Duchenne muscular dystrophy (DMD) leads to structural heart disease, including dilated cardiomyopathy, in 90% of patients >18 years of age. Despite the ubiquity of cardiomyopathy associated with DMD, ventricular aneurysms in these patients have rarely been reported. We present a case of a basal inferoposterior aneurysm of the left ventricle in a 23-year-old male patient with DMD. Mr. W.D. is a 23-year-old male patient with DMD. He was referred for evaluation of cardiac abnormalities due to underlying DMD. He denied chest discomfort, shortness of breath, palpitations nor syncope. On physical examination, his blood pressure was 100/60 mm Hg with a heart rate of 72 beats per minute. The jugular venous pressure was within normal limits. There were normal cardiac heart sounds with no murmurs and no evidence of pedal edema. Twelve lead electrocardiography demonstrated right bundle branch block with Q waves in the inferolateral leads Figure . TransthDuchenne muscular dystrophy (DMD) is an x-linked dystrophinopathy that occurs in 1/3600 to 1/6000 males . DMD preCardiomyopathies are noted in DMD patients as young as 10 years of age . ApproxiCardiac involvement in DMD is caused by the progressive loss of cardiomyocytes, which is replaced with connective tissue and lipid infiltrates, creating wall motion abnormalities, reduced LVEF and conduction anomalies . The losA screening electrocardiography (ECG) is recommended in all DMD patients . The mosDue to the prevalence and severity of cardiac disease in DMD patients, recent guidelines recommend TTE at the age of diagnosis, followed by every 2 years until 10 years of age, and annually thereafter .Despite the pervasiveness of structural heart disease in DMD patients, an isolated left ventricular aneurysm (LVA) is a rare occurrence. Ventricular aneurysm can be visualized on TTE as a dyskinetic or akinetic evagination of the ventricular wall . TransthTrue LVA commonly result from myocardial injury, leading to thinning and fibrosis of all three layers of the myocardium, with subsequent remodelling of the ventricle . As the Despite the ubiquity of cardiomyopathy associated with DMD, ventricular aneurysms may be incidentally detected on routine non-invasive cardiac imaging.DMD: Duchenne muscular dystrophy; ECG: electrocardiography; LV: left ventricle; LVA: left ventricular aneurysm; LVEF: left ventricular ejection fraction; TTE: transthoracic echocardiography.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.XD, MZ, NS, and DJ contributed to the writing of the manuscript. All authors read and approved the final manuscript.All work was preformed at the St. Boniface General Hospital, University of Manitoba 409 Tache Avenue, Winnipeg, Manitoba, Canada, R2H 2A6


Heart Failure (HF) is an acute or chronic syndrome, that causes a lot of damaging effects to every system. The involvement of different systems is variably related to age and others comorbidities. The severity of organ damage is often proportional to the duration of heart failure. The typology of HF and the duration determine which organs will be affected and vice versa the severity of organ damage supplies precious information about prognosis and outcome of patients with heart failure. Moreover, a classification based not only on symptomatic and syndromic typical features of heart failure, but also on functional data of each system, could allow us to apply the most appropriate therapies, to obtain a more accurate prognosis, and to employ necessary and not redundant human and financial resources. With an eye on the TNM staging used in oncology, we drawn up a classification that will consider the different involvement of organs such as lungs, kidneys, and liver in addition to psychological pattern and quality of life in HF patients. For all these reasons, it is our intention to propose a valid and more specific classification available for the clinical staging of HF that takes into account pathophysiological and structural changes that can remark prognosis and management of HF. Heart Failure (HF) is an acute or chronic unhealthy condition, characterized by the inability of the heart to warrant its pump function in terms of adequate oxygen supply to the body tissues. An enchanting explanation of the HF's condition was proposed by Neubauer who defined HF like an “engine out of fuel” . Even thIn 2006, Senni et al. /72 × serum creatinine concentration; the value resulted is multiplied by 0.85 in female patients. The reference values are 57–115 in women and 95–145 in men . 2) = 186 × serum creatinine − 1.154 (μmol/L) × age − 0.203 (×0.742 if the patient is a woman) (×1.21 if the patient is black) [Simplified MDRD formula, to calculate creatinine clearance, takes in consideration parameters as serum creatinine, ethnicity, and gender. The formula is GFR (mL/min/1.73 ms black) . Moreoves black) . Cys-C is black) . The uses black) . It is possible to evaluate blood urea nitrogen (BUN) in order to complete the renal assessment, but it is necessary to consider that BUN is an ambiguous marker of renal impairment because it is strongly influenced by catabolism and catabolic alteration. The parameters to be considered for the evaluation of renal function are shown in In order to overview other possible damaged organs in HF, we report an interesting study that supports this concept: “heart disease affecting the liver and liver disease affecting the heart” . HF brinThe etiology of liver congestion in HF depends on different variables . When th2) [Finally, another organ that can be affected by HF is also central nervous system. In fact cerebral hypoperfusion and impaired cerebral function occur in HF , 49. Cer2) , 52. In conclusion, we would like to purpose this score to weight organ's malfunction that can occur in HF. Considering the presence and the number of malfunctioning organs in HF, we can have the M staging as represented in In our opinion it can be very useful to gain a classification of HF and its progression with a methodological scoring like the TNM evaluation used in oncology. The latest guidelines are mostly based on syndromic and symptomatic classification of HF that, in some cases, could be insufficient. Moreover, the NYHA classification has already been shown to be insubstantial in the evaluation of some kind of patients , 54. We 1L1M0) and to apply second-tier line therapies in patients with H2L2Mn stage. In fact, the presence of malfunction of other organs authorizes the physicians to employ type of therapies that will be not only cardioprotective, but also nephroprotective, hepatoprotective, and so on, justifying the increased cost of therapy in proportion to the benefits obtained. Besides, this type of classification can be very useful in assessing the true end-stage patients (H4L3M3). In these cases, the classification HLM allows us to pursue the most appropriate therapy targeting the quality of life remained with palliative support. With a TNM-like evaluation we do not risk to rely on single parameters, sometimes aspecific, but we have the opportunity to evaluate all the necessary parameters and enclose them in a single compressive classification representing the patient in that moment. This classification will allow us to use a traditional therapy for patients in initial stage of HF (HStarting with a patients' followup, applying this new staging system, the future prospect is to stratify prognosis, consider the course of therapy, and evaluate cardiovascular events of patients affected by HF.


We used cardiovascular magnetic resonance (CMR) to investigate the association between epicardial adipose tissue (EAT) thickness and silent myocardial ischemia, as well as coronary artery stenosis, in asymptomatic type 2 diabetic patients.The study included 100 type 2 diabetic subjects . Silent myocardial ischemia, as determined by CMR, was defined as evidence of inducible ischemia or myocardial infarction. Signal reduction or stenosis of ≥ 50% in the vessel diameter was used as the criteria for significant coronary artery stenosis on coronary magnetic resonance (MR) angiography.vs. 11.5 ± 2.1 mm, p = 0.01), but did not differ between the subjects with or without silent myocardial ischemia on CMR images . Multivariate logistic regression analysis indicated that EAT thickness was an independent indicator for significant coronary artery stenosis after adjusting for traditional risk factors .EAT thickness was positively correlated with body mass index (BMI), waist-to-hip ratio, systolic blood pressure, postprandial glucose, fasting/postprandial triglyceride (TG), serum glycated hemoglobin (HbA1c) level, and homeostasis model assessment of insulin resistance (HOMA-IR) score. Significant coronary artery stenosis was found in 24 patients, while 14 patients had silent myocardial ischemia in CMR . EAT thickness was greater in patients who had coronary artery stenosis (13.0 ± 2.6 mm Increased EAT thickness assessed by CMR is an independent risk factor for significant coronary artery stenosis in asymptomatic type 2 diabetes. However, EAT thickness was not associated with silent myocardial ischemia. Transthc burden . Similarsyndrome . HoweverOver the past several years, cardiac magnetic resonance (CMR) has been increasingly used for the assessment of patients with ischemic heart disease . CMR offThe study included 100 Korean asymptomatic diabetic patients who were enrolled in a prospective trial that evaluated the role of endothelial progenitor cell count in CAD . Study m2), and waist circumference was measured at the midpoint between the lateral iliac crest and the lowest rib. Hip circumference was measured at the maximal protrusion of the greater trochanter, and waist-to-hip ratio (WHR) was calculated as the ratio of waist-to-hip circumference. Blood pressure was measured twice with a mercury sphygmomanometer on the right upper arm after resting for at least 10 minutes in sitting position, taking the average values of systolic and diastolic blood pressures. Metabolic syndrome was defined according to criteria of the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP’s). The modified ATP III definition of metabolic syndrome requires the presence of at least three or more of the following five components: 1) elevated waist circumference ≥ 90 cm , ≥ 80 cm ; 2) elevated triglyceride (TG) > 150 mg/dL (1.695 mmol/L); 3) reduced high-density lipoprotein (HDL) cholesterol < 40 mg/dL , < 50 mg/dL ; 4) hypertension or elevated blood pressure ≥ 130/85 mm Hg; or 5) diabetes or elevated fasting plasma glucose ≥ 5.6 mmol/L [The patients’ records were reviewed to verify the duration of diabetes. The body mass index (BMI) was calculated as weight divided the square of height (kg/mLaboratory methods were described in detail in previous reports . BrieflyCMR was performed using a 3.0 Tesla magnetic resonance imaging (MRI) unit  with a 32-channel receiver coil. Myocardial ischemia was evaluated based on first-pass myocardial perfusion MR images acquired during adenosine stress (140 μg/kg/min for 3 minutes) and at rest with bolus injection of 0.01 mmol/kg of gadopentetate dimeglumine  for each session. After the perfusion study, whole heart coronary MR angiography  was performed without additional injection of the contrast medium. Cine MRI was performed with a balanced steady-state free-precession sequence along the cardiac short axis and horizontal long axis. Delayed enhancement MRI was obtained to assess myocardial viability using a 3-dimensional phase-sensitive inversion recovery sequence 10 minutes after the rest perfusion study.CMR images were independently evaluated by two experienced cardiac radiologists, who were not informed of the identity or any clinical information about the patients. After independent evaluation of the images, final conclusions were made by consensus interpretation. Abnormal findings on CMR included inducible ischemia, myocardial infarction, global left ventricular (LV) systolic dysfunction, and coronary artery stenosis. Inducible ischemia was defined as a perfusion deficit induced by adenosine stress on first-pass perfusion images that was reversed on resting perfusion images with no evidence of delayed myocardial hyper-enhancement on delayed enhancement images. Myocardial infarction was defined as an area with hyper-enhancement consistent with coronary distribution on delayed enhancement MRI. Silent myocardial ischemia by CMR was defined as an evidence of inducible ischemia or myocardial infarction. Global LV systolic dysfunction was defined as LV ejection fraction < 45% measured from cine MRI. Based on coronary MR angiography, the degree of stenosis was qualitatively defined as significant, suspected, minimal, or normal. Focal areas of marked signal loss, signal reduction, or stenosis of ≥ 50% in the vessel diameter were used as the criteria for significant stenosis ,14.Fat thickness in the left atrioventricular groove was measured as previously mentioned in studies by other investigators ,16. The t test or Mann–Whitney U test for continuous variables and a χ2 test for discrete variables. We then used multivariate logistic regression analysis to assess whether the associations between EAT thickness and the presence of significant coronary artery stenosis or silent myocardial ischemia were independent of age, gender, and traditional coronary risk factors. A P-value < 0.05 was considered significant.All statistical analyses were performed with PASW statistics software . Continuous variables with a normal distribution were expressed as mean ± SD, and discrete variables were expressed as percentages. The relationship between EAT thickness and other metabolic parameters was examined using Pearson’s correlation coefficient (R). Statistical comparisons between groups according to significant coronary artery stenosis or silent myocardial ischemia were performed using the Student’s 2 (range: 18.7 – 35.6 kg/m2), and the mean WHR was 0.91 ± 0.06 (range: 0.78 – 1.10). Of these 100 patients, 78 had metabolic syndrome. A total of 24 patients had significant coronary artery stenosis defined as stenosis ≥ 50% on coronary MR angiography, and 14 patients had silent myocardial ischemia on CMR images . Ten patients had both silent myocardial ischemia and significant coronary artery stenosis. The average thickness of the layer of EAT at the left atrioventricular groove was 11.9 ± 2.3 mm . The mean LV ejection fraction was 68 ± 3%, and all patients had preserved LV systolic function (range: 56 – 77%). The mean LV mass was 83 ± 21 g (range: 43 – 165), which was significantly greater in males than in females . None of the women was a smoker in this study.Table Subjects with any anatomical (stenosis ≥ 50%) or functional abnormality had a consultation with a specialized cardiologist. Among 28 patients recommended to undergo invasive coronary angiography, 20 patients were submitted for invasive coronary angiography, and 8 were submitted for revascularization (7 percutaneous coronary interventions and 1 coronary artery bypass graft).EAT thickness was positively and independently correlated with metabolic parameters including BMI, waist circumference, waist-to-hip ratio, systolic blood pressure, postprandial glucose, fasting/postprandial triglyceride, HbA1c level, and HOMA-IR. However, EAT thickness was not correlated with either LDL-cholesterol or HDL-cholesterol levels Table .vs. 11.5 ± 2.1 mm, p = 0.01). When subjects were divided based on presence of myocardial ischemia, only BMI was statistically different between the patients with and without silent myocardial ischemia  (Table vs. 11.5 mm (IR 3.4), p = 0.031). Similar EAT thickness was found between males with ischemia and without ischemia (11.9 mm (IR 4.2) vs. 12.5 mm (IR 2.9), p = 0.947) (Table p = 0.026) (Table We divided the subjects into two different classes: 1) subjects with or without significant coronary artery stenosis, and 2) subjects with or without silent myocardial ischemia. As shown in Table 3) Table A. In a set al.[et al.[2, indicating that the measurement of EAT may be more useful in Asian populations with low BMI than in obese subjects.Numerous studies have implicated epicardial adipose tissue (EAT) in the development and aggravation of CAD ,3,4,17. et al.. Park etl.[et al. recentlyIn the present study, we measured the EAT thickness at the end-diastolic phase on the horizontal long-axis plane in cine MRI. Nelson et al.  validateNumerous studies have focused on the quantification of EAT, but the best imaging tool and the most optimal parameter for EAT measurement remain uncertain . Many inet al. reported that EAT thickness of the left AV groove provides a more accurate assessment of metabolic risk [et al.[et al.[Controversy still exists regarding which measurement of EAT best reflects its metabolic role. Wang lic risk  and conflic risk . Neverthk [et al. and Seegl.[et al. recentlyThe present study has four main findings. First, it verifies that EAT thickness measured by CMR is closely associated with significant CAD evaluated by coronary MR angiography. Second, it demonstrates that EAT is not associated with silent myocardial ischemia, as assessed by combined stress perfusion and delayed enhancement infarction in CMR. Third, it shows that higher EAT thickness is an independent risk factor for significant CAD, after adjusting for traditional risk factors such as age, gender, BMI, HbA1c, and blood pressure. Fourth, it shows a gender-based discrepancy in the association between EAT thickness and myocardial ischemia.et al.[Clinical relevance of EAT on ischemic heart disease was indicated from our data, which showed that EAT measured by CMR was statistically related to insulin resistance-related metabolic parameters, such as BMI, waist circumference, waist-to-hip ratio, systolic blood pressure, postprandial glucose, fasting/postprandial TG, HbA1c level, and HOMA-IR score. This finding is consistent with data from previous studies that used echocardiography  or CT 3 for asseet al., who shoet al.[vs. 71 ± 16 g, p<0.001) despite similar EAT thickness (12.0 ± 2.1 mm vs. 11.8 ± 2.5 mm) (Table Interestingly, EAT thickness was significantly associated with silent myocardial ischemia in the female population in our study. Some plausible explanations for this finding include hormonal influences on adipose tissue metabolism  or diffeet al. showed aThis study had some limitations. First, this was a retrospective analysis; therefore, we were unable to explain the causal relationship between EAT and CAD or myocardial ischemia. Second, we did not investigate any inflammation markers. The pathophysiological mechanism of CAD has been suggested to involve the release of inflammatory signals from epicardial or perivascular adipose tissue, which then promote atherogenesis in the coronary arteries . Many stWe demonstrated that increased EAT thickness assessed by CMR was an independent risk factor for significant coronary artery stenosis in asymptomatic type 2 diabetes patients. However, this thickness was not associated with silent myocardial ischemia. In a subgroup analysis, EAT thickness was associated with silent myocardial ischemia in females but not in males. Further studies are warranted to discover why EAT is associated with coronary stenosis but not with myocardial ischemia, in asymptomatic type 2 diabetic patients. In addition, the possible gender-based differences in the role of EAT should be further evaluated.EAT, Epicardial adipose tissue; TTE, Transthoracic echocardiography; MSCT, Multi-slice computed tomography; CAD, Coronary artery disease; CMR, Cardiovascular magnetic resonance; MI, Myocardial infarction; CVD, Cerebrovascular diseases; PAD, Peripheral artery disease; BMI, Body mass index; WHR, Waist-to-hip ratio; HbA1c, Glycated hemoglobin; GA, Glycated albumin; LDL, Low-density lipoprotein; HDL, High-density lipoprotein; HOMA-IR, Homeostasis model assessment of insulin resistance; MRI, Magnetic resonance imaging; LV, Left ventricular; SPECT, Single photon emission computed tomography.The authors declare that they have no competing interests.HMK researched data and wrote/edited the manuscript. KJK reviewed the manuscript. HJL performed the radiologic analysis. HTY contributed discussion. JHM researched data. ESK contributed discussion. BSC contributed discussion. HCL contributed discussion. BWL reviewed/edited the manuscript. YJK performed the radiologic analysis and reviewed/edited the manuscript. All authors read and approved the final manuscript.


Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and the most common diagnosis in patients referred for cardiac transplantation. Genetic studies in DCM have identified mutations in over 30 genes. To date, there is only scarce data regarding the interdependencies between the various genotypes and their impact on cardiac morphology and myocardial tissue appearance. Since non-contrast cardiac magnetic resonance (CMR) is considered the reference method for morpho-functional analysis and late gadolinium enhanced (LGE) CMR method of choice for myocardial tissue assessment, we sought to investigate the characteristics of LGE in asymptomatic and symptomatic carriers of known cardiomyopathy mutations and their clinical associations.Thirtyeight carriers of lamin A/C (LMNA), cardiac troponin T (TNNT2) or myosin binding protein C (MYBPC3) gene mutations  were investigated with a 1.5T clinical scanner (Philips Achieva). Short axis slices covering entirely both ventricles were acquired using standard SSFP-sequences for measurement of LV and RV volumes and ejection fraction (EF). Focal myocardial fibrosis was assessed in LGE CMR images acquired 10 minutes after i.v. injection of 0.2 mmol/kg Gd-DTPA (Magnevist). Standard SSFP and LGE CMR images were assessed by different observers who were blinded to measurement results and clinical data. Associations between clinical characteristics, gene mutation and LGE were analyzed.LGE was present in 19 of 30 (63%) MYBPC3 carriers, all 6 (100%) TNNT2 carriers and 1 of 5 (20%) LMNA carriers. Midwall patterns of LGE located in the basal and/or mid-ventricular septal wall were the most commonly seen patterns in all gene mutations . The presence of LGE was positively associated with age . No further significant correlations were found between the presence, pattern or location of LGE and gender, cardiovascular risk factors, baseline systolic LV function or conduction abnormalities. Of all patients with known mutations, 24/38 (63%) were asymptomatic. No significant difference in LGE features was found between symptomatic and asymptomatic mutation carriers .LGE, predominantly presenting with basal and/or mid-ventricular septal midwall patterns, is a common finding in cardiomyopathy patients with known gene mutations. Its presence seems to be independent of the symptomatic stage of the disease or its phenotypic manifestation.none


Cardiomyopathies represent a group of diseases of the myocardium of the heart and include diseases both primarily of the cardiac muscle and systemic diseases leading to adverse effects on the heart muscle size, shape, and function. Traditionally cardiomyopathies were defined according to phenotypical appearance. Now, as our understanding of the pathophysiology of the different entities classified under each of the different phenotypes improves and our knowledge of the molecular and genetic basis for these entities progresses, the traditional classifications seem oversimplistic and do not reflect current understanding of this myriad of diseases and disease processes. Although our knowledge of the exact basis of many of the disease processes of cardiomyopathies is still in its infancy, it is important to have a classification system that has the ability to incorporate the coming tide of molecular and genetic information. This paper discusses how the traditional classification of cardiomyopathies based on morphology has evolved due to rapid advances in our understanding of the genetic and molecular basis for many of these clinical entities. Cardiomyopathies are a broad spectrum of diseases that affect the muscle or myocardium of the heart. This results in a failure of the heart to provide adequate oxygenated blood to the body and remove carbon dioxide and other waste products. The heart is an extremely specialised, richly innervated muscular pump that is designed to beat continuously, without stopping for the entire lifespan of its owner. To put this in perspective, a human heart beating at 70 bpm will beat approximately 2.5 billion times during a 70-year lifespan.“Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, which may lead to cardiovascular death or progressive heart failure-related disability .”The official definition of cardiomyopathy by the American Heart Association in 2006 is as follows.There are many ways to classify cardiomyopathies. Previously, a cardiomyopathy was defined as “a heart muscle disease of unknown cause”  and was Therefore in 1995, a task force established by the WHO/ISFC compiled a new system which included ARVD and unclassified cardiomyopathies . The term “specific cardiomyopathy” was used to describe heart muscle disorders which are as a result of cardiac or systemic diseases such as coronary artery disease, valvular heart disease, or hypertension .A more complete classification based on the AHA definition above divides cardiomyopathies into (1) primary cardiomyopathies, which affect the heart alone, and (2) secondary cardiomyopathies, which are the result of a systemic illness affecting many other parts of the body. These are then further broken down into subgroups within these two broad categories incorporating new genetic and molecular insights .“A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality .”Distinguishing between primary and secondary cardiomyopathies can be challenging as many diseases classified as primary can have extra cardiac components, and many secondary cardiomyopathies can mainly or exclusively affect the heart. Whether or not this is the best method of classification has generated some debate within the literature , 63. WitWhile diagnosis of cardiomyopathy rarely begins with the identification of a genetic mutation, it is rational to incorporate genetic mutation testing within a framework of classification as it is important while formulating a plan of treatment and also in informing families of their prognosis .Hypertrophic cardiomyopathy (HCM) has been defined by the presence of myocardial hypertrophy incongruent with the haemodynamic stress required for the degree of hypertrophy and the exclusion of infiltrative diseases such as amyloidosis and storage diseases , 66, 67.In the absence of hypertension and valve disease, left ventricular hypertrophy (LVH) occurs in approximately 1 : 500 of the general population . In day-If the HCM is familial, then it is usually transmitted in an autosomal dominant pattern of inheritance caused by mutations within genes that encode for various proteins of the cardiac sarcomere. Currently, there are over 500 mutations in 13 genes that have been identified that cause HCM and 50% of these are familial , 69–72 .Pathologically, left ventricular (LV) cavity size is normally reduced and this can progress to LV dilatation and heart failure, albeit in a minority of patients. There are many patterns of hypertrophy and all are consistent with a diagnosis of HCM but concentric hypertrophy is more suggestive of a systemic cause such as glycogen storage disease. Moreover, mutations in the genes encoding for cardiac troponins can be associated with mild phenotypes but, conversely, a high incidence of cardiac death . The norRestrictive cardiomyopathies have a diverse range of aetiology; however, all are recognised as having distinct haemodynamic features separating them from other forms of cardiomyopathy. Restrictive cardiomyopathies in general are defined as showing normal ventricular size (nondilated and nonhypertrophied) with impaired haemodynamic function, elevated filling pressures, and diastolic dysfunction, and in most cases normal systolic function , 77.Presentation can include symptoms of both right and left sided failure; decreased exercise tolerance, dyspnoea, peripheral oedema, and palpitations are the most common symptoms . Due to Various aetiologies have been identified as causing restrictive cardiomyopathy and range from idiopathic (primary) restrictive cardiomyopathy, to systemic conditions including infiltrative, noninfiltrative, and storage disorders, as well as endomyocardial disorders, various medications, and iatrogenic causes . FamiliaPrognosis in symptomatic patients is quite poor, depending on aetiology. Idiopathic restrictive cardiomyopathy has been associated with a significant difference in 10-yr survival when compared to expected survival in groups matched for age and sex . In compDCM is a common cause of congestive cardiac failure (CCF) and is defined by the presence left ventricular systolic dysfunction with left ventricular dilatation the absence of coronary artery disease or other causes such as hypertension or valvular pathology . The rigThe 2009 HFSA  has relePeripartum cardiomyopathy is a specific subgroup of dilated cardiomyopathy defined as the development of heart failure with evidence of left ventricular dysfunction, within the last month of pregnancy to within 5 months of delivery, without other identifiable cause or underlying cardiac condition , 86. GroARVD is a heart muscle disease which, pathologically, consists of progressive fibrofatty replacement of the right ventricular musculature which may or may not involve the left ventricle. It predisposes towards malignant arrhythmias originating from the right ventricle and is a major cause of sudden death in young athletes . Major aIt is a familial disease in around 50% of cases and is usually transmitted in an autosomal dominant fashion . The firGenetics is obviously important as it adds certainty to the diagnosis, but given the incomplete penetrance of the disease the established diagnostic criteria are essential.The 2009 Heart Failure Society of America (HFSA) genetic evaluation of cardiomyopathy practice guideline and 2005 American College of Cardiology/American Heart Association (ACC/AHA) HF guidelines include recommendations with regard to genetic counselling and genetic testing in patients and families with certain cardiomyopathies. As far as treatments are concerned, gene therapy is still quite young and transferring concepts from animal models to human therapies is yet to be seen. Therapeutic interventions of the future are likely to focus on the signaling events from abnormal gene to protein and finally clinical phenotype, and the modification of the genetic and environmental factors mediating this process .LMNA gene defects (where penetrance rates are noted to be very high over 30 years and associated with high rates of sudden death) and in particular SCN5A defects, early implantation of ICD may be considered in these populations, especially in the setting of family history of sudden cardiac death or implantable cardiac defibrillator usage [As sudden cardiac death is a possible first presenting complaints for patients with dilated cardiomyopathy especially those with or usage .Gene therapy in animal models of heart failure aimed at improving sarcoplasmic calcium transport has been investigated with therapeutic promise and may lead to further application in human model of restrictive cardiomyopathy .In patients with ARVC, genotyping and early ICD implantation as primary prevention may be indicated in patients with Naxos disease and recessive forms of ARVC .Screening of family members of patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular is recommended as family members are frequently asymptomatic and disease progression is often quite short and although asymptomatic early noninvasive investigations may prove abnormal , 113.Due to the commonality of autosomal dominant inheritance of hypertrophic cardiomyopathy and the high degree of penetrance associated with many of the gene mutations, it is recommended that first-degree relatives are regularly screened for inheritance of the disease . With thFor example, patients with gene mutations of desmosomal components (those most commonly seen in ARVC), penetrance is low and there is commonly age related variability in expression and therefore, early identification holds an unknown prognostic significance for patients in question , 116.Classification systems in all branches of science are designed to allow categorisation within a consistent framework thereby imparting a degree of homogeneity to satisfy researchers and clinicians alike. Over the years, many classification systems have been put forward for cardiomyopathy based on origin, structural abnormality, functional status, and etiology. Not surprisingly, this has failed to some degree. From a purely functional viewpoint, cardiomyopathy is not a static condition but can move from one functional group to another due to cardiac remodelling. Similarly, using etiology has limitations given that similar genotypes can express different phenotypes depending on where the disease is in its natural history. Despite these shortcomings, a genetic diagnosis does offer some definite advantages. Karibe et al. reported a novel tropomyosin mutation that was associated with a mild phenotype but had a poor prognosis when contrasted to other mutations in the gene (13 deaths in 26 affected family members) . Genetic


Two predominant sheet-populations were observed, with sheet-angles of either positive (β+) or negative (β−) polarity relative to a ‘chamber-horizontal plane’ . In contracture, mean ‘intersection’-angle  between β+ and β− sheet-populations increased from 86.2 ± 5.5° (slack) to 108.3 ± 5.4° (p < 0.001). Subsequent high-resolution DTI of fixed myocardium, and histological sectioning, reconfirmed the existence of alternating sheet-plane populations. Our results suggest that myocardial tissue layers in alternating sheet-populations align into a more chamber-horizontal orientation during contraction. This re-arrangement occurs via an accordion-like mechanism that, combined with inter-sheet slippage, can significantly contribute to ventricular deformation, including wall-thickening in a predominantly centripetal direction and baso-apical shortening.Deformation and wall-thickening of ventricular myocardium are essential for cardiac pump function. However, insight into the histo-anatomical basis for cardiac tissue re-arrangement during contraction is limited. In this report, we describe dynamic changes in regionally prevailing cardiomyocyte (fibre) and myolaminar (sheet) orientations, using Diffusion Tensor Imaging (DTI) of ventricles in the same living heart in two different mechanical states. Hearts, isolated from Sprague–Dawley rats, were Langendorff-perfused and imaged, initially in their slack state during cardioplegic arrest, then during lithium-induced contracture. Regional fibre- and sheet-orientations were derived from DTI-data on a voxel-wise basis. Contraction was accompanied with a decrease in left-handed helical fibres  in basal, equatorial, and apical sub-epicardium (by 14.0%, 17.3%, 15.8% respectively;  An exDetailed knowledge of fibre- and sheet-arrangement, and of their changes during the contractile cycle, is essential for understanding cardiac mechanics. Cardiomyocyte contraction provides the cellular basis for force-generation and shortening, predominantly along the fibre-direction. Given the incompressible nature and constant volume of the cytosol, cell shortening is associated with radial widening. Interestingly, the increase in myocyte diameter during contraction would raise wall-thickness by only 8%, while in reality systolic wall-thickening by 40% or more is observed. Thus, cell-diameter increases account for a fraction only (about one fifth) of total ventricular wall-thickening during contraction . Other cdynamic sheet re-arrangement during ventricular contraction is still lacking. Limited insight into sheet-dynamics may be one of the reasons why even the most-advanced histo-anatomically detailed mathematical models of cardiac contraction, while covering the ventricular twisting motion caused by the transmurally varying fibre orientation, tend to under-represent the atrio-ventricular valve plane shift . Computational heart models also tend to only partially capture the predominantly centripetal (from “Centrum” [Latin for: the centre] and “petere” [Latin for: to seek/to aim at] – i.e. directed towards the centre) wall-thickening, which is achieved with relatively stable epicardial outlines  has been validated as a powerful tool for non-destructive determination of 3D myocardial histo-anatomy  The arrain-vitro . Howeverin-vivo are of key importance for cardiac pump function.The aim of this study was to measure fibre- and sheet-orientations in one and the same living heart, at two different mechanical states. To overcome the obstacles outlined above, rat hearts were excised and perfused via their coronary vasculature (Langendorff-mode) inside a magnetic resonance imaging (MRI) scanner. DTI experiments were conducted in a slack state , and subsequently during contracture . These investigations were complemented with higher-resolution DTI after chemical fixation of hearts, and histological follow-up. As a result, we provide novel evidence for the existence of alternating myocardial sheet-populations in rat ventricles, confirmed using DTI and histological data, and insight into their spatial rearrangement during cardiac contraction. Using DTI, we were able to show that sheet-populations in living myocardium deform in an accordion-like fashion, increasing the inter-sheet-angle during contraction, so that sheets become more chamber-horizontally aligned. These data from two mechanical states in the same heart may help to explain how the combined contribution of fibre-orientation and sheet-re-arrangement helps, during contraction, to shorten baso-apical dimensions of the ventricles, while increasing wall-thickness in a preferentially centripetal direction. These ‘signature-deformations’ of the ventricles 22.14 Pa (110 mmHg) and a flow rate of ∼5 ml × min−1. All perfusates were oxygenated within the reservoir and gravity-fed into the body of the perfusion rig via flexible water-jacketed Tygon tubing. Incoming and effluent solutions were carried to/from the centre of the magnet inside a rigid plastic support tube, which provided a water-tight compartment to protect the MRI equipment, and facilitated the positioning of heart perfusion chamber at the iso-centre of the magnet and the radio-frequency coil. Following excision . The aorta was swiftly cannulated for coronary perfusion in Langendorff mode. An incision into the pulmonary artery wall just past the right ventricular outflow valve was performed to prevent intra-ventricular fluid accumulation. After the initial wash using normal Tyrode solution , cardioplegic arrest was induced using a modified Tyrode solution with elevated K+ . Following imaging of the heart in its slack state . All solutions were titrated to pH 7.4, and osmotic pressure was checked prior to use with a freezing-point reduction semi-micro osmometer to be within 300 ± 10 mOsm . To ensure a complete tissue equilibration in target solutions, measurements were started 20 min after solution switching (room temperature).All animal work was conducted in accordance with Schedule 1 of the UK Home Office Guidance on the Operation of Animals (Scientific Procedures) Act of 1986, with approval of the Oxford University ethical review board. Hearts were excised from female Sprague–Dawley rats, after concussion of the brain followed by cervical dislocation (2.2.2n = 2) were briefly washed by Langendorff-perfusion with normal Tyrode, arrested using cardioplegic Tyrode, and fixed in either slack state (high-K+) or contracture (high-Li+) via coronary perfusion with Karnovsky's fixative (for further detail see (For high resolution DTI imaging (see Section tail see ). Fixed 2.2.3+-Tyrode, and fixed by coronary perfusion with Karnovsky's fixative, as described above. Hearts were stored in Karnovsky's for 48 h, and then wax-embedded. Embedding involved dehydrating the tissue in several steps with ascending concentrations of ethanol, xylene, and finally wax, as described in detail elsewhere .2.3−1, rise time 130 μs, inner diameter 60 mm). A birdcage coil with an inner diameter of 39 mm  was used to transmit/receive the MRI signals for the perfused heart experiments. For high resolution DTI of fixed hearts, a birdcage coil with an inner diameter of 28 mm was used .All imaging was performed using an Agilent 9.4 T (400 MHz) MR system , comprising of a horizontal magnet (bore size 210 mm), a VNMRS Direct Drive console, and a shielded gradient system  wall thickness were measured 15 times in an uninterrupted cycle of 11 min intervals, using a 2D multi-spin-echo pulse sequence. Imaging parameters were as follows: number of slices = 5, slice thickness = 1 mm , matrix size = 128 × 128, field of view (FOV) = 20 mm × 20 mm, number of averages = 2, TR = 2.5 s. Sixteen echoes per excitation were acquired with TE values equally spaced between 4.6 ms and 73.3 ms.2.3.2eff = 15 ms , matrix size = 128 × 128, slice thickness = 1 mm, number of slices = 13 , number of averages = 12. The in-plane FOV was adjusted to match the size of each heart, and ranged from 19 to 23 mm, giving an isotropic in-plane resolution of 148–180 μm. Diffusion gradient strength was 31 G cm−1, with a gradient duration of 2.5 ms, separation of 9.6 ms, and maximum b-value = 679 s mm−2 (including imaging gradients and cross-terms between imaging and diffusion gradients). Ten non-co-linear gradient directions were used, arranged according to an optimized scheme based on the electrostatic repulsion principle  were chemically fixed, as described in Section 2.4ν1, ν2, ν3) and eigenvalues . From these, the Apparent Diffusion Coefficient (ADC) was calculated as the mean of the three eigenvalues, and the Fractional Anisotropy (FA) was determined using the standard method described in Diffusion tensors were calculated on a voxel-by-voxel basis via a weighted linear least squares fit method, using in-house software developed in IDL . Tensors were then diagonalized to produce the sorted eigenvectors (b0) DTI images. In every slice, voxels within the LV myocardium in which ν1 had a minimal out-of-plane component  were selected as a first estimate of the mid-wall region. The centre of a best-fit circle through these pixels provided a first estimate of the centre of the LV in each slice. The long-axis direction was then recalculated as the best-fit line through the centres of all these circles, allowing for transformation of the eigenvectors into a new coordinate system defined by the fitted long-axis. The intersection of the derived long-axis with each LV cross section was taken as the new LV centre in each slice. This served as the origin of a local cylindrical coordinate system, and the local radial axis  was defined as normal to the longitudinal axis. The circumferential direction was defined as normal to the radial axis (i.e. the tangent). As this model represents a simplification of the true underlying geometry, errors may occur in the estimation of the LV long axis. These errors are likely to be greatest near the apex, where local geometry is more spherical, and the local long axis direction is inherently ill-defined. Further away from the apex, Eigenvectors were transformed from the global magnet coordinate system into the anatomical coordinate system of the heart using the method described in α, defined as the angle between (a) the projection of ν1 onto the circumferential–longitudinal plane : −30° ≤ α ≤ 30°, and right-handed helical fibres (RHF): α > +30°.Myofibre orientation was expressed in terms of the helix angle , α, defiThe transverse (or imbrication) angle is defined as the angle between the local circumferential direction and the projection of the fibre direction onto the circumferential–radial plane. As myofibres run near-parallel to the epicardial surface in much of the ventricular tissue, transverse angles are generally small, ranging from −20° to +20° in the rat heart . As the β, which describes the angle between the heart's chamber-horizontal plane (defined as perpendicular to the LV long axis) and the apparent sheet orientation in a transmural  long-cut (see v3. Sheet angles (β) were calculated therefore for every voxel by projecting v3 onto the voxel-specific longitudinal–radial plane: the angle between this projection and the radial unit vector is equal to (90° – β). Note that this method using the tertiary eigenvector is un-ambiguous in terms of defining sheet orientations in a 3D space, and their projection onto the longitudinal–radial ‘cutting plane’. However, when sheet angles are defined using the secondary eigenvector as a substitute, errors can be introduced into sheet angle calculations, as the secondary eigenvector (which runs in the sheet) does not uniquely define the sheet plane in 3D. Sheet angles were defined as positive if the sheet projection in the transmural long-cut moves towards the LV base as one follows the sheet radially from endo- to epi-cardium (δ), was calculated as β1 and β2 are the measured sheet angles in each population  were established in each dataset to define apical, equatorial and basal regions of the ventricles (covering approximately one third of the LV base–apex length each), and mean values of helix and sheet angles were calculated as a function of transmural position for each ROI in an individual heart, in slack state and during contracture. In addition to the DTI metrics described above, wall thickness, defined as the mean transmural distance between the LV epi- and endo-cardium in the un-weighted DTI images, was measured along four transmural paths, in the most ‘superior’  slice of the equatorial ROI in each heart (i.e. the slice positioned at one-third of the long-axis length from the base of the heart ).t-test  changes within one heart, in two mechanical states), inter-individual comparisons used an un-paired two-tailed t-test. In cases where the data were non-normally distributed , a G-test and a two-sample Kolmogorov–Smirnov test were used, respectively, to examine statistical significance of contracture-induced change . LV wall-thickness in equatorial slices from the T2 experiments was initially 2.5 ± 0.7 mm, and 2.4 ± 0.6 mm after 160 min. Linear regression of the T2 and wall thickness values, with ANOVA analysis of the slope of the regression line, confirmed that, overall, the samples remain stable over this period.In the initial control experiments, hearts scanned at 11 min intervals over a 165 min period showed little sign of gross anatomical change, such as would be indicative of progressive interstitial oedema. Any oedema developing acutely upon exposure to crystalloid perfusion could not be assessed, as scans could be started only at ∼15 min after organ excision, due to preparation time-requirements. The mean myocardial T2 at the beginning of observations and after 160 min remained stable . However, FA and ADC showed no significant difference between slack state and contracture, suggesting that neither ‘cellular density’ nor the intra-voxel distribution of fibre-orientations changed significantly on the whole-ventricular scale. In slack state and contracture, the ratio of λ1/λ2 was 1.51 ± 0.03 and 1.48 ± 0.07 respectively, and the ratio of λ2/λ3 was 1.47 ± 0.04 and 1.43 ± 0.10 respectively.Mean equatorial LV wall-thickness, mean ADC, and mean FA throughout the myocardial volume before and after induction of contracture are shown in 3.3G-tests. All individual tests on 3 locations  for n = 8 hearts  were significant at the 10−6 level. To aggregate the data across hearts, the contingency tables were merged into a single table per location in the heart. The total fibre counts per sample were normalized, to avoid giving undue weight to samples with a large fibre count overall. Differences were significant for all three cardiac tissue regions: basal (3.68 × 10−9), equatorial (1.07 × 10−129) and apical (4.84 × 10−58). In order to examine the source of the difference, the terms of the G statistic were decomposed by orientation. Values for LHF, CF and RHF were (respectively) in the basal region 27.31, 2.65, and 8.88, in the equatorial tissue 403.51, 23.36, and 167.05, and in the apical part 146.98, 0.71, and 116.26. The CF values were smallest throughout, showing that the significant differences (above) are driven predominantly by changes in LHF and RHF values, rather than by a change in the proportion of CF per se. An example of changes in helix-angle distribution throughout an axially-orientated slice in one of the perfused hearts, before and during contracture, is illustrated in Contraction-associated changes in fibre-orientation in perfused hearts are shown in β+ and β− populations , included the range −30° ≤ β ≤ 30°. A two-sample Kolmogorov–Smirnov test confirmed that the distribution of sheet-angles changed significantly (p < 0.001) between the two mechanical states, in basal, equatorial, and apical regions of the hearts. The greatest shift in sheet-orientation was observed in the equatorial region, where the absolute values (|β|) of the mean sheet-angle in the β+ population decreased by 8% , and in the β− population by 8% . A shift of similar magnitude was observed in the basal region, with a decrease in β+ by 6% , and in β− by 7% . A smaller shift occurred in the apical region, where the only significant change was a 4% decrease in the absolute β− sheet-angle . The 95% confidence intervals of sheet-angle distributions, illustrated in panels B, D, and F of Sheet-angle distribution histograms at rest and during contracture are also shown in δ in t-test, p < 0.001). Regionally, increases in mean sheet intersection-angle of 23%, 29% and 26% were observed in the basal, equatorial and apical parts of the hearts, respectively .The re-alignment of sheets into more horizontal planes during systole can make a significant contribution to wall thickening. β+ or β− populations, and the relative proportion of sheet-angles that were orientated more radially (in the range 30° < β < 30°) was only ∼11%. In contracture, this fraction of sheet-angles outside of the dominant β+ or β− populations increased to 15%.The presence of intersecting sheet-patterns was reconfirmed using high-resolution DTI of fixed myocardium, and histology. Histograms of sheet-angle distribution in the entire myocardial volume, derived from high-resolution DTI data in slack state and contracture, are shown in β+ and β− sheet-populations during ventricular deformation. Statistical comparison of changes in sheet- and fibre-angles was restricted, therefore, to same-heart DTI data from live-perfused organs.Histological assessment re-confirmed the presence of regions where opposing sheet-populations meet in mid-myocardial layers of right ventricle (RV), LV, and septum . However4The aim of this study was to measure regional changes in fibre- and sheet-architecture in different mechanical states in one and the same sample, using DTI of living heart tissue. During the time required for DTI (64 min), hearts offer a histo-anatomically stable substrate. According to our sample-stability assessment, there is no significant build-up of oedema, beyond what will have occurred immediately after cardiac excision and the onset of saline perfusion , over a decrease in sub-epicardial LHF and an accompanying increase in sub-endocardial RHF throughout the myocardium. The latter may be caused in part by the fact that there is a centripetal translocation of myocardial tissue mass, which is associated with a reduction in the mean radii of tissue layers. This is the more pronounced the further away tissue locations are from the epicardium. During contraction, the RHF-containing sub-endocardial tissue will therefore occupy a larger fraction of the ventricular cross-section, compared to the resting state. In addition, it is possible that endocardial tissue, including trabaeculations, becomes compacted during contraction, so that fibres that may not be traceable by DTI in the slack state become apparent in contracture.A previous study by Our data further show that sheet-populations with alternating polarity, forming V-, X-, N-, W- or M-like shapes in transmural long-cuts, are present throughout the living myocardium, and that the intersection-angle between these populations increases during contraction. This change in sheet intersection-angles is caused by a dynamic re-organization of ventricular tissue, which is most apparent in the basal and equatorial regions of the heart. Higher resolution DTI data, taken from fixed hearts, re-confirm the existence of alternating sheet-populations, and  they also indicate an increase in sheet intersection-angles during cardiac contraction.Similar patterns of alternating sheet-orientations can be detected  in previous DTI  and highx/y/z coordinates used in the following. Moving clock-wise, the top-right panel identifies fibre-orientation in the x/y plane  for a representation of sub-epicardial, mid-myocardial and sub-endocardial layers. Mechanical activity is assumed to be maximal in the fibre-direction (black large arrows). This is decomposed into components in x (blue solid arrows) and y-directions (blue dashed arrows). Mid-myocardial fibres lie along the x-direction and, hence, have a horizontal force component only (y = 0). One can now carry the x-component of mechanical activity over to the x/z plane, shown in the bottom-right panel, and plot this in a tangential manner onto epi-, mid- and endocardial layer representations, shown with their different radii. This allows one to visualize that the centripetal component  will be smallest at epicardial locations. Moving towards the mid- and endocardial layers, the reduced radius will favour z-translation of mechanical activity in the x-direction . Since the projection is ‘cut’ in the horizontal plane, the tangential force component that is shown is largest in the mid layer . Note, though, that curvature-based translation of tangential into centripetal forces occurs also in other planes . Now that we have a conceptual illustration of relative mechanical driving forces for deformation in all three directions (x/y/z), we can consider how this could affect a simplified version of sheet populations (only two shown) in the y/z-plane (bottom left of Y and Z component amplitudes (established above) to epi-, mid- and endocardial layers. These transitions result in baso-apical shortening of the ventricular block model, and wall thickening predominantly in the endocardial direction. These changes arise simply as a result of activation along fibres with transmurally varying angle  the predominantly centripetal displacement of ventricular muscle mass, (b) the absence of major epicardial contour displacements, and (c) ventricular shortening in the ‘longitudinal’  direction, is illustrated in This schematic illustration is focussed on conceptualizing a small sub-set only of the mechanical re-arrangements, and it is highly simplified. Thus, it doesn't address integrated 3D effects, ignores the presence of multiple sheet-populations across the wall in many regions, excludes chamber-twisting, and it is mechanically ‘imprecise’ . Yet, it may serve as an illustration of how the presence of sheets, and the increase in their intersection angles during cardiac contraction, may contribute to those changes in ventricular shape that are not well-captured by current conceptual and computational models. The ball-park of measured 25–33%;  and theo4.1λ2/λ3 was only 3% lower than the ratio of λ1/λ2 in our study, which suggests only a small sorting error for the secondary and tertiary eigenvectors. Furthermore, the use of cardioplegic solutions to induce arrest, and of Li+ to provoke contracture, will offer approximations only of normal slack and end-systolic states. However, this was required to accommodate the relatively long DTI scan-times in the absence of tissue fixation (which would have defied the purpose of this study). Lastly, the terminology used in the majority of studies in this area may be misleading. The term ‘fibres’ refers purely to the locally prevailing cell-orientation. The term ‘sheets’ describes laterally reinforced cell layers that are linked locally, largely through perimysial collagen, forming local ‘sheetlets’ rather than continuous planes.One of the key limitations to our study is that, with a DTI slice-thickness of 1 mm compared to an average sheet-thickness of ∼50 μm ,b, measu5existence of multiple alternating sheet-populations throughout the ventricular myocardium, but also for their dynamic re-arrangement during contraction into more chamber-horizontal planes. The associated increase in sheet intersection-angles may contribute both to the predominantly centripetal ventricular wall-thickening and to the baso-apical shift in the atrio-ventricular valve-plane in vivo. A thorough understanding of the 3D reorganization of fibre- and sheet-structures in the heart is vital for accurate modelling, whether conceptual or computational, of electrical and mechanical behaviour of the heart. This is relevant for the interpretation and optimization of clinical observations, such as related to wall-thickening or ejection-fraction, for example in sinus node vs. ventricularly paced beats. Further work in this area, particularly at higher spatial resolution, in mechanical states representative of more points of the cardiac cycle, and including disease conditions with local (e.g. scarring) or diffuse (e.g. fibrosis) alterations in tissue integrity, is likely to lead to a significant improvement in our understanding of cardiac electro-mechanical structure–function relations.We used DTI to measure regional changes in fibre- and sheet-orientation in living hearts at rest and during contracture. We observed significant changes in the balance of LHF and RHF during contracture, which colloquially could be termed ‘sub-endocardial tissue gain’, which is in keeping with the mainly centripetal direction of ventricular wall thickening. In addition, both DTI and histology data provide strong evidence not only for the Please see also related communications in this issue by


Its slow clinical adoption is partly due to the lack of robustness in SSFP cine imaging  or prescA 600 µs (instead of 1000 µs) RF pulse and 192 (instead of 256) readout point in SSFP shortened the TR/TE from 3.4/1.5 ms to 2.7/1.2 ms. At 40 ms temporal resolution and 85% phase resolution, the segments/heart beat increased from 12 to 15, reducing patient's breath-hold time.The IRB approved study scanned 8 healthy volunteers (age 26±2) with a 3T MR scanner . Cines of 10 short-axis slices covering the whole heart were acquired with retrogated breath-held SSFP . The short TR sequence was used first. Frequency scout was then performed. After that, cine acquisition for the whole heart was repeated using the standard protocol. LV myocardial mass, end-diastolic volume (EDV), end-systole volume (ESV) and ejection fraction (EF) were analyzed by an experienced observer using QMass MR  (papillary muscles included). Correlation analysis was performed between paired measurements. Two-tailed paired t-test was conducted to assess the statistical differences with p<0.05 regarded as significant.The scan time for 1 slice of cine was about 6 and 9 heart beats for the protocols with short and standard TR respectively. Banding artifact was common in cine images obtained with the standard TR protocol, while images from the protocol using short TR scan were impervious to the artifact. Analysis results were shown in Table The short TR SSFP cine is more robust to field inhomogeneity at 3T. It eliminates frequency scout and increases patient throughput. Initial results showed that short TR cines gave comparable myocardial mass, EDV and ESV. The measured EF was 1% lower than the standard protocol, and may be caused by the reduced image spatial resolution. Our preliminary study suggested that by slightly trading spatial resolution for shorter TR in SSFP, cine imaging at 3T can be more robust and efficient. The approach may greatly facilitate patient throughput in 3T CMR. Evaluation on more volunteers and patients will be done to fully validate the method.None.


A very low calorie diet (VLCD) in patients with type 2 diabetes mellitus (T2DM) results in cardiac remodeling and improved diastolic function. It is unknown how long these effects sustain after reintroduction of a regular diet.To examine the long-term effects of initial weight loss by a VLCD on cardiac dimensions and function in T2DM patients.2) were treated by a VLCD  during 16 weeks. Cardiac function was measured by magnetic resonance imaging before and after the 16-week VLCD and again after 14 months of follow-up on a regular diet.Fourteen patients with insulin-dependent T2DM . Left ventricular (LV) mass and LV mass/LV end-diastolic volume ratio decreased after the 16-week VLCD ) and remained decreased after 14 months of follow-up  The improvement in LV diastolic function, measured by the early (E) and atrial (A) diastolic filling phase ratio after the 16-week VLCD, was sustained after 14 months of follow-up (E/A ratio: 0.96±0.07 (baseline); 1.12±0.06 (after VLCD); 1.06±0.07 ).Body mass index decreased from 35±1 kg/mWeight reduction by a 16-week VLCD in T2DM patients results in sustained cardiac remodeling and improved diastolic function after 14 months of follow-up, despite weight regain on a regular diet.


Reduced levels of creatine and total adenine nucleotides  are hallmarks of chronic heart failure and restoring these pools is predicted to be beneficial by maintaining the diseased heart in a more favourable energy state. Ribose supplementation is thought to support both salvage and re-synthesis of adenine nucleotides by bypassing the rate-limiting step. We therefore tested whether ribose would be beneficial in chronic heart failure in control mice and in mice with elevated myocardial creatine due to overexpression of the creatine transporter (CrT-OE).2 = 0.63, p<0.0001), but did not correlate with myocardial creatine or TAN levels.Four groups were studied: sham; myocardial infarction (MI); MI+ribose; MI+CrT-OE+ribose. In a pilot study, ribose given in drinking water was bioavailable, resulting in a two-fold increase in myocardial ribose-5-phosphate levels. However, 8 weeks post-surgery, total adenine nucleotide (TAN) pool was decreased to a similar amount (8–14%) in all infarcted groups irrespective of the treatment received. All infarcted groups also presented with a similar and substantial degree of left ventricular (LV) dysfunction (3-fold reduction in ejection fraction) and LV hypertrophy (32–47% increased mass). Ejection fraction closely correlated with infarct size independently of treatment (rElevating myocardial ribose and creatine levels failed to maintain TAN pool or improve post-infarction LV remodeling and function. This suggests that ribose is not rate-limiting for purine nucleotide biosynthesis in the chronically failing mouse heart and that alternative strategies to preserve TAN pool should be investigated. Multiple lines of evidence suggest that energy starvation may play an important role in the pathophysiology of heart failure de novo purine synthesis Adenine nucleotides are too polar to cross the plasma membrane, so loss is a consequence of conversion to nucleosides, e.g. during ischaemia and heart failure, elevated AMP provides increased substrate for 5′-nucleotidase resulting in formation of adenosine, which as a nucleoside, can be lost from the cell by diffusion de novo purine synthesis, increasing demand for ribose-5-phosphate. In this context, D-ribose supplementation increases the rate of adenine nucleotide synthesis up to 6 fold in rat, guinea-pig and dog heart; attenuating the decrease in [ATP] and accelerating functional recovery For example, in acute ischaemia there is a rapid and profound loss of TAN pool. Since adenine nucleotides (particularly ADP) inhibit activity of PRPP synthetase It is not known whether ribose supplementation might also prevent the gradual decline in TAN pool observed in chronic left ventricular (LV) failure. Most notable is a study that gave oral D-ribose with folic acid (a co-factor) to rats with monocrotaline-induced right ventricular dysfunction and showed preservation of TAN pool, reduced fibrosis and diastolic dysfunction after 4 weeks in vitro model of ischaemia that was not observed for either agent alone in silico study, that went on to hypothesise that a concomitant increase in TAN pool, total exchangeable phosphates (TEP) and creatine levels was necessary to maintain chemical energy in the failing heart Further evidence suggests synergy when ribose treatment is combined with creatine. This combination was shown to reduce cardiomyocyte apoptosis in an This study was carried out under Home Office project licence 30/2754, which was approved by the committee for Animal Care and Ethical Review at the University of Oxford, and conforms to UK Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act, 1986. All surgery was performed under full general anaesthesia using isoflurane with post-operative opioid analgesia provided as standard.Transgenic mice over-expressing the creatine transporter (CrT-OE) have previously been created in our laboratory and backcrossed to C57BL/6J for more than 10 generations Female adult C57BL/6J mice underwent coronary artery ligation or sham surgery (n = 7 in each group). Four weeks following surgery, TAN pool was measured in homogenates containing entire left and right ventricles (including scar tissue) using HPLC as previously described 3. De-proteinised and neutralized LV extract and 32 units GAPDH were mixed with assay mixture  in a cuvette and incubated for 3 min at 25°C. The first reaction was initiated by addition of 1.25 U of transketolase and absorbance (A1) of NADH followed at 340 nm, 25°C for 10 min. A1 originates from the presence of glyceraldehyde-3-phosphate and xylulose-5-phosphate in the extract. After the first reaction reached completion, 5 units of ribulose-5-phosphate 3-epimerase and 10 units of phosphoriboisomerase were added to the cuvette. The absorbance (A2) was recorded at 340 nm, 25°C for 10 min. Ribose-5-P content of ventricular tissue was expressed as nmol/g wet tissue weight.A 10% (w/v) solution of D-ribose (Sigma-Aldrich) in drinking water was chosen based on the oral dose for human patients and rats (0.15–0.8 g/kg/d) Female adult mice (21–30 g) were randomly allocated to 4 experimental groups:S consisted of WT mice, which underwent sham surgery and were not fed ribose;Group MI consisted of WT mice, which underwent myocardial infarction (MI) surgery and were given normal drinking water;Group MI+R consisted of WT mice, which underwent MI surgery and were given ribose in drinking water (10% (w/v) D-ribose solution);Group MI+R+C consisted of CrT-OE mice, which underwent MI surgery and were given ribose in drinking water (10% (w/v) D-ribose solution).Group 1H-MRS examination to pre-select animals with moderately elevated myocardial creatine (88–142 nmol/mg prot). At least one week later, WT and CrT-OE mice had coronary artery ligation surgery to induce chronic myocardial infarction as previously described in detail by Lygate CrT-OE mice underwent Mice with infarct size below 25% of LV circumference were excluded as these animals do not develop the hallmarks of heart failure 2, matrix size 256×256, echo time (TE)/repetition time TR) = 1.79/4.6 ms, 15° sinc excitation pulse, number of averages (NA) = 2.All experiments were carried out on a 9.4 T (400 MHz) MR system (Agilent Technologies) using a quadrature-driven birdcage resonator . For high-resolution magnetic resonance cine imaging (cine MRI), 8–10 short-axis slices, covering the heart from base to apex, were acquired using a cardiac-triggered and respiration-gated fast low-angle-shot sequence with the following parameters: field of view (25.6 mm)1H-MRS was performed as previously described Cardiac All data are expressed as mean ± standard deviation. Cine-MRI, haemodynamic and HPLC data were analysed blinded to treatment group. Comparison between two groups was by Student’s t-test. To compare four groups, a one-way ANOVA with Bonferroni’s post-hoc test was used. Linear regression was used to assess the relationship between variables. A chi-square test was performed to assess survival. Differences were considered significant when p<0.05.TAN pool was measured by HPLC in the remote myocardium of sham-operated and chronically infarcted mouse hearts (n = 7 of each) and was found to be 32.4±2.2 and 27.9±3.6 nmol/mg protein respectively (p = 0.017). This confirmed that TAN pool is reduced by 14% following chronic infarction in the mouse, making it a suitable model to study the effects of ribose supplementation.max = 12344±2904 (n = 4) vs 11623±4302 mmHg/s (n = 3)).Ribose 10% (w/v) in drinking water was palatable with no change in food and water intake or in body weight, representing an average daily intake of ∼1.5 g/kg of ribose per mouse. Treatment for seven weeks resulted in a 2-fold increase in ribose-5-P levels compared to matched controls receiving pure water  and underwent myocardial infarction. There was no difference in peri-surgical mortality (during or within 24 hours of surgery) between WT and CrT-OE strains (p = 0.54). Similarly, there was no difference in long-term mortality (24 hours to 8 weeks) between the four study groups (p = 0.43). At the end of the study, mice were retrospectively matched for infarct size . Cardiac output was maintained to similar levels as in non-infarcted mice , suggestmax) and lusitropic (decrease in |dP/dtmin|) properties of the heart was observed  was lower and Left Ventricular End Diastolic Pressure (LVEDP) elevated in the infarcted groups . A reducobserved . All thed groups .Individual phosphocreatine, ATP, ADP and AMP levels cannot be reliably measured in the mouse heart in this experimental model, since measurements mainly reflect degradation during sample collection and preparation. However, the sum of these components are biochemically meaningful. Total creatine levels were lower by 15% in MI mice compared to sham (p<0.01)  with a s2 = 0.63, p<0.0001).There was no relationship between LV TAN or total creatine levels and ejection fraction in the infarcted mice . In contThis is the first study to assess the effect of ribose administration in chronic left-sided heart failure. We show that oral ribose is palatable and bioavailable and that reduced TAN pool is a feature of murine heart failure, albeit to a lesser extent than in larger mammals. However, ribose treatment was ineffective at preventing this decline, and neither ribose on its own, nor in combination with elevated creatine, altered the pattern of adverse cardiac remodelling and LV dysfunction characteristic of the failing heart.We demonstrated that ribose administered in drinking water was well tolerated by mice and induced a 2-fold increase in ribose-5-P concentration in the myocardium. This confirms that ribose is bioavailable when given orally in the mouse. The concentration of ribose observed in control hearts was in agreement with the published literature for rat hearts Similarly, we confirmed that over-expression of the creatine transporter resulted in elevated myocardial creatine levels, and these were maintained supra-physiological following infarction despite a decrease of 10% from starting values. The levels obtained are within the range recently shown to be beneficial in ischaemia-reperfusion injury In the infarcted mouse heart, we observed a consistent decrease in TAN pool by 8–14%. This is a small change compared to other species and therefore did not always reach significance. Decreases of up to 50–60% have been measured in the failing rat heart de novo purine synthesis is inhibited in the failing heart de novo purine synthesis, which meant that ribose levels were not limiting. For this reason, ribose supplementation may paradoxically be effective in models with the largest reductions in TAN pool.Previous studies have shown beneficial effects in acute models of ischaemia where a large and rapid drop in TAN pool occurs as a consequence of nucleotide depletion and subsequent adenosine release Following the above argument, we cannot rule out that a longer duration of heart failure may have resulted in a more robust loss of TAN and more pronounced effects of ribose treatment. It is a limitation of our study that elevated myocardial ribose levels were demonstrated only in healthy hearts, and this was due to the assay requiring tissue from the entire heart. We cannot therefore eliminate the possibility, however unlikely, that ribose uptake is impaired in chronically failing myocardium. Furthermore, in most published studies, ribose was administered prior to the induction of acute dysfunction. This may have brought the myocardium into a more favourable condition to handle the subsequent insult, possibly by activating adenine nucleotide salvage pathways in silico modelling that combined elevation of creatine, TAN and total exchangeable phosphate pools would be favourable to the failing heart de novo purine nucleotide synthesis in the failing mouse heart. However, it does not rule out an effect of ribose in heart failure models where the drop in TAN pool is more profound. Other approaches to preserve TAN pool deserve to be tested, and may yet prove beneficial, for example, inhibition of 5′-nucleotidase to prevent nucleotide degradation, modulation of glucose-6-phosphate dehydrogenase as the rate limiting enzyme of the pentose phosphate pathway, up-regulation of adenosine kinase, and nucleotide transporter inhibitors.This aim of this study was to test the hypothesis arising from Using a combination of genetic modification and supplementation we elevated ribose and creatine levels in the mouse heart. This did not prevent gradual loss of total adenine nucleotides in remote myocardium following chronic myocardial infarction and did not protect against cardiac remodelling and development of heart failure.


Experimental data suggests that exclusive heart rate reduction with ivabradine is associated with the amelioration of the endothelial function. Since it is presently unknown whether this also applies to humans, the aim of this pilot study was to investigate whether heart rate reduction with ivabradine modulates the endothelial function in humans with an established coronary heart disease.Using high-sensitivity ultrasound, we analysed the flow-mediated (FMD) and nitro-mediated dilation (NMD) of the brachial artery in 25 patients (62.9 ± 8.4 years) with a stable coronary heart disease and a resting heart rate of ≥70 beats per minute (bpm). To assess acute effects, measurements were performed before and 4 hours after the first intake of ivabradine 7.5 mg. Sustained effects of an ivabradine therapy (5 mg to 7.5 mg twice daily) were investigated after 4 weeks.2 = 0.086).We found a significant decrease in heart rate, both 4 hours after the intake of 7.5 mg of ivabradine (median -8 [interquartile range (IQR) -14 to -4] bpm) and after 4 weeks of twice daily intake (median -10 [IQR-17 to -5] bpm) (p < 0.05). However, the FMD did not change significantly: neither after first dose of ivabradine nor after sustained therapy . No significant changes of the NMD were observed. In regression analysis, the heart rate and FMD did not correlated, irrespective of the ivabradine intake (rIn conclusion, in our study heart rate reduction through ivabradine does not improve the endothelial function in patients with a stable coronary heart disease. Moreover, we found no correlation between the heart rate and the endothelial function. Numerous epidemiologic studies suggest that an elevated heart rate (HR) is associated with an increase in cardiovascular morbidity and mortality -5. This f channels, reduces the resting and exercise HR without affecting cardiac contractility, blood pressure, intracardiac conduction, or ventricular repolarisation [Ivabradine (Iva), a selective inhibitor of Irisation -17. It trisation . Since iPatients with a stable coronary heart disease and betablocker intolerance  or with an insufficient HR reduction during betablocker treatment were included in the study from January 2010 to September 2011. The main inclusion criterion was a resting HR of ≥70 beats/min in two consecutive ECGs. Exclusion criteria were a recent (<2 months) myocardial infarction or revascularisation procedures (<4 weeks), ventricular or atrioventricular pacing, atrial fibrillation or flutter. We required routine laboratory parameters to lay within the normal range. It was also necessary that blood lipids, blood pressure, body mass index (BMI) and HbA1c as well as glucose levels demonstrated good adjustment according to guidelines for secondary prevention in coronary heart disease . The stuThis prospective, non-randomized study was designed to evaluate the acute and sustained effects of Iva on the endothelial function. At the first study visit (control), baseline FMD/NMD data were assessed in the morning after a 12-hour overnight fast and 4 hours thereafter. At the second study visit, FMD/NMD measurements were performed before and 4 hours after a first dose of Iva (7.5 mg) to investigate acute effects on the endothelial function. After the morning measurement, patients consumed a standardized meal, which consisted of two wheat rolls, one package of low fat cream cheese  and half a liter of still water. Patients thereafter received Iva (5 mg) twice daily for four weeks. In case of a HR of ≥60/min at day 14 (documented in two resting ECGs at least 5 min apart), the Iva dosage was increased to 7.5 mg twice daily. After 4 weeks of Iva intake, FMD/NMD values were assessed again at 08.00 a.m. (sustained effect). Blood pressure and HR were documented simultaneously at each time point , as recently described . The endValues for the FMD and HRs in tables, text and figures are presented as median values (Q1 – Q3). The baseline characteristics are means ± standard deviation. All statistical tests were two-sided with the level of significance at 5%. The non-parametric test design was chosen because of the small sample size. The paired design was considered by using the Wilcoxon test. Comparison between the FMD and HR took place with regression analysis. Statistical analyses were performed by using IBM SPSS Statistics Version 20.2. 44% of patients were receiving betablocker treatment. Medians of FMD and NMD measurements over the whole study period are shown in Table 2 = 0.086) . The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.NJ, VS and FS have designed and coordinated the study. FS, NJ, FK, RH and CG have analysed the data. NJ and FS have written the manuscript. FS and RH have performed the measurement of the endothelial function for the study. NJ, FS, FK, VS, KS and GB performed the planning of the study and the patient selection. All authors have read and approved the final manuscript.


Transplant rejection affects the course and survival after heart transplantation (HTx). As a non-invasive alternative to myocardial biopsy, which is the gold standard used for screening and for the diagnosis of rejection, regional left ventricular (LV) myocardial motion analysis has been suggested. But myocardial biopsy is invasive and its diagnostic value is restricted by high sample errors due to the patchy distribution of early rejection. Alterations of regional wall motion , especia27 heart transplant recipients  without signs or former episodes of rejections or relevant transplant vasculopathy (LVEF=63±5%) were examined using phase contrast MRI (Tissue Phase Mapping) to assess 3D-myocardial velocities. Systolic and diastolic peak radial and long-axis velocities were evaluated in each LV segment. These functional parameters were analyzed with respect to time after HTx and CIT.Shorter times after HTx (n=8 patients <12 month after HTx versus n=19 >12 month) resulted in an increase of systolic radial velocities  and a reduction of diastolic long-axis velocities . With longer CIT (>155 minutes) an increase of peak systolic radial velocities  and a reduction of diastolic long-axis velocities  were demonstrated compared to those with shorter CIT (<155 min)  Program "Advanced Cardiovascular MRI Research Center", Deutsche Forschungsgemeinschaft (DFG): Grant # FO 507/2-1, FO 507/3-1


In acute myocardial infarction (AMI), reperfusion injury is often associated with hemorrhage and microvascular obstruction (MVO), which are independent predictors of poor patient outcomes. T2 and T2* cardiovascular magnetic resonance (CMR) approaches have been instrumental in detecting hemorrhage; however, the relative sensitivity of each of these measures remains to be investigated. In this patient study, our objective was to quantitatively compare the extent of hemorrhage relative to the area-at-risk (AAR) post-AMI using T2 and T2* mapping techniques.50 patients with STEMI underwent a CMR exam on a 1.5T scanner (GE Signa Excite) at 48 hrs post percutaneous-coronary-intervention. T2 was quantified using a cardiac-gated T2-prepared spiral imaging sequence (TE=2.9-184 ms). T2* was determined from a multi-echo gradient-echo acquisition (TE=1.4-12.7 ms). Infarct/MVO was assessed using early gadolinium enhancement (EGE) imaging. Using T2* maps, hemorrhage extent was quantified as the region where T2* was at least two standard deviations (SD) below that in remote myocardium. From T2 maps, AAR was determined as the region where T2 was at least two SD above that in remote myocardium. Any ‘signal voids' within this area were identified as hemorrhage and the computed AAR was accordingly corrected. T2 and T2* values were recorded in these regions. Areas were expressed as a percentage of LV myocardium. Only patients with MVO were included in the analysis since hemorrhage is typically associated with an MVO.19 patients (38%) presented with an MVO. Hemorrhage extent determined by T2 was significantly less than that computed from T2* . AAR assessed by T2 was underestimated if the hemorrhagic region was not accounted for . Hemorrhage extent, by both T2 and T2*, demonstrated linear relationship with AAR Fig. , althougT2* appears to be a more sensitive and specific indicator of hemorrhage. T2 underestimates the hemorrhage extent and AAR due to counteracting influence from edema. In patients with MVO/hemorrhage, both T2 and T2* imaging may be necessary to accurately quantify hemorrhage extent and AAR.NA.


Type 2 Diabetes Mellitus (T2DM) and prediabetes are associated with an increased cardiovascular risk and heart failure independent of the presence of obstructive coronary artery disease, caused in part by myocardial microvascular dysfunction. Recent studies have reported contractile dysfunction and increased rotation with the onset of diabetic cardiomyopathy in uncomplicated T2DM patients. Independently, higher resting myocardial blood flow (MBF) has been reported in T2DM. The objective of this study was to determine whether there is a correlation between LV Epicardial Rotation (LV ER) and resting MBF in T2DM patients with angiographically normal coronaries, measured by tissue tagging and perfusion cardiovascular Magnetic Resonance (CMR).Sixty five patients with no coronary stenosis >30% on invasive angiography were recruited and categorized into T2DM, prediabetes and normal controls groups according to American Diabetes Association guidelines. All patients underwent rest and adenosine stress myocardial perfusion CMR at a single mid-LV location, cine imaging covering the entire heart and myocardial tissue tagging in three LV short axis locations . LV volumes and mass were calculated from cine images. LV rotation in three myocardial layers  was calculated from CSPAMM tissue images using Tag Track . For this study, only rest MBF was calculated using Fermi-constrained deconvolution for the entire myocardium.Patient characteristics and results are shown in Table T2DM patients when compared to age-matched patients with prediabetes and normal controls have higher peak LV ER. Resting MBF correlates with LV ER. These results suggest that LV ER analysis in uncomplicated T2DM patients may be useful for non-invasive screening of early subtle contractile dysfunction associated with microvascular dysfunction in diabetes patients.This work has been funded by British heart foundation in part with the Libyan ministry for higher education and scientific research.