diastolic velocity, the deceleration time from the peak of the early diastolic wave to baseline (DCT) and the E/A ratio were assessed from the mitral inflow velocity pattern. The mitral annular motion velocity was recorded at the medial mitral annulus site in the apical 4-chamber view by pulsed tissue Doppler echocardiography. Peak early (e’) and late (a’) diastolic velocity of the annulus were measured and the ratio of peak early diastolic transmitral flow velocity to annular velocity (E/e’) was calculated . Further-1.094 × age-0.287, where age is in years, SCr is in mg/dL and GFR is in mL/min/1.73 m2 body surface area. The product of this equation was multiplied by a correction factor of 0.739 in women.Blood samples for determination of serum creatinine, fasting blood sugar, glycosylated hemoglobin, immunoreactive insulin, C-peptide immunoreactivity, N-terminal pro B-type natriuretic peptide (NT-pro BNP) and lipid profiles  were drawn in patients with T2DM. Moreover, the homeostasis model assessment ratio (HOMA-R) index was calculated as fasting plasma glucose × fasting plasma insulin/22.5 for assessing insulin resistance . Non-estVAT and subcutaneous adipose tissue (SAT) were measured quantitatively by computed tomography (CT) , as previously reported . BrieflyAll statistical analyses were performed using SPSS version 17.0 . Data are expressed as mean ± standard deviation (SD). The relationships between variables were assessed using Pearson’s correlation coefficient. We compared baseline characteristics and echo pmeters between the control group and patients with T2DM using an unpaired t-test. Categorical data were compared between the two groups using a chi-square test. When we found echocardiographic pmeters that were different between the diabetics and controls, Pearson’s linear correlation analysis was used to determine the correlations between these echocardiographic pmeters and the clinical data in just the patients with T2DM. Multiple linear regression analysis was also performed using the clinical data to evaluate the independent determinants of these echocardiographic pmeters in the T2DM patients. A log-transformation was used to normalize the distributions of triglyceride, HOMA-R and NT-proBNP level. A P-value <.05 was considered statistically significant.Table 2, respectively. LV mass index of both diabetic patients with and without hypertension were increased as compared with control subjects  as shown in previous studies [Table  studies -8. Patie studies -8. WhereLaboratory data and visceral fat area measured by CT scanning are shown in Table p<0.001), IRI  and log HOMA-R .The correlation between clinical factors and the diastolic pmeters are also shown in Table In the current study, we found that LV diastolic dysfunction and hypertrophy were more prominent in patients with T2DM than in age-matched healthy controls, as previously reported -8. FurthMany previous studies have demonstrated a high prevalence of LV diastolic dysfunction and hypertrophy in patients with T2DM -8. HowevMyocardial injury in T2DM has a complicated pathophysiology ,9, and mVisceral adipose tissue is an important functional organ which abundantly secretes adipocytokines . In the r=0.281, p<0.001). HsCRP can reflect inflammatory processes in various organs and is not only the mechanism by which VAT causes diastolic dysfunction. Presumably other inflammatory cytokines and anti-inflammatory cytokines relate to visceral fat accumulation and are also significant determinant factors for cardiac dysfunction in T2DM.Increased inflammatory cytokines such as IL-6, IL-8 and MCP-1 have been shown to be significant indicators of a greater degree of heart failure with preserved EF . High plAge-related decline in LV diastolic function even in a healthy population has been widely reported using conventional and tissue Doppler methods ,19. GendAs for LV hypertrophy, the waist/hip and VAT/SAT ratios were found to be independent determinants in addition to systolic blood pressure. The waist/hip ratio, an indicator of obesity, was reported to be a predictor of cardiovascular mortality . AbnormaWhile we included asymptomatic patients without overt cardiovascular disease, we did not completely exclude latent patients with coronary artery disease using stress testing or coronary angiography. We did not measure serum adipocytokine levels and could not evaluate adipose dysfunction. Further investigation is required to determine the direct association between VAT and the level of adipocytokine dysfunction in diabetic cardiomyopathy. We included patients with the comorbidity of hypertension in this study. Hypertension caused by activation of the renin-angiotensin system in diabetes mellitus plays an important role in the development of cardiac dysfunction in T2DM. In addition, patients with T2DM have high prevalence of hypertension in the real clinical setting and are more subject to LV hypertrophy caused by hypertension than those without diabetes . These cThis study confirms that diastolic dysfunction and LV hypertrophy are major characteristics of abnormal cardiac structure and function in T2DM. Among many clinical variables, excess VAT may play a significant role in the development of diastolic dysfunction and LV hypertrophy beyond glycemic control. Visceral fat accumulation would be a potential therapeutic target to improve cardiac dysfunction rather than glycemic control in T2DM.There is no relationship with any industry.RI and MD have designed this study in whole and drafted this manuscript. MM, SM, SC, TK and HS have contributed to design the echo part in this study and interpret its results. CI and FS have contributed to design the visceral adipose tissue part in this study and interpret its results including laboratory data. HW has contributed to design this study in part and interpret the clinical data. TM has contributed to statistical analyses in this study. HD has revised this manuscript critically for important intellectual content and approved finally the manuscript submitted. All authors read and approved the final manuscript.This work was partially supported by a Grant-in-Aid for Scientific Research C (24500554) from the Japan Society for the Promotion of Science (Masao Daimon).


Right heart catheterization (RHC) is required for definitive diagnosis of pulmonary hypertension (PH) and serial echocardiograms or RHC are necessary for long term disease management. However, RHC is invasive, costly and risky for the patient. EchocarTo evaluate the use of Cardiac MR for measuring right ventricular parameters in order to assess Pulmonary Hypertension.23 patients with PH and 12 controls underwent CMR on a 1.5T Siemens Avanto scanner. All patients underwent RHC to diagnose PH within 1 month of CMR study. The CMR protocol included cine SSFP of the whole heart and phase contrast MRI of the pulmonary valve (PV). The following conventional right ventricular (RV) functional parameters were calculated: ejection fraction (EF), end diastolic volume (EDV) and end systolic volume (ESV). Time to peak systole (TPS), an indirect measure of RV strain, was derived from the volume-time curves of the RV. PV flow analysis was performed and the following parameters were calculated: peak velocity, full-width at half maximum (FWHM), acceleration time (AT) and ejection time (ET).The results of RV functional parameters and PV flow values are shown in Tables TPS, calculated by CMR, may be a useful additional quantitative measure for diagnosis of PH and may be of value in long-term non-invasive assessment of treatment efficacy.


Although survival of patients with repaired tetralogy of Fallot (TOF) into adulthood exceeds 90%, hemodynamic and electrophysiologic abnormalities contribute to substantial morbidity in this population. The rate of late complications such as exercise intolerance, heart failure, tachyarrhythmias, and death accelerates in the third decade of life. However, identifying predictors for adverse outcomes remains difficult, as the event rates for major outcomes, such as ventricular tachycardia (VT) and death are low. Small, single center studies have suggested that cardiac magnetic resonance (CMR) measures of ventricular size and function are independent predictors of major adverse clinical outcomes. However, the small number of outcome events and the single center study design limit general acceptance of these findings. A multicenter registry may allow identification of generalizable predictors of major adverse outcomes and will provide opportunities for robust analyses to address clinically relevant questions in this population.The purpose of this report is to describe the creation of an international multicenter registry to identify CMR predictors of adverse outcomes in patients with repaired TOF.Four large congenital heart centers enrolled subjects with repaired TOF into a prospectively designed database with a statistical and a CMR core. Demographic and clinical information, QRS duration, exercise, Holter monitor, interventional procedures, and outcome data were collected. CMR images were transferred to the core laboratory where ventricular volumes, mass and flow data were contoured by investigators blinded to patient outcome.Of the 1142 patients enrolled to date , 42% had a palliative shunt prior to TOF repair, 454 (40%) had undergone pulmonary valve replacement, and 236 (21%) had documented arrhythmia (sustained VT in 29 subjects). At the time of data collection, 21 patients (2%) were deceased. Of the 1490 CMR examinations received to date, 1262 have been analyzed by the core laboratory and results will be presented.This multicenter registry will allow much greater statistical power to evaluate major outcomes in patients with repaired TOF. The initial release of this registry includes 4 large congenital heart centers, but ultimately it will transition to a longitudinal registry with involvement of additional centers. The process of establishing a core congenital CMR laboratory for uniform data analysis and an electronic database for standardized data entry are the first steps to identifying predictors of adverse outcomes meaningful to this patient population.