A novel method to assess left ventricular (LV) mechanical dyssynchrony using three-dimensional echocardiography (3DE) and semi-automated border detection was investigated, which might be superior in prediction of response to cardiac resynchronisation therapy (CRT) compared to traditional measures that rely solely on segmental time-to-contraction. Twenty-eight heart failure patients underwent real-time 3DE before CRT and at 6–12 months follow-up. Analysis of 3DE was performed using TomTec Research-Arena software featuring semi-automated endocardial border detection. The following echocardiographic parameters were calculated in a 16-segment model: areas under segmental time-volume-curves (STV); delay between contraction of the earliest and latest segment (L-E); and standard deviation of segmental time-to-contraction (SDI). Response to CRT was defined as ≥10% decrease in LV end-systolic volume at follow-up. Baseline Pre-STV had a higher sensitivity than SDI for prediction of response , with equal specificity (78%) and a higher area under receiver operator characteristic curve. In contrast, L-E had a sensitivity of 83% and a specificity of 56%. Using 3DE, methods that combine segmental time-to-contraction with segmental contractility might improve LV dyssynchrony assessment compared to traditional methods based on segmental time-to-contraction alone. Pre-STV might be a better predictor of response to CRT than SDI. Heart failure remains a complex clinical syndrome. While optimal medical therapy improves survival, cardiac resynchronisation therapy (CRT) has been proven as an effective adjuvant treatment for patients with moderate-to-severe systolic heart failure and wide QRS on optimal medical therapy . HoweverMost echocardiographic methods to assess left ventricular (LV) mechanical dyssynchrony rely on timing differences of contraction of individual LV segments, for example Tissue Doppler Imaging (TDI) , 6 and tAssessment of LV mechanical dyssynchrony by 3DE is based on semi-automatic endocardial border detection –16. ThesIn the present study, we investigate the novel measure of integrating area under time-volume curves for assessment of LV mechanical dyssynchrony in heart failure patients. We hypothesize that this approach, in comparison to traditional 3DE parameters of LV mechanical dyssynchrony, may be of additional value in prediction of response to CRT.A total of 28 heart failure patients were included, with a good echocardiographic apical window and who were eligible for CRT by traditional criteria , defined as the standard deviation of times from QRS complex tot minimal segmental volume; and latest minus earliest segment (L-E), which is defined as the time between earliest and latest segment to reach minimal volume. Both SDI and L-E are expressed as a percentage of RR-interval.sum of all segmental volumes is at its minimum, which does not necessarily mean that at that moment, each individual segmental volume is at its minimum. On the contrary; as is evident from the concept of SDI, each segment reaches its individual minimal volume at different times, which are further spread apart as dyssynchrony worsens. In measurement of Pre-STV, not only timing of minimal volume, but also segmental volume difference between the moments of global and individual minimal volumes is assessed. An individual segment that has reached minimal volume shortly before global end-systole, will be in an early phase of relaxation at global end-systole, with a slight increase in segmental volume. Pre-STV is not only dependent of timing difference but also of this volume difference; the area-under-curve, indicated in Fig. Furthermore, the software calculates Pre-systolic time-volume loss (Pre-STV), which is defined by the area under time-volume curve, as shown in Fig. The example given in Fig. The rationale of Pre- and Post-STV is that they do not only assess time to contraction but also segmental LV function. This way, values of segments that show dyssynchrony in combination with decreased contractility are low, which might be of additional value in prediction of response to CRT. Pre- and Post-STV might serve as a correction of SDI for regional contractility.After 6–12 months, patients returned for repeat 3DE, all parameters mentioned above were measured and compared to their values at baseline. Response was defined as a ≥10% reduction in ESV compared to baseline and predictive value for response of the abovementioned parameters was calculated , 17.For assessment of reproducibility, a subgroup of 15 patients was analyzed by two independent observers. The first observer then repeated analysis after 3 weeks.p-value < 0.05 was considered statistically significant. Reproducibility was assessed using Bland–Altman analysis.Values were expressed as average ± standard deviation, in ml and ms or percentage of the R–R interval. Comparison of values at baseline and follow-up of responders and non-responders was performed using the student’s T-test. Predictive value of response was calculated by ROC curve calculation and by sensitivity, specificity, negative (NPV) and positive predictive value (PPV) calculation. A For baseline patient characteristics, see Table Echocardiographic and clinical parameters at baseline and at follow-up are given in Table Responders demonstrated a significant decrease in LV volumes (by definition in ESV) and increase in EF whereas non-responders demonstrated a non-significant increase in LV volumes and no change in EF.p < 0.01).L-E at baseline was significantly higher in responders. At follow-up, it showed a significant decrease in responders and no change in non-responders. SDI showed a similar pattern. There was a large and significant difference in Pre-STV at baseline between responders and non-responders. At follow-up, Pre-STV decreased significantly in responders with no change in non-responders. Post-STV at baseline was not significantly different in non-responders and in responders. No significant changes were observed during follow-up. There was a large and significant difference between Pre- and Post-STV at baseline  at follow-up reached borderline statistical significance, and there was no significant difference between baseline and follow-up. NYHA class and QOL (Minnesota Living with Heart Failure questionnaire) score improved equally in responders and non-responders whereas 6-MWT  increased significantly only in responders.p = 0.38). L-E, SDI and Pre-STV showed significant correlation to reverse remodeling, defined as ESV change at follow-up, with the highest correlation for Pre-STV. Area under ROC curve of Post-STV was not significantly higher than 0.5. There was no correlation between Post-STV and reverse remodeling.Predictive values for response to CRT of selected echocardiographic parameters are given in Table Bland–Altman plots of reproducibility of SDI, L-E and Pre-STV are shown in Fig. The present study is the first to demonstrate the capacity of 3DE to assess mechanical dyssynchrony combined with segmental contractility to predict response to CRT in heart failure patients.While CRT is a well-established therapeutic approach in moderated-to-severe heart failure patients with reduced LVEF (≤35%) and wide QRS ≥120 ms) [20 ms [1]p = 0.01). However, new approaches like the one we tested might help in finding a simple, robust parameter to add to the current criteria proposed by guidelines to decide upon or not to propose to a patient a CRT device.Several studies focused on echocardiographic indices of mechanical dyssynchrony in heart failure patients to predict response to CRT, defined as a reduction in ESV at follow-up. In single-center studies, reasonable predictive values were reported for very distinct echocardiographic parameters: time difference between 4 basal segments, and standard deviations of time with TDI (in a 12-segment model) and 3DE (in 16- or 17-segment model) , 21–27. The present study investigates cardiac mechanical dyssynchrony fundamentally differently from all previous studies, and is proof-of-concept of assessment of mechanical dyssynchrony using parameters that are not only dependent of segmental timing, but also on (decreased) segmental endocardial inward motion. It is conceivable that non-responders with high SDIs might have dyssynchrony mainly in hypokinetic segments. By correcting SDI for regional contractility, STV can provide more comprehensive information on the severity of mechanical dyssynchrony with the ultimate goal of improving the prediction of response to CRT.Correlation between STV and SDI is moderate because STV and SDI are fundamentally different parameters. Firstly, STV is calculated by summation of values of all segments, whereas SDI is a standard deviation , 16, 26.Secondly, since basal segments have higher volumes than the mid- and apical segments, their contribution to the total value of STV is greater than that of mid- and apical segments. This is in contrast to methods that use only timing parameters and where basal, mid- and apical segments contribute equally to the final value.Finally, reproducibility of SDI is moderate in both the present and in previous studies , 8, 15, In agreement with our results regarding the changes observed in Pre-STV, similar changes were found in a TDI study on heart failure patients received CRT, where peak systolic contraction in 6 basal segments was delayed homogeneously to a timing close to that of the latest segment, so that regional variation after CRT was abolished . This seIn prediction of response to CRT, the key issue remains accurate and reproducible assessment of left ventricular mechanical dyssynchrony in both contractility and in timing. With minor adaptations in analysis software, (Pre)-STV may be visualised in a polar map, which may aid in optimising biventricular pacemaker lead location. In future studies, time difference between basal, mid- and apical segments  and timeThe present study was not a randomized, controlled study, but rather a hypothesis generating investigation of a new and still unproven method in a small patient group with a relatively short follow-up period. At present, this method should not be used clinically without further investigation.Further limitations were in the nature of the software. End-systole was defined as the moment of minimal LV volume. No attention was given to opening or closing of mitral and aortic valves and the isovolumetric relaxation time was not assessed. Although Post-STV is a measure of early diastolic function, we were not able to investigate the events that occur around end-diastole. We could not evaluate if segments in the vicinity of the (postero)lateral pacemaker lead showed the highest Pre- or Post-STV, if they showed the most improvement, or if this had any influence on response to CRT.The present method which integrates segmental timing and wall motion might describe LV mechanical dyssynchrony better than methods based solely on timing. In our patient group, Pre-STV might serve as a correction for regional contractility of SDI, and is a better predictor of volume response to CRT than SDI or L-E. Larger scale studies are needed to confirm its prognostic value.


Transthoracic echocardiography (TTE) provides non-invasive measures of diastolic left ventricular (LV) function by assessing mitral inflow and mitral annular motion. Given the excellent spatial and temporal resolution of CMR, we developed a novel method to calculate several correlative measures of diastolic and systolic LV function. The maximum velocity of the atrioventricular junction (AVJ) during early diastole represents a correlate of the maximum velocity of the mitral annulus (e'). To determine the correlation between CMR and TTE indices of diastolic function, we performed a retrospective analysis.We evaluated 50 consecutive patients who underwent TTE and CMR examinations within 30 days. The longitudinal motion of the lateral atrioventricular junction (AVJ) was tracked at 25 times through the cardiac cycle using the 4-chamber cine view. The baseline position of the AVJ was defined at end diastole and its longitudinal displacement was measured relative to a reference line drawn between the LV apex and the midpoint of the mitral annulus Figure . Based oThe mean and standard deviation EF determined by CMR was found to be 38% ± 15%. Significant correlations were found between EF and MD , both measures of longitudinal LV systolic function, as well as MVED and e' , which reflect peak mitral annular velocities during early, passive diastolic filling. A negative correlation was observed between MVED and E/e' , suggesting an inverse relationship between peak AVJ velocity during early diastole and left atrial pressure. Significant correlations were also noted for VDS and e' , VDS and a' , as well as VDS/MVED and DT .Maximum displacement of the AVJ determined by CMR correlates with EF and serves as a simple measure of LV systolic function. MVED provides a novel CMR correlate of the tissue Doppler echocardiography measure e'. Assessment of AVJ motion variables may provide additional CMR metrics of systolic and diastolic function without increasing scanning time.NIH 1R21HL108218-01.


Fragmented QRS (fQRS) is a convenient marker of myocardial scar evaluated by 12-lead electrocardiogram (ECG) recording. fQRS is defined as additional spikes within the QRS complex. In patients with CAD, fQRS was associated with myocardial scar detected by single photon emission tomography and was a predictor of cardiac events. fQRS was also a predictor of mortality and arrhythmic events in patients with reduced left ventricular function. The usefulness of fQRS for detecting myocardial scar and for identifying high-risk patients has been expanded to various cardiac diseases, such as cardiac sarcoidosis, arrhythmogenic right ventricular cardiomyopathy, acute coronary syndrome, Brugada syndrome, and acquired long QT syndrome. fQRS can be applied to patients with wide QRS complexes and is associated with myocardial scar and prognosis. Myocardial scar detected by fQRS is associated with subsequent ventricular dysfunction and heart failure and is a substrate for reentrant ventricular tachyarrhythmias. It has been show in some studies that a subtle abnormality within the QRS complex can represent conduction disturbance and myocardial scar. A notch in the QRS complex in patients with left ventricular hypertrophy has been suggested to be a result of an intraventricular conduction defect . InjuredECG recording that is used to detect fQRS is not a specific setting and is the same as routine 12-lead ECG recording: high-pass filter: 0.05-20 Hz , low-pass filter: 100-150 Hz, AC filter: 50 or 60 Hz, paper speed: 25-50 mm/sec  and voltage: 1mm/mV-5.A low-pass filter is usually used to reduce electrical and musculature noises when recording the 12-lead ECG, but cut-off frequency of the low-pass filter influences detection of fQRS . Figure Das et al. defined fQRS as the QRS complexes with the presence of an additional R wave (R') or notching in the nadir of the R wave or the S wave, or the presence of >1 R' (fragmentation) in 2 contiguous leads, corresponding to a major coronary territory. Typical bundle branch block (BBB) pattern (QRS ≥ 120 ms) and incomplete right BBB were excluded from the their original definition .fQRS on a 12-lead ECG was originally defined as narrow QRS complex duration (<120 ms) . The QRSWhen we reported fQRS in Brugada syndrome, we also defined fQRS in right BBB because patients with Brugada syndrome often had right BBB . Most  is another tool for identifying the myocardial fibrosis and dysfunction. Abnormal late enhancement of gadolinium in patients with cardiac dilated cardiomyopathy (DCM) ,11 Figu or cardiWe studied the mechanism underlying fQRS in an experimental model of Brugada syndrome . We creafQRS represents myocardial scar and will be associated with ventricular dysfunction and occurrence of congestive heart failure. In CAD, fQRS represents prior occurrence of myocardial infarction and will have a risk of subsequent occurrence of ischemic events. Indeed, Das et al. demonstrated that fQRS is an independent predictor of cardiac events in patients with CAD .Myocardial scar is also a substrate for reentrant ventricular tachyarrhythmia. A signal averaged electrocardiogram (SAECG) reveals the presence of late potential that indicates low-amplitude high-frequency potentials outside the terminal QRS complex. Abnormal late potential represents a slow conduction zone with damaged myocardium around the fibrosis of healed myocardial infarction . The preResults of the first two studies on fQRS in CAD were reported in 2006 ,8. Das efQRS also had diagnostic value for detection of a myocardial scar in patients with CAD and a wide QRS complex. In the presence of wide QRS duration, fragmented wide QRS (f-wQRS) was present in 47.2% of patients and had good sensitivity and specificity for detection of myocardial scar. fQRS in a wide QRS complex had good sensitivity (86.8%), specificity (92.5%), positive predictive value (92.0%), and negative predictive value (87.5%) for detecting scarred myocardium [Although some studies have shown the clinical significance of fQRS for detection of myocardial scar in patients with CAD, one study failed to show significance of fQRS for detection of myocardial scar . The reaSince fQRS represents myocardial scar, fQRS may be associated with heart failure and ventricular tachyarrhythmia. Some studies have shown a relationship between existence of fQRS in patients with CAD and prognosis. In patients having narrow QRS complexes (< 120 ms), all-cause mortality (34.1% vs. 25.9%) and cardiac event rate (49.5% vs. 27.6%) were higher in patients with fQRS than in patients without fQRS . TorigoePatients with organic heart disease often have right or left BBB, and wide QRS complexes are associated with adverse prognosis for the patients. For example, the HERO-2 trial  showed tIn acute coronary syndrome, fQRS appeared within 48 hours  from the onset of symptoms and persisted thereafter . fQRS onThe correlation between fQRS and ischemic/non-ischemic cardiomyopathy with reduced LV function was investigated in some studies. fQRS was present in 23-75% ,11,28-30A wide QRS complex was observed in 14-47% of patients with heart failure. A wide QRS complex, especially left BBB, is associated with more advanced myocardial injury, worse left ventricular function and higher mortality than those in the case of a narrow QRS complex  Figure . Two stuSarcoidosis is a granulomatous disease that affects systemic organs. Cardiac involvement of sarcoidosis induces atrio-ventricular block, right BBB, ventricular tachyarrhythmia, and heart failure and is associated with adverse outcomes in the patients. The presence of fQRS on a 12-lead ECG in patients with sarcoidosis was associated with cardiac involvement detected by late enhancement on Ga-MRI . BBB ri.Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized pathologically by fibrofatty replacement of the right ventricular myocardium and ventricular tachycardia . EpsilonBrugada syndrome is characterized by cove-type ST elevation in right precordial leads and episodes of ventricular tachyarrhythmia. Experimental studies have shown that ST elevation and arrhythmia result from right ventricular repolarization abnormality. Some clinical studies have also shown the existence of depolarization abnormality and it was also associated with high-risk patients . We evalAcquired long QT syndrome (ALQTS) is a disease due to secondary repolarization abnormality. Repolarization abnormality, such as prolongation of QT interval and prolongation of the peak to end of T wave represented transmural or intraventricular dispersion of repolarization, and was associated with occurrence of tosades de pointes . We alsoIn adult patients with repaired tetralogy of Fallot , fQRS prfQRS was frequent in patients with mitral stenosis caused by rheumatic fever . RheumatfQRS is a useful marker of myocardial scar and can predict cardiac events and mortality in various heart diseases. However, some studies showed negative data of fQRS for diagnosis and prognosis of the diseases. For improvement of diagnosis and prediction of prognosis, qualitative analysis of fQRS might be required. Magnetoelectrocardiography is a possible method to evaluate qualitative analysis of fQRS, but it cannot be used as a routine examination . We have


The extent of congenital heart disease in Cameroon remains largely unknown. The aim of this study was to determine the occurrence and pattern of congenital heart diseases in the Cardiac Centre of St Elizabeth Catholic General Hospital, situated in a rural area of Cameroon.Between November 2002 and November 2008, a population of 2 123 patients with suspected cardiac pathologies were consulted at St Elizabeth Catholic General Hospital referral cardiac centre. Of these patients, 292 subjects were recruited for the study, based on detection of (1) precordial murmurs and/or cardiomegaly on chest X-ray examination, or (2) congenital heart diseases on transthoracic Doppler echocardiography examination.Congenital heart diseases and inorganic murmurs were found in 95.5 and 4.5% of the patients, respectively. Congenital heart diseases included tetralogy of Fallot (26.1%), isolated ventricular septal defect (38.8%), atrioventricular cushion defect (7.3%), isolated atrial septal defect (2.8%), arterial duct cases (12.4%), common arterial trunk (1.3%), isolated stenosis of the pulmonary artery (2.6%), coarctation of the aorta (1.1%), congenital mitral valve regurgitation (1.2%), atresia of the triscupid valve (1.6%), double-outlet right ventricle (2.1%), anomalous pulmonary venous return (1.5%) and left isomerism (1.2%).Our data show that there is a high occurrence of congenital heart disease in this hospital in a rural zone of sub-Saharan Africa and that isolated ventricular septal defect is the predominant pathology. Post-surgical follow up remains very challenging as many parents cannot afford their children’s medical treatment or are generally not well educated. Congenital heart disease is defined as an abnormality in the cardio-circulatory structure or function, which is either present at birth or appears much later in life. The prevalence and pattern of this group of disorders varies both within and between regions and countries.3In the majority of developing nations, and especially in most countries in the African continent, only a small and insignificant portion of the population can afford the cost of diagnosis, medical treatment and/or surgical correction of congenital heart diseases. The situation is even worse for those living in rural areas where access to basic healthcare is already a serious issue. Despite their wealth in natural resources, rural areas in developing countries are usually the poorest regions in terms of financial resources. These regions depend entirely on the availability of public health funding to finance and support their healthcare. Most of the time these funds do not reach them or are simply not provided.The Shisong referral cardiac centre is specialised in both adult and paediatric cardiology and is part of Shisong’s St Elizabeth Catholic General Hospital, located in a rural area of the northwest province of Cameroon. This geographic location strategically complies with the principal mission of this hospital, which is to provide healthcare support to economically deprived rural areas of the country.Since November 2002, when the cardiac centre became operational, a significant number of patients have presented at the hospital and been treated for various pathologies.The only scientifically based approach to draw public health attention to the seriousness of the problem is to provide evidence-based data that support our observations. Currently, there are no epidemiological data available on the prevalence and management of congenital heart diseases in Cameroon, and only a limited number of published studies on rural areas of sub-Saharan Africa.The ethics committee of St Elizabeth Catholic General Hospital approved the study. Between November 2002 and November 2008, a population of 2 123 patients aged between two months and 41 years (mean: 10.03 ± 9.7 years) was seen in the cardiac centre for various pathologies. Patients with one or a combination of the following pathological features: precordial murmurs, past history of recurrent respiratory heart diseases, clinical indications of suspicious cardiopathy and/or cardiomegaly on chest X-ray examination (cardiothoracic index > 0.55) underwent further screening tests for detection of congenital heart diseases. A total of 292 patients  were recruited for the study.Initially, patients underwent clinical examination, followed by a comprehensive transthoracic Doppler echocardiogram using an Acuson 4–7 MHz. In addition, a complete two-dimensional echocardiography examination was performed according to the recommendations of the American Society of Echocardiography.Depending on the pathology, patients diagnosed with congenital heart diseases were put on a surgical list for sanitary evacuation to a collaborative centre (Instituto Polyclinico San Donato) in Italy where corrections of pathology were performed. The Tertiary Sisters of St Francis and two other charity organisations, the Cuore Fratello and Associazione Bambini Cardiopatici nel Mondo, paid for treatments and all inccured costs. Upon returning to Cameroon, patients were followed up at the Shisong cardiac centre.t-test. SPSS 11 statistical analysis software was used for all analyses and a p-value ≤ 0.05 was considered significant.Values are expressed as mean ± standard deviation (SD) and statistical analyses were performed using the Student’s n = 279) and the second (4.5%) inorganic murmurs (n = 13).Two groups of patients were identified based on their diagnoses. The first group (95.5%) had an echocardiographic diagnosis of congenital heart disease (n = 2), north-west , littoral , central , and west  regions. The remaining patients (n = 11) were from the other provinces and neighbouring countries such as Gabon (n = 1) and Nigeria (n = 3). In addition, there are also more than 260 tribes in Cameroon. The patients’ tribal origins were There are 10 provincial regions in Cameroon and patients’ geographic origins were distributed as follows Of the 1 831 patients remaining out of the total patients consulting (2 123), 321 had rheumatic heart disease (RHD) while the rest had no heart-related pathologies.Congenital heart diseases were distributed as follows Tables , 3: tetrp ≤ 0.005) high percentage of large isolated peri-membranous ventricular septal defects (85%) compared to restrictive (10.2%) and muscular (4.8%) defects. Complete atrioventricular cushion defects (63.5%) were also significantly higher (p ≤ 0.005) than incomplete (39.5%) cushion defects. Combined pathologies, such as ventricular septal defect with isolated atrial septal defect were found in 1.8% (n = 5) of patients; ventricular septal defect with arterial duct in 2.1% (n = 6); ventricular septal defect with pulmonary valve stenosis in 8.9% (n = 25); and left isomerism with arterial duct in 1% (n = 3) of cases.There was a significantly  of the patients. This observation is in line with previously published studies.This study shows that over a period of six years, 2 123 patients were seen at the St Elizabeth Catholic General Hospital cardiac centre and that congenital heart diseases were the most prevalent diagnosed pathologies, found in 13.1%  of the patients (aged 9 days to 35 years old) presenting abnormal echocardiograms had congenital heart diseases.et al. conducted in Egypt showed a low incidence (1.01/1 000) of congenital heart diseases among school children.8Transthoracic echocardiography data from the retrospective study of Mahmoud Because of its state-of-the-art facility, the Shisong Cardiac Centre, which is relatively new, is a renowned referral centre in the region. Consequently, many patients have been referred by practitioners in various disciplines, including cardiologists, paediatricians and general practitioners from different parts of the country, for better management of heart murmurs, confirmation of suspected diagnosis of congenital heart diseases and/or enrolment in the sanitary evacuation programme. This could explain the difference between our results and those of the Egyptian study.We found that the most encountered congenital pathologies were isolated ventricular septal defect and tetralogy of Fallot. Both pathologies were also most frequently found by Bannerman and el Haq among patients with congenital heart diseases.et al., late presentation to practitioners was observed in 79.3% of cases.9The majority of these patients could not afford treatment due to the high cost and, as evidence of the difficulty in accessing healthcare, numerous late presentations to practitioners were registered. In a previous study by Ariane We diagnosed a peri-membranous ventricular septal defect and a tetralogy of Fallot in a 13- and 16-year-old boy and girl, respectively. Adults with natural evolutive congenital heart diseases were found in 1.5% of cases.n = 114) of cardiac surgeries realised abroad. Previous studies from Senegal,n = 75), 28% (n = 435), 26% (n = 61), and 22.5% (n = 12) of the patients who needed a cardiac surgical intervention actually had one done. Updated data from these countries could help clarify the state of the situation to date.In the sub-Saharan region of Africa, St Elizabeth Catholic General Hospital has registered the highest percentage (41%, Although the cardiac centre of St Elizabeth Catholic General Hospital is relatively new, it has been the point of attraction for a growing number of new patients from neighbouring countries. Cameroon is a bilingual nation characterised by a French- and English-speaking region. However, despite the cardiac centre being located in the English-speaking region, more than 60% of the consulting patients come from the French-speaking region.In a country with over 260 tribes, all patients are seen irrespective of their tribe and/or religious beliefs. In that respect, the hospital is a crossroads of several tribes. It might seem taboo, but it is important to highlight the multi-tribal orientation of the hospital as Cameroon is a country where the way someone is treated could be determined by his/her tribal origin, depending if that tribe is well represented or not in society.We also found that congenital heart diseases were predominant in the Banso and Bamileke people. However, this could be due to the fact that the majority of patients came from these regions, which are closest to the hospital. Bamileke are known to marry close relatives and therefore we could hypothesise that genetic background could be linked to the predominance of congenital heart diseases found in this tribe. However, unless scientifically proven, this must remain an assumption.Since there are only a few cardiac centres in the country, and more importantly because patients cannot afford the cost of treatment, pre- and post-surgical follow up is very challenging. There is a need to establish programmes to better inform patients about their disease and the importance of proper follow up. More than 60% of children have a very poor academic background and almost the same percentage of rural parents do not have a secondary school education.Long-term post-surgical death rate is estimated at 0.7% and the main cause of death is thought to be malignant arrhythmias occurring after correction of the congenital heart disease. In developed countries, particularly Europe and America, diagnosis and treatment of cardiac pathologies are readily affordable by most citizens through coverage by insurance plans. In the majority of developing nations, especially countries on the African continent, this is not yet the case.Thanks to the positive partnership between St Elizabeth Catholic General Hospital, Policlinico San Donato in Milan, Tertiary Sisters of St Francis, Associazione Bambini Cardiopatici nel Mondo and Cuore Fratello, some hope is offered to patients and their families. The initiative of St Elizabeth Catholic General Hospital in supporting early detection, diagnosis, treatment and patient follow up is encouraging; however, public health involvement and better funding are required to cover the expenses so that all patients are afforded the opportunity to receive proper treatment in a timely manner.The data showed that a wide range of congenital heart diseases were represented in the cardiac centre of St Elizabeth Catholic General Hospital, Shisong, situated in a sub-Saharan rural area of Africa, and that isolated ventricular septal defect was the most prevalent pathology. However, despite successful cardiac surgery and treatment, patient follow up remained a significant challenge.


Heart failure (HF) is a pathological condition during which the pump function of the heart is compromised. There are two major forms: diastolic and systolic HF. Whilst the majority of patients exhibit systolic HF (reduced ejection fraction), diastolic HF  has also been found in almost half of HF patients. A major question in this field is the inter-relationship between diastolic and systolic HF. The mechanisms underlying both pathologies are still poorly understood.In this study, personalised biomechanical models of the human left ventricle (LV) were generated semi-automatically from cardiac magnetic resonance images (MRI) using finite element modelling techniques to investigate both diastolic and systolic ventricular mechanics. Geometric information of the LV throughout the cardiac cycle was derived via semi-automatic segmentation technique called guide-point modelling with myocardial volume preserved throughout the cardiac cycle. After image segmentation, the guide-point model at diastasis was used as the reference mechanics model to simulate ventricular mechanics. Passive and contractile myocardial mechanical properties were then tuned to best match the segmented surface data at end-diastole and end-systole, respectively. Global and regional indices of myocardial mechanics, including muscle fibre stress and extension ratio were then quantified and analysed.This mechanics modelling framework was applied to the Sunnybrook Cardiac Database which consisted of normal, hypertrophy and non-ischemic HF cases. Comparison of the estimated passive stiffness and peak active contractile stress between the normal and diseased cases provided some preliminary insight into the changes in myocardial mechanical properties during heart failure. It was found that the passive tissue stiffness was greater for the HF and hypertrophy patients compared to the normal subjects. This is consistent with fibrosis that is observed during failure. On the other hand, the estimated maximum active contractile stress did not vary significantly between the diseased and healthy cases which may suggest that systolic heart failure may not be associated with changes in systolic mechanical properties.This automated approach enables minimally invasive personalised characterisation of cardiac mechanical function in health and disease. Determining more specific variations in mechanical properties between diseased and normal human hearts will help in the understanding of the underlying mechanisms of HF.This work is funded by the Health Research Council of New Zealand.


Defective copper regulation is implicated as a causative mechanism of organ damage in diabetes. Treatment with trientine, a divalent-copper-selective chelator, improves arterial and renal structure/function in diabetes, wherein it also ameliorates left-ventricular (LV) hypertrophy. However, direct in vivo evidence that trientine can improve cardiac function in heart failure has hitherto been lacking.To determine whether trientine treatment could improve in vivo outcome, we measured cardiac function in groups of trientine-treated diabetic (TETA-DIA), non-drug-treated diabetic (DIA) and sham-treated control (SHAM) rats, by using in vivo high-field cardiac magnetic-resonance imaging (cMRI) and an ex vivo isolated-perfused working heart method. Forty age-matched animals underwent a cMRI scan after which 12 were randomized to the SHAM group and 28 underwent streptozotocin-injection; of these, 25 developed stable diabetes, and 12 were then randomized to receive no treatment for 16 weeks (DIA) and the other 13 to undergo 8-weeks’ untreated diabetes followed by 8-weeks’ drug treatment (TETA-DIA). Animals were studied again by cMRI at 8 and 16 weeks following disease induction, and finally by measurement of ex vivo cardiac function.P < 0.001), as well as other functional indexes. LVEF, CO (both P < 0.001) and the other indexes deteriorated further at 16 weeks in DIA, whereas trientine (TETA-DIA) improved cardiac function by elevating LVEF and CO (both P < 0.001), and also partially reversed the increase in LVM/body-mass (P < 0.05). In ex vivo hearts from DIA, the CO response to increasing preload pressure was deficient compared with SHAM (P < 0.001) whereas the preload-CO relationship was significantly improved in TETA-DIA animals (P < 0.001).After eight weeks diabetes, rats (DIA/TETA-DIA) had developed significant impairment of LV function, as judged by impairment of ejection fraction (LVEF), cardiac output (CO), and LV mass (LVM)/body-mass (all Trientine treatment significantly improved cardiac function in diabetic rats with substantive LV impairment. These results implicate impaired copper regulation in the pathogenesis of impaired cardiac function caused by diabetic cardiomyopathy, and support ongoing studies of trientine treatment in patients with heart failure. In britimer)) . Intra-cP-values of < 0.05 have been adjudged significant. P-values of 0.05 ≤ P ≤ 0.10 have been included in tables if they occurred.Data in tables have generally been expressed as means (± 95% CI). The significance of between-group differences at specific time-points has been assessed by the fitting of ANOVA models (with post-hoc Tukey’s tests as required) and of time-dependent effects by linear mixed-effects modelling (LME) . Work-flows were as shown in Figure P < 0.0001) and trientine had no effect on glucose levels   Table . The eff1) Table . LV func1) Table , 3, 4.Th1) Table , 3, 4.We have employed LVM normalized to BW (LVM/BW) as an index of body-mass, as in previous studies . Some woP < 0.001). Although TETA-DIA rats had significantly lower LVM/BW values than DIA at Week 16 (P < 0.05), their values were still significantly higher than those of SHAM animals (P < 0.001). Furthermore, the LVM/BW:time interaction term for trientine treatment was significant . Trientine thus ameliorated the relative cardiac hypertrophy in diabetic rats.Changes in the LVM-to-body-weight ratio (LVM/BW)  over theP < 0.001, Figure Diabetes significantly lowered the percentage of cardiac fat volume to myocardial volume in the LV . By contrast, eight weeks oral trientine treatment significantly improved LVEF (P < 0.001) so that, following treatment, mean LVEF in trientine-treated diabetic animals was equivalent to that in non-diabetic controls (P > 0.05).Eight weeks diabetes significantly lowered many indexes of LV function Table  includinP < 0.0001) as normal organ growth progressed, but this increase did not occur in the DIA animals  and further still in DIA animals between Weeks 8 and 16 (P < 0.0001). The lack of normal increase in CO is consistent with impaired growth in diabetic animals  although the CO of TETA-DIA animals remained significantly lower than in SHAM rats (P < 0.01). Trientine also improved other indexes that had previously been impaired by diabetes (Table P < 0.0001), LVESV/LVM (P < 0.0001) and LVEDV/LVM (P = 0.030). These data are consistent with drug-evoked improvements in systolic and diastolic function.CO increased progressively in SHAM rats during the study P < 0.000 as normas Figure  and 3. Cs Figure B. Eight P < 0.0001). However, CO in untreated-diabetic rats did not respond normally once preload values were increased above the peri-physiological value of ~15 cmH2O, as shown by flattening of the preload-CO curve above this point . By contrast, the preload-CO curve in trientine-treated diabetic animals was restored to normal, and was significantly improved compared with that for untreated diabetic animals . These findings are consistent with the in vivo effects of trientine treatment on LVEF and CO measured in the cMRI studies presented above. Thus in vivo and ex vivo measurements of CO following trientine treatment are mutually consistent in that both have demonstrated substantive drug-mediated improvement in CO of diabetic animals.We also measured ex vivo CO at increasing preload values to determine the relationship between in vivo and ex vivo estimates of this variable in the same individuals Figure  5]. Ex . Ex 5]. Linear mixed effects modelling (LME) “provides a generally flexible and powerful methodology for the analysis of grouped data such as repeated measures” , and wasP = 0.035) whereas it had no measurable effect on blood glucose levels or heart rate. It significantly improved LVM/BW (P = 0.0077), whereas the P-value corresponding to the corresponding non-indexed variable, LVM, was 0.046: this contrast provides evidence that supports the use of LVM/BW as opposed to unindexed LVM to measure time-dependent therapeutic effects on LV mass. This finding is consistent with previous reports [Results of LME-based analysis of the effects of trientine treatment on indexes of cardiac function have been shown in Table  reports .P < 0.0001) (Table P < 0.0001) were arguably more prominent than those on LVEDV (P = 0.0091) and LVEDV/LVM (P = 0.0013), which may point to a greater effect of trientine on systolic function in this study. Trientine treatment has previously been shown to exert therapeutic effects on both diastolic and systolic function in rats with diabetes-induced heart failure [Trientine exerted substantive effects to improve CO, CO/LVM, LVEF, stroke volume, and stroke volume indexed to LVM  Table , consist failure .Here we have reported cMRI-derived measurements of the effects of trientine treatment on cardiac function in rats with established heart failure caused by diabetes. Effects of diabetes on cardiac function were characterized, inter alia, by substantive impairment of functional indexes including LVEF, CO/LVM , LVEEight weeks trientine treatment significantly improved cardiac function without modifying hyperglycemia, thus effectively breaking the link between defective glucose homeostasis and organ damage, and implicating defective copper regulation in the mechanism by which diabetes causes heart failure. Cardiac function improved in every drug-treated rat, consistent with marked trientine-evoked improvement in cardiac performance in rats with established heart failure caused by diabetic cardiomyopathy. Furthermore, the beneficial effect of trientine treatment on CO in these studies was consistent between the cross-sectional and time-dependent in vivo cMRI analyses, and the subsequent cross-sectional ex vivo endpoint measurements in the same individuals.Thus, trientine treatment substantively improved cardiac function in this widely-used model of diabetes-evoked heart failure. Previous studies have shown that trientine treatment can improve LV hypertrophy, ex vivo indexes of diastolic and systolic function, and numerous cardiac biomarkers in animals with diabetes-induced heart failure ,34-36. TDifferent values for LVEF have been reported in the literature by different groups for normal rats or those with heart failure ,37-39. BTreatment with the long-acting calcium channel blocker, azelnidipine in STZ-diabetic rats has also been reported to cause significant improvements in myocyte contractile function, oxidative stress and myocardial apoptosis, which were attributed to improved myocellular calcium homeostasis . HoweverThe current results extend our previous work in nonclinical models of diabetic organ damage ,36,42,43bsa) without adverse remodeling consequences [The current study complements and extends our previous studies in patients with T2DM and LV hypertrophy, in whom 12-months trientine treatment significantly improved LV mass indexed to body-surface area  that can inhibit acute inflammatory responses in vivo . In a reWhat information is currently available about the dosage and tolerability of trientine in diabetes? In previous nonclinical studies ,7,34,35,bsa values after 12-months trientine treatment [The current study has limitations. Trientine treatment significantly improved cardiac function in diabetic rats with established heart failure. Nevertheless, although substantively improved, their cardiac function was still markedly impaired after eight weeks drug treatment compared with non-diabetic controls. In comparison, T2DM patients with LVH displayed on average a ~50% lowering of elevated LVMOur measurements of myocardial fat indicate that the model of severe STZ-evoked diabetes we employed here is unlikely to yield useful information about copper/trientine-myocardial lipid interactions. We have employed the STZ-mediated model of diabetes-induced heart failure because it is reproducible and consistent in terms of time of onset, progression, and severity, and its cardiac structure/function responses are clearly consistent with those in diabetic patients ,12. HoweOur measurements of simultaneous copper and triethylenetetramine concentrations in diabetic animals and humans undergoing trientine treatment confirm that the molar trientine free-base to Cu(II) ratio is consistently > > 1 in the urine ,44. Thes-MS, EPR and particle-induced X-ray emission (PIXE), has demonstrated the presence of copper excess in the whole body [Administration of trientine and measurement of the resulting urinary copper excretion unmasks the extent of the copper overload in diabetes ,12,14,45ole body ,12, urinole body . Thus, dHow might particular organs be selectively targeted by copper-mediated oxidative stress? Elevated pathogenetic tissue binding of copper occurs in diabetes ,6. This What biological properties of copper underpin its pathogenetic behaviour in diabetes? Most intracellular copper is tightly bound and regulated by copper-binding proteins , and intThere are several strong endogenous copper chelators including spermine, spermidine and carnosine, which are localized mainly within cells. There are no available data known to us concerning their ability to extract systemic copper into the urine in diabetes, or to treat diabetic cardiomyopathy. Spermine was reportedly highly toxic when administered to chicks  and longSome studies with clinically significant drugs used to treat diabetic patients, such as metformin, pioglitazone and some of the ARBs, have suggested that they are chelators that could exert their therapeutic effects through copper chelation ,60. The Mechanisms of action of trientine and metformin are now briefly compared with respect to roles of copper. Metformin is an anti-hyperglycemic biguanide drug that is used extensively in the treatment of type 2 diabetes . It actsIn conclusion, eight weeks trientine treatment caused significant improvement in numerous indexes of cardiac function as determined by cMRI in a widely employed nonclinical model of diabetes-induced heart failure, the STZ-diabetic rat. These findings support and extend previous studies in diabetic rats, and are consistent with results from a recent Phase 2 trial of trientine treatment in diabetic patients with LVH. The Cu(II)-selective chelator trientine is the first in a new class of orally-active molecules with application in the experimental pharmacotherapy of the diabetic complications. The evidence presented here supports the further clinical investigation of trientine treatment in patients with diabetes and heart failure.aAbbreviations: AGEs, advanced glycation endproducts; ANOVA, analysis of variance; ARB, angiotensin II receptor blocker; BW, body-weight; cMRI, cardiac magnetic-resonance imaging; CI, 95% confidence interval of the mean; CO, cardiac output; Cu(I), univalent copper; Cu(II), divalent copper; ECM, extracellular matrix; EPR, electron paramagnetic resonance spectroscopy; LME, linear mixed-effects; LVEDV, LV end-diastolic volume; LVEF, left-ventricular ejection fraction; LVESV, LV end-systolic volume; LVM, LV mass; PET, positron-emission tomography; PIXE, particle-induced X-ray emission spectroscopy; RBS, Rutherford backscattering spectroscopy; STZ, streptozotocin; T1DM, type-1 diabetes; T2DM, type-2 diabetes; TE, echo time; TR, repetition time; TTM, tetrathiomolybdate.G.J.S. Cooper is an honorary consultant to PhilERA, holder of patent rights to trientine for the treatment of diabetes and related metabolic diseases. All other authors declare no duality of interest.JL designed, performed and interpreted research, and drafted the manuscript; BP designed and interpreted research and revised the manuscript; SP supervised and interpreted research and reviewed the manuscript; SC performed and interpreted research and revised the manuscript; ML performed research and reviewed the manuscript; HX designed research and reviewed the manuscript; GG performed and interpreted research and reviewed the manuscript; AP designed and supervised research and revised the manuscript; BC designed and interpreted research and revised the manuscript; AY designed, supervised and interpreted research and revised the manuscript; GC designed, supervised, and interpreted research, and drafted the manuscript. All authors have seen and approved the manuscript.


Fibrotic burden of LV myocardium quantified by CMR provides additional information about LA size and mechanics than morphological severity of LV hypertrophy measured by LV mass index alone.Progressive myocardial stiffness of the LV in patients with hypertrophic cardiomyopathy (HCM) impedes early diastolic filling and left atrial (LA) emptying functions. Over time, LA of patients with HCM progressively dilates and undergoes structural and functional remodeling with serious cardiac events such as development of atrial fibrillation and diastolic heart failure despite optimal medical therapy.We studied 65 HCM patients  with CMR. The fibrotic content of the LV myocardium  was obtained using serial R1 mapping by cine-IR method before and up to 30 minutes after contrast injection. LA volumes and LA emptying function across 3 phases of the cardiac cycles, and LV function were also quantified. We sought to determine the strongest variables that predispose the patients to have LA dilatation and impaired LA emptying function.FIMeanSeg demonstrated strong positive correlation with LA volumes across all 3 phases of the cardiac cycle, with the strongest correlation with LAMax volume at end-ventricular systole (r=0.41, P = 0.0005, Figure FIMeanSeg provides independent association with LV volume beyond knowledge of ventricular functional parameters and severity of ventricular hypertrophy by LV mass. This novel method may add to the current characterization of impaired diastolic function in HCM patients and may have prognostic implications.Yucheng Chen got the salary from China Scholarship Council.


The prevalence of atrial fibrillation (AF) is increasing in parallel with an ageing population leading to increased morbidity and mortality. The most feared complication of AF is stroke, with the arrhythmia being responsible for up to 20% of all ischemic strokes. An important contributor to this increased risk of stroke is the left atrial appendage (LAA). A combination of the LAA's unique geometry and atrial fibrillation leads to low blood flow velocity and stasis, which are precursors to thrombus formation. It has been hypothesized for over half a century that excision of the LAA would lead to a reduction in the incidence of stroke. It has only been in the last 20–25 years that the knowledge and technology has been available to safely carry out such a procedure. We now have a number of viable techniques, both surgical and percutaneous, which will be covered in this paper. Atrial fibrillation (AF) is the most prevalent arrhythmia seen in clinical practice with over 2.2 million people in the United States being affected . Given tP = 0.01 for superiority) [P < 0.001 for noninferiority). Furthermore, the higher 150 mg dose was shown to be superior to warfarin  [3. The LAA is often described as being redundant. A number of studies have shown that it plays an important role in the regulation of the intravascular volume status as well as hemodynamic conditions. Excision of the LAA is thought to lead to a reduction in the incidence of stroke in patients with AF. New techniques have emerged which have enabled this process to be done percutaneously without exposing patients to high-risk invasive surgery. Due to the complexity and variability of the LAA anatomy, multi-modality imaging techniques play an integral role in the workup of these patients and directing percutaneous closure. This is particularly important to ensure correct sizing of a device and reduce the risk of complications such as device embolisation or free-wall perforation.Oral anticoagulant therapy, most commonly with warfarin, has been used to reduce the risk of stroke in patients with nonvalvular AF who are at high risk of thromboembolism . Overallriority) . Dabigatriority) . Even wiriority) . The LAAriority) . The sizHistorically, obliteration of the left atrial appendage was first used in conjunction with mitral valvotomy, prior to the utilization of cardiopulmonary bypass. Madden carried out the first LAA surgical excision in humans in 1949, publishing 2 cases the same year . InitialThe success of the Maze procedure was illustrated in a retrospective analysis by Cox et al.  looking A number of different surgical methods have been used to close the LAA. There are 2 general techniques adopted. Firstly, excision of the LAA can be performed by either removing the LAA and oversewing or a stapled excision. Secondly, exclusion of the LAA can be achieved with sutures or clips on either the endocardial or epicardial surface, isolating the LAA from the left atrium. Additionally, small case series have been reported using a thoracoscopic approach for exclusion of the left atrial appendage without the need for an open sternotomy. The success of each method has been highly scrutinized as clinical evidence has questioned their success.The Left Atrial Appendage Occlusion Study included 77 patients undergoing CABG . They weThe poor success of certain LAA exclusion techniques had previously been suggested by a study looking at a group of 50 patients who had undergone mitral valve surgery in addition to ligation of the LAA . A transThe FDA has approved the use of the AtriClip device  for closure of the LAA. It consists of 2 rigid titanium tubes with elastic nitinol springs covered with a knit-braided sheath. The LAA is inserted into the device, which then clips at the base, separating the appendage from the left atrium. The initial trial assessing the safety and efficacy of the device was carried out in Europe . It inclNewer surgical techniques are still currently under investigation in an attempt to improve success rates of LAA closure. One such technique involves invaginating the LAA into the left atrium prior to applying a purse-string suture along the base of the LAA . Once thCurrent practice focuses on the excision of the LAA, given its higher success rates. This usually involves a median sternotomy and is usually best used in patients who require an additional cardiac surgery, in light of the associated surgical risks. As techniques improve and procedures become less invasive, this may well change. In light of the paucity of long-term follow-up data following surgical LAA excision and exclusion: further research is required to define long-term outcomes and need for ongoing anticoagulation following these approaches.There are a number of devices that are available for closure of the left atrial appendage see . Only thThe antiplatelet and anticoagulant regimens used in the clinical trials varied depending on the device see .The AMPLATZER Septal Occluder  was initially designed for patent foramen ovale and atrial septal defect closure. A small trial of 16 patients across 4 centres assessed its use in left atrial appendage occlusion . A standNo further clinical trials have been conducted using this system for left atrial appendage occlusion. A new device, the AMPLATZER Cardiac Plug, has been designed by the same manufacturer and is currently undergoing clinical trial (see below).The PLAATO system  consists of a percutaneously delivered self-expanding nitinol cage covered with an expanded polytetrafluoroethylene and 3 rows of anchors, delivered via a transseptal approach.Initial assessment in a canine model demonstrated proof of concept with left atrial appendage occlusion being achieved in all cases. Complete healing over the device's membrane surface was demonstrated on both gross and histological examination in 90% by 1 month and in all cases by 3-month follow-up .Subsequent human trials demonstrated a high procedural success rate with successful implantation in 108 of the 111 patients enrolled  92.3% to 99.4%) . Patientn = 4), secondary complications after gastrointestinal bleeding (n = 1), and an incarcerated hernia (n = 1): but none were adjudicated as related to the device or procedure [During the initial follow-up period of 90.7 documented implant years covering the initial postimplant period, there were 7 major adverse events in 5 patients . This inrocedure .At 5-year follow-up of the North American cohort of 64 patients, there were 7 (11%) deaths, 5 (8%) major strokes, 3 (5%) minor strokes, 1 (2%) cardiac tamponade requiring surgery, 1 (2%), death from probable cerebral haemorrhage, and 1 (2%) myocardial infarction . Only 1 The PLAATO device has been discontinued for commercial reasons.The WATCHMAN device  is a percutaneous left atrial appendage closure system delivered via a transseptal approach, and implanted at or immediately distal to the ostium of the left atrial appendage. The device consists of a self-expanding nitinol frame with fixation barbs and a permeable polyester fabric which covers the atrial facing device surface. The WATHMAN device is available in 5 sizes ranging from 21 mm to 33 mm in diameter, to accommodate patient variation in left atrial appendage anatomy and size: with device sizing and placement guided by fluoroscopy and transesophageal echocardiography.In light of the permeability of the device membrane to blood, warfarin is prescribed with a target International Normalised Ratio (INR) of 2.0 to 3.0 for a period of 45 days postdevice implantation to allow endothelialisation of the device. This is discontinued following this period, if repeat transesophageal echocardiography demonstrates either complete closure of the left atrial appendage or minimal residual peridevice flow, defined as a jet width of <5 mm. Following cessation of warfarin treatment, dual antiplatelet therapy with clopidogrel (75 mg daily) and aspirin (81–325 mg daily) was prescribed until completion of the 6-month follow-up visit, with the use of aspirin alone lifelong thereafter .Evaluation of the WATCHMAN device against a conventionally treated warfarin control population was performed in the PROTECT-AF trial , the firHowever, safety concerns do exist with the placement of the WATCHMAN device: with an excess of adverse outcomes in the WATCHMAN device group compared to warfarinised controls. This is illustrated in the PROTECT-AF trail , where tEarly data from the ASA Plavix (ASAP) registry , suggestThe AMPLATZER cardiac plug  was developed based on the AMPLATZER double-disk septal occluders (see above) designed for closure of atrial septal defects and patent foramen ovale. The AMPLATZER cardiac plug system like the other left atrial appendage occluders is designed for implantation through femoral venous access via the transseptal route.The device consists of a lobe, designed to sit within the left atrial appendage, and an occlusive disc, which fits over the left atrial appendage orifice. The lobe and disc are connected by a central waist, with the lobe containing hooks to ensure device position.A retrospective review of the preregistry data demonstrated good procedural success with successful device implantation achieved in 132 of the 141 patients (94%) treated . SeriousInterim data from the AMPLATZER Cardiac Plug's European postmarket registry reveals similar procedural success with no device embolizations during the implant procedure. Procedure related adverse events were not significantly changed when compared to the previous data, occurring in 8 out of the 145 registry patients (5.5%) within 7 days after procedure. These consisted of 3 significant pericardial effusions, 3 device embolizations, 1 cardiac perforation, and 1 arteriovenous fistula. Three cases of thrombus on the device and one case of late device embolization were detected during the post 7-day followup .The AMPLATZER cardiac plug has received European regulatory approval and is available for clinical use in Europe. Additionally, the device is currently undergoing a phase 1 randomised controlled trial compared to conventional warfarin therapy to obtain United States Food and Drug Administration (FDA) approval.The Coherex Wave Crest left atrial appendage occlusion system is a percutaneous transseptally delivered left atrial appendage occluder, consisting of a nitinol frame with retractable coils and anchors to enable optimal device positioning. The device consists of a multicomposite membrane including a porous expanded polytetrafluoroethylene on the left atrial side of the device, nonporous expanded polytetrafluoroethylene barrier layer, and a foam substrate on the left atrial appendage opposing surface to minimise residual leaks.Initial pilot phase results in 9 patients demonstrated 2 embolic events, prompting device modifications prior to further trials. These modifications included provision of a bidirectional anchor, refined shape, increased radial strength, and improved occluder geometry.The Coherex Wave Crest has thus far been implanted in 52 patients. Limited outcome data is currently available with data in a subset of 10 patients treated at a single institution revealing one embolic event with no cases of pericardial effusion or thrombosis . Furtherendocardial and epicardial access. A preoperative CT is required to exclude large bilobar appendages and other anatomic variants. A magnet-tipped guide wire system is placed at the endocardial surface of the left atrial appendage apex, via femoral venous access and a transseptal puncture. A second magnet-tipped guide wire system is percutaneously introduced into the pericardium overlying the left atrial appendage apex. This requires an anterior approach to percutaneous pericardial access using a 17G Tuohy needle. The magnet-tipped wires, which establish contact easily, align the endocardial and epicardial aspect of the left atrial appendage under fluoroscopy. The LARIAT Suture Delivery Device is guided over the left atrial appendage in an over-the-wire approach to slip a pretied suture loop over the appendage under transesophageal echocardiographic guidance to achieve appendage closure. The LARIAT delivery system can be opened and closed to allow optimal device positioning prior to device deployment [The LARIAT procedure  for percutaneous left atrial appendage closure requires both ployment , 38.Due to the need for pericardial access, those patients with possible pericardial adhesions are unsuitable for the LARIAT procedure. This includes those with a prior history of cardiac surgery, pericarditis, or chest radiotherapy.Early human experience demonstrated successful left atrial appendage ligation in 78 of 82 patients undergoing this procedure . The remNo published postprocedural follow-up data is currently available, and further results are currently awaited.Surgical methods of LAA closure have been used for more than 20 years, with varying degrees of success. Historically LAA excision has been more successful than exclusion; however, newer surgical techniques are continuously being studied. A number of percutaneous left atrial appendage closure devices are currently undergoing clinical trial. Only three of these device systems are currently available for commercial use. The LARIAT suture delivery system is the only device system with both FDA and European CE mark approval for its use. The remaining two devices (WATCHMAN and AMPLATZER cardiac plug) carry European regulatory approval for this indication. Percutaneous left atrial appendage closure devices are usually associated with high procedural success rates. However, they are also associated with a significant incidence of peri-procedural adverse events; including significant pericardial effusions, major bleeding, procedure-related ischemic stroke, device embolization, and death. Cardiac imaging plays a vital role in assessing anatomical suitability and guiding placement of these devices.The European Society of Cardiology Guidelines for the management of Atrial Fibrillation suggests that patients with contraindications to chronic oral anticoagulation might be considered as candidates for left atrial appendage occlusion . The 201There is a subset of patients who are at a high risk of both cardioembolic stroke and bleeding. It is likely that these patients would be ideal candidates for LAA closure; however, its role still needs to be properly defined.


Post-infarction remodelling (PIR) determines left-ventricular (LV) function and prognosis after myocardial infarction. The aim of this study was to evaluate transthoracic ultrasound-mediated microbubble stimulation (UMS) as a novel gene- and cell-free therapeutic option after acute myocardial infarction and reperfusion (AMI/R) in mice.For myocardial delivery of UMS, a novel therapeutic ultrasound-system  and commercially available microbubbles  were utilized in a closed-chest mouse model. UMS was performed as myocardial post-conditioning (PC) on day four after 30 minutes of coronary occlusion and reperfusion. LV-morphology, as well as global and regional function were measured repeatedly with reconstructive 3-dimensional echocardiography applying an additional low-dose dobutamine protocol after two weeks. Scar size was quantified by means of histomorphometry. A total of 41 mice were investigated; 17 received PC with UMS. Mean ejection fraction (EF) prior UMS was similar in both groups 53%±10 (w/o UMS) and 53%±14 , reflecting comparable myocardial mass at risk 17%±8 (w/o UMS), 16%±13 . Two weeks after AMI/R, mice undergoing UMS demonstrated significantly better global LV-function (EF = 53%±7) as compared to the group without PC . The fraction of akinetic myocardial mass was significantly lower among mice undergoing UMS after AMI/R . Our experiments showed a fast onset of transient, UMS-induced upregulation of vascular-endothelial and insulin-like growth factor , as well as caveolin-3 (Cav-3). The mice undergoing PC with UMS after AMI/R showed a significantly lower scar size. In addition, the microvascular density was significantly higher in the borderzone of UMS-treated animals.via up-regulation of VEGF-a, IGF-1 and Cav-3, and consecutive improvement of myocardial borderzone vascularization.UMS following AMI/R ameliorates PIR in mice  Acute myocardial infarction (AMI) and its sequelae are some of the most common causes of death in the western world, even worldwide. The cicatrization of the infarcted left-ventricular (LV) myocardium leads to morphological and functional changes of the contractile tissue, also referred to as post-infarction remodelling (PIR) Clinically, myocardial revascularization is the method of choice in treatment of AMI and the minimization of PIR. Experimental treatment options encompass gene- and cell-based interventions to preserve the contractile performance after AMI. Firstly, myocardial perfusion can be improved by growth factor induced neo-vascularisation  or insulin-like growth factor 1 (IGF-1)) Ultrasound-mediated stimulation of microbubbles (UMS) has been shown to modulate myocardial expression patterns and to improve myocardial transplantation of bone marrow derived cells in rats ad libitum diet.All experiments have been approved by the animal care committee at the University of Bonn and the local government authorities. Also, they conform to the guidelines of the American Heart Association for the use of animals in research and corresponds to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health . All animals were housed at a constant room temperature of 24°C and 12 h light–dark cycle and maintained on an 2-flow. Mice were intubated with a 22 gauge cannula  and connected to a ventilation system . Correct intubation and ventilation was confirmed by observing thorax excursions. The animals were placed in a supine position on a feedback heat pad. Their body temperature was measured with a rectal probe and maintained at 36.5°C. The anaesthesia was maintained with 1.2–1.5% isoflurane in 100% O2, the animals` heart rates were monitored and kept within physiological ranges to minimize cardio-depressant effects. The respiratory rate was set at 115/min and 10 µL tidal volume per gram body weight. Sufficient analgesia was determined by testing the rear foot reflex.In order to minimize inflammatory interaction of surgical trauma and AMI, an established closed-chest model of AMI and reperfusion (AMI/R) was utilized  [8]. 56 rd, the other through the 5th intercostal space and stored subcutaneously. The thorax was closed with a prolene suture .A left lateral thoracotomy was performed in the forth intercostal-space. The pericardium was opened and gently removed to identify the left anterior descending coronary artery (LAD). The LAD was cautiously under-stitched with an 8–0 prolene suture  with a U-shaped tapered needle 1 mm distal of the left auricle. The suture was cut at the needle side and both ends were threaded through 1.0 mm section of a PE 10 tube to form a loose snare around the LAD. To check the correct position of the LAD ligature both ends were transiently tightened. If the position of the ligature was correct paleness of the distal antero-lateral myocardial segments could be observed. Both ends were exteriorized one through the 3After closing the skin, the mice were weaned from the ventilator and kept in a warm cage. Post-operative care comprised fentanyl 0.1 µg/g bodyweight bid s.c. for analgesia and 7.5 mg/kg bodyweight of the antibiotic enrofloxacine  s.c. for 5 days.For our AMI/R experiments myocardial infarction took place seven days after coronary instrumentation . The Mic2 consisting of 5×5 target points with a gap of 1 mm and was placed into the anterior LV-wall aimed at the infarcted area. The ultrasound pulse was delivered with a frequency of 0.2 Hz to allow a sufficient replenishment of the contrast agent. The Control procedure was insonication protocol prior to infusion of microbubbles, as described previously by Miller and co-workers The ultrasound-mediated stimulation of microbubbles (UMS) allows myocardial post-conditioning (PC) by locoregional stimulation of commercially available ultrasound contrast agent with high-intensity focussed ultrasound. For UMS, BR1  2, Tecan Group Ltd., Switzerland). EB extravasation was calculated as µg EB per mg dry tissue, thus revealing the level of transendothelial extravasation within the targeted myocardial tissue Additional experiments were conducted to confirm the myocardial delivery of UMS. Evans blue (EB)  is a dye that binds on albumin and therefore stays within the intravasal compartment. Extravasation is an indicator of increased capillary permeability UMS shows transient biological effects and allows nanoparticles to be delivered transendothelially across sites of UMS-induced transient pore formation Nanospheres were injected simultaneously with microbubbles and UMS protocol was administered with different peak pressures . Hearts were harvested directly after the administration of UMS and processed for histological analyses. Nanosphere delivery was determined with overlap fluorescent and reflected light microscopy using an Olympus BX 41/Color View II System and Cell-P software .Morphological and functional imaging was performed 4 and 14 days after the application of UMS. All mice were anesthetized with isoflurane  in 100% oxygen by facemask to avoid cardiodepression and ensure near physiological heart rate. Echocardiography was performed with a commercially available high-resolution ultrasound system  equipped with a linear-array transducer (CL15-7) operating at 15 MHz and providing frame rates up to 284 Hz. A parasternal long-axis image was used to guide the perpendicular angulation of the transducer for acquisition of the short-axis slices. Then, sequenced 2D, parallel short-axis images of the left ventricle were obtained in 500 µm steps from the aortic root towards the apex by means of a micrometer-screw driven tripod. Ten to fourteen short- axis segments were recorded depending on the overall size of the left ventricle An experienced investigator performed echocardiographic analyses blinded to treatment strategy. End-diastolic measurements were obtained at the peak of the R-wave, whereas end-systolic measurements were obtained at the time of minimum internal chamber dimensions. The acquired sequential 2D short-axis cineloops of the left ventricle were used to measure LV-volumes at end-diastole and end-systole and ejection fraction (EF). Myocardial compartments were differentiated by visual assessment following established echocardiographic criteria: For investigation of expression patterns we varied applied peak pressure  and harvesting time  in mice undergoing LV-myocardial UMS. Animals with administration of contrast agent following the insonication protocol served as controls 2 Reader . We investigated the protein content [pg/mg myocardial tissue] in: 1. control-groups without any treatment; 2. instrumented mice with AMI/R but without UMS; 3. instrumented mice with AMI/R and with UMS; 4. UMS only.To determine the protein expression of IGF-1, the myocardial tissue was homogenized and incubated on ice for 5 min in 1 mL of ELISA buffer containing 20 mM TRIS-HCL, 50 mM sodium chloride, 50 mM sodium fluoride, 10 mM EDTA, 20 mM sodium pyrophosphate, 1 mM Triton X-100  in aqua bidest with protease inhibitors  per 100 mg tissue. The samples were incubated on ice for 10 min and centrifuged for 15 min at 4°C at 14000 rpm. The supernatant was used for measuring myocardial protein levels of IGF-1  using a Tecan SafireTwo weeks after the UMS-application heart samples were prepared for microtome sectioning by rinsing directly in cardioplegic solution after harvesting. Hearts were cannulated via the ascending aorta with a modified Langendorff-system and retrogradely perfused with 4% paraformaldehyde  at 100 mm Hg pressure for 10 min to avoid the collapse of the left-ventricle 2 in the scar, both borderzones, and the posterior wall To evaluate microvascular density CD31 immunohistochemistry was performed. Therefore cryosections were pre-treated with citrate for 15 min in the microwave oven, incubated for 30 min in hydrogen peroxide 3%, and rinsed two times in PBS pH 7.4 for 5 min. Then they have been blocked with the Vectastain rat kit  for 15 min. CD31 staining was performed using the rat anti-mouse CD31 antibody  over night at 4°C with a dilution ratio of 1∶50 in an IgG-block. As a secondary antibody biotin was incubated for 30 min. The antibody was detected with peroxidase using the Vectastain Rat ABC kit  for 30 min and developed with diaminobenzol (DAB) and nickel for 5 min. Microvascular density was assessed by counting the number of CD31-positive vessels in the region of interest. Results were collected as vessels per mmt-test. Comparison over time, as well as between rest and stress, were tested with the paired Student’s t-test. A value of p<0.05 was considered significant. Data are indicated as mean± SD.Statistical significance between treatment groups was tested by means of the unpaired A total of 41 C57BL6 mice undergoing AMI/R were randomized into two treatment groups receiving either UMS (n = 17) or control procedure (n = 24). The functional and morphological impacts of UMS on cardiac function after experimental AMI/R were repetitively investigated by means of r3DE on day 4 and 14. Echocardiographic left-ventricular dimensions are displayed in In order to estimate regional LV-function, the akinetic mass of LV-myocardium was quantified by means of r3DE. In parallel, on day 4 there were no significant differences between both groups (17%±8 (w/o UMS), 16%±13 (UMS), p = ns). However, by day 14 the akinetic myocardial mass of UMS-treated mice remained stable (13%±8), whereas the control group demonstrated a significant increase   A+B. To Histological analyses of scar size were concordant with functional results. We observed a significant reduction of myocardial scar burden in mice treated with UMS , To investigate potential mechanisms, further experiments were conducted. We characterized the efficacy of myocardial delivery of UMS utilizing EB and nanospheres. UMS effects were more pronounced in the anterior LV-wall as demonstrated by a significantly higher amount of extravasated EB. This well-known effect of UMS was shown to be dose-dependent, revealing lowest extravasation at low emission power (0.3 MPa). In parallel, the transendothelial distribution across microvascular structures showed a dose-dependent increase . These dTo investigate the underlying pathomechanisms, the myocardial expression patterns of three potential mediators were investigated: vascular-endothelial growth factor (VEGF-a), insulin-like growth factor-1 (IGF-1) and caveolin-3 (Cav-3). In general, the mRNA-levels of all three increased transiently within 15 minutes after UMS and reached their maximum after 6 hours . The expvia modulation of myocardial expression patterns and improvement of borderzone vascularization after AMI/R in mice.Our data demonstrate the ability of UMS to ameliorate post-infarction remodelling Novel treatment options of PIR focus on early prevention of functional deterioration and scar formation, since myocardial damage caused by AMI have been known to be irreversible. Novel treatment options of AMI with additional benefit to reperfusion include cell- and gene-based strategies Since UMS may provide a new treatment option after AMI/R and is able to influence PIR on top of reperfusion, we investigated potential mechanisms of the UMS effect. Firstly, the UMS-mediated overexpression of VEGF-a may help explain functional improvements and amelioration of PIR This study is limited by the mechanistic proof of the UMS effect. Only a selection of the known and suspected factors was investigated. However, the experimental setup aimed to demonstrate the proof of principle. Moreover, we aimed at therapeutic targets, which are available for future comparative studies with gene- and cell-based therapeutic approaches. Some challenges will remain crucial for the translation of UMS into larger animal models or even the clinical scenario, two of which are: locoregional delivery of ultrasound energy deep into the body through the skin into a moving organ and coverage of a therapeutically significant volume in a clinically acceptable amount of time. Distinct focused devices are under current development to cover the mentioned requirements and will allow translation into the canine model with comparable penetration depth, target volume, and thoracic impedance as compared to humans. However, from a technical point-of-view, delivery of UMS to a larger organ seems to be simpler than in mice.via the up-regulation of VEGF-1, IGF-1 and Cav-3 and consecutive improvement of myocardial borderzone vascularization. However, further studies need to elucidate the pivotal mechanism.UMS allows a cell- and gene-free amelioration of PIR on top of reperfusion


Thalassemia intermedia (TI) patients were shown to have significantly higher cardiac output and cardiac volumes with respect to thalassemia major (TM) patients. So, to compare biventricular parameters in TI patients with established ranges from TM may be misleading.The aim of this study was to establish the ranges for normal biventricular volumes and ejection fraction (EF) and for left ventricular (LV) mass assessed by cardiovascular magnetic resonance (CMR) in TI.Among the 294 TI patients with > 18 years of age enrolled in the Myocardial Iron Overload (MIOT) network who underwent CMR, we selected 68 patients with no known risk factors or history of cardiac disease, normal electrocardiogram, no myocardial iron overload  and no myocardial fibrosis. Biventricular parameters were quantitatively evaluated in a standard way by SSFP cine images using MASS® software. LV and right ventricular (RV) end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) were normalized by body surface area , as well as the LV mass.The selected patients had a mean age of 36.5 ± 9.2 and 37 were males.Biventricular volumes indexes were significantly larger in males than in females, with the exception of the RV ESVI. The LV mass was significant higher in males while the LV and the RV EFs were not different between the sexes. No significant differences among TI regularly (N=36), sporadically (N=16) and no transfused (N=16) were found in biventricular parameters, so no division was made on the basis of the transfusional regimen.The biventricular parameters are detailed in table Reference ranges for biventricular volumes and function specific to adult TI patients were defined. These new reference ranges are important for avoiding a misdiagnosis of cardiomyopathy in TI patients.The MIOT project receives "no-profit support" from industrial sponsorships (Chiesi and Apotex). This study was also supported by: "Ministero della Salute, fondi ex art. 12 D.Lgs. 502/92 e s.m.i., ricerca sanitaria finalizzata anno 2006" e "Fondazione L. Giambrone".


The left ventricular (LV) lead in cardiac resynchronization therapy (CRT) can be placed on any non-septal LV wall, most commonly the lateral wall. Presence of myocardial scar adversely affects CRT outcome, particularly if it involves the LV pacing site. It is increasingly important to identify and localize myocardial scar in CRT candidates, the majority of whom have left bundle branch block (LBBB). We aimed to describe the diagnostic performance of electrocardiographic (ECG) criteria based on the Selvester QRS score in localizing myocardial scar into 5 LV wall segments and in detecting non-septal scar in patients with LBBB using Cardiac Magnetic Resonance as the gold standard.In 39 cardiomyopathy patients with strictly defined LBBB , late gadolinium enhancement cardiac magnetic resonance images (CMR-LGE) and 12-lead ECGs were analyzed for scar presence in 5 LV wall segments. Using stepwise regression analysis, multiple subsets of the Selvester QRS score ECG criteria were identified for each of the 5 individual segments and for the 4 non-septal segments together. The diagnostic performance of each of these subsets is displayed in the graph below. The one subset for each location that had the highest combination of sensitivity plus specificity was selected.The best identified subset of Selvester QRS score criteria for screening of non-septal scar had 75% (95% CI: 51-90%) sensitivity, 95% (78-99%) specificity, 92% (67-99%) positive predictive value and 84% (65-94%) negative predictive value. For each individual wall segment, 40-60% sensitivities and 77-100% specificities were found.The 12-lead ECG can convey information about scar presence and location in patients with cardiomyopathy and LBBB. ECG screening criteria for scar in potential CRT LV pacing sites were identified. Further exploration is required to determine the clinical utility of the 12-lead ECG in combination with other imaging modalities to screen for scar in potential LV pacing sites in CRT candidates.The study was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health , the DW Reynolds Foundation and the FDA Critical Path Initiative.


It remains incompletely understood whether patients with transfusion related cardiac iron overload without signs of heart failure exhibit already subclinical alterations of systolic left ventricular (LV) dysfunction. Therefore we performed a comprehensive evaluation of systolic and diastolic cardiac function in such patients using tagged and phase-contrast CMR.19 patients requiring regular blood transfusions for chronic anemia and 8 healthy volunteers were investigated using cine, tagged, and phase-contrast and T2* CMR. LV ejection fraction, peak filling rate, end-systolic global midventricular systolic Eulerian radial thickening and shortening strains as well as left ventricular rotation and twist, mitral E and A wave velocity, and tissue e' wave and E/e' wave velocity ratio, as well as isovolumic relaxation time and E wave deceleration time were computed and compared to cardiac T2*.Patients without significant iron overload  had similar parameters of systolic and diastolic function as normal controls, whereas patients with severe iron overload , had significant reduction of LV ejection fraction (54 ± 2% vs. 62 ± 6% and 65 ± 6% respectively p < 0.05), of end-systolic radial thickening (+6 ± 4% vs. +11 ± 2 and +11 ± 4% respectively p < 0.05) and of rotational twist  than patients without iron overload (T2* > 20 ms) or normal controls. Patients with moderate iron overload , had preserved ejection fraction , but showed reduced maximal LV rotational twist (1.8 ± 0.4 degrees). The magnitude of reduction of LV twist , of LV ejection fraction , of peak radial thickening  and of systolic  and diastolic twist and untwist rate  in patients were directly correlated to the logarithm of cardiac T2*.Multiple transfused patients with normal ejection fraction and without heart failure have subclinical alterations of systolic and diastolic LV function in direct relation to the severity of cardiac iron overload. Among all parameters, left ventricular twist is affected earliest, and has the highest correlation to log (T2*), suggesting that this parameter might be used to follow systolic left ventricular function in patients with iron overload. Repeated transfusion of packed red cells in patients with chronic anemia leads to chronic iron overload in many different organs, and especially the heart. Such chronic cardiac iron overload can cause heart failure, systolic -3 and diT2* measurement by cardiovascular magnetic resonance (CMR) is a novel technology which allows to non-invasively assess the severity of hepatic and cardiac iron overload -7. In thYet, the impact of moderate iron overload on alterations of left ventricular function still remains incompletely understood. Indeed an inverse curvilinear relation between T2* and left ventricular (LV) ejection fraction (EF) was demonstrated when T2* was smaller than 20 ms ,16. Yet,This prospective study included consecutive patients with a chronic anemia treated by transfusion of packed red cells, who underwent a clinically indicated T2* CMR study to quantify myocardial iron content. Only healthy patients without clinical signs of heart failure and with normal cardiac function by echocardiography were considered for inclusion into this study. Patients with signs or history of heart failure, depressed LV-function, significant valve disease, or cardiac arrhythmia were excluded. We thus studies 19 patients with anemia  with a 5 element phased array coil. T2* measurement of the liver was performed using single-breath-hold, 20-echo (1.07 to 21 ms) gradient echo sequence in an 10 mm axial slice through the liver. Repetition time (TR) was 150 ms, field of view 360 mm, image matrix 176 × 176 and flip angle 35°. Then, after horizontal and long-axis localizers, myocardial T2* was assessed from a midpapillary ventricular short-axis slice using a cardiac-gated, segmented, multiecho gradient echo sequence obtained in a single breath-hold, similar to the technique described by Westwood et al. [Finally, mitral inflow velocity and mitral annular motion velocity were evaluated using a free breathing, ECG gated segmented K space gradient echo sequence prescribed in a short-axis orientation at the level of the mitral valve as described by Paelinck et al. . Images -TE/T2*. R2* was computed as the reciprocal of T2*.Regions of interest were placed in the septal wall of the heart and in the liver. Cardiac and hepatic T2* times were computed by mono-exponential fit to the equation y = K e Cine SSFP CMR images were analyzed by a blinded observer using the freely automated software SEGMENT . The endLA2c and ALA4c are the areas of the left atrium planimetered in 2 and 4 chamber views and lLA the length of the atrium respectively.Left atrial volume was computed at the time of maximal atrial filling just before mitral valve opening using the area-length method as Tagged CMR images were analyzed quantitatively using Harmonic Phase Imaging Analysis  as previously described  and as iThe first derivative of twist versus time was computed to yield respectively systolic twist rate and diastolic untwist rate.Phase contrast images were analyzed on a dedicated work station . A region of interest was placed in the center of the mitral valve and in the aortic valve outflow tract and mean velocity of both regions was plotted over time Figure . LV ejecAll continuous values are reported as mean ± one SD. Patients with anemia were separated into 3 groups according to cardiac T2* times . Mean values of LV dimensions, and various systolic and diastolic parameters by CMR were compared among patients with different cardiac T2* values and controls using one-way ANOVA. Individual comparisons were performed post-hoc using Bonferroni test. The various CMR parameters were also compared with cardiac and hepatic T2* and R2* measurement using Pearson's regression analysis. All tests were two sided and a P value < 0.05 was considered indicative of statistical significance.The clinical characteristics of the nineteen patients with anemia and normal controls are shown in Table Controls had significantly larger body size than patients. Also heart rate was significantly higher in anemia patients than in controls.As expected, patients had significantly higher hepatic and cardiac T2* values than controls. There was considerable variation of cardiac T2* values in chronically transfused patients. In 9 patients T2* was normal (cardiac T2* > 20 ms), 5 others had moderate iron overload (cardiac T2* 11-20 ms) and 5 patients showed severe iron overload (cardiac T2* < 10 ms).All tagging studies were successfully completed and could be evaluated, however data from 4 phase contrast studies was missing or non evaluable. Results are shown in table By study design, all patients had LV ejection fraction > 50%. In patients without significant iron overload, LV ejection fraction and strains were not significantly different from controls. Rotation of the LV base was similar in patients and in controls. However the rotation of the apex and uncorrected LV torsion were significantly lower in patients than in controls. This was due to shorter LV length and diameter of the hearts of patients. Indeed, when corrected for LV length and diameter, LV twist was similar in patients without significant iron overload (T2* > 20 ms) and in controls.Asymptomatic patients with severe cardiac iron overload (cardiac T2* < 10 ms) displayed significant reductions of LV ejection fraction, radial thickening and LV torsion and LV twist as compared to controls and patients with T2* > 20 ms. In patients with moderate cardiac iron overload (cardiac T2* 10-20 ms), LV ejection fraction was preserved, however LV twist was significantly reduced as compared to controls.Among all diastolic parameters studied, none did attain statistical significance.The magnitude of reduction of LVEF, of systolic radial thickening and systolic LV twist and systolic LV twist rate in patients correlated linearly with the severity of cardiac but not with hepatic iron overload Table . Among dThis study evaluated systolic and diastolic function by tagged and phase contrast CMR in patients with repeated transfusion. The originality of our study is twofold: Indeed as opposed to earlier work, we studied only asymptomatic patients without clinical signs of heart failure and with preserved ejection fraction. In addition, we computed myocardial strains from tagged MR to precisely evaluate myocardial contractility in our patients.Earlier work demonstrated that LV ejection fraction is reduced in patients with severe cardiac iron overload -4,16. OtOur study corroborates earlier reports of reduced systolic function in severe cardiac iron overload -4,16. InIn contrast to systolic function, our study found no alterations in diastolic function in patients with iron overload. The only parameter which correlated significantly with the severity of iron overload in patients was diastolic LV untwisting velocity. Also in the literature, reports on diastolic dysfunction in patients with iron overload are conflicting. Indeed some studies using echocardiography ,24,31,32Interestingly in the present study we did not observe increases in atrial volumes, or in LV mass in patients with iron overload, as reported by others ,22,34. AThe findings of the present study illustrate the harmful effects of iron overload on systolic function even before overt cardiac dysfunction or heart failure develops. Conventional echocardiographic techniques have failed to distinguish LV function of patients with thalassemia and iron overload from that of normal controls when global function was examined. Our study suggests that myocardial strains and in particular LV torsion and twist are more sensitive parameters than global LV ejection fraction for early detection of systolic dysfunction in patients with iron overload. Also LV untwisting velocity was the only useful parameter of diastolic dysfunction correlating with iron overload. This is particularly interesting, since speckle tracking echocardiography can now evaluate strains and in particular LV torsion and twist non-invasively. In principle, this technique might thus also be useful for following patients with chronic iron overload. Unfortunately, as we have previously shown , 2D echoSevere iron overload causes magnetic susceptibility effects which may affect to some extent the image quality of our tagging sequence with echo-planar readout. Although the sharpness and persistence of tags were found to be reduced in some patients with severe iron overload in late diastole, we could compute strain in systole and early diastole in all patients. Another limitation is that we assessed diastolic function using a phase contrast imaging, with a lower temporal resolution compared to Doppler echocardiography. This may have affected our ability to precisely evaluate parameters of diastolic dysfunction. Yet this approach was shown in a validation study to provide as accurate measurements of diastolic function as Doppler echocardiography does .We have shown in a small patient cohort that LV rotational twist is the earliest and most affected parameter in hearts with moderate iron overload, and shows the best correlation versus the severity of cardiac iron overload. This suggests that this parameter might be useful to monitor development of LV systolic dysfunction in patients with cardiac iron overload.The authors declare that they have no competing interests.SS, SP, SM and BG: acquisition of CMR studies. SM and CV: patient recruitment. SS and BG: study design, analysis of data and manuscript redaction. AP, JLVO and DV study design and review of manuscript. All authors read and approved the final manuscript.Grant support by the Fondation Nationale de la Recherche Scientifique of the Belgian Government (FRSM 3.4557.02)