To explore the pathological changes of three-dimension structure of ventricular myocardial fibers after anterior myocardial infarction in dog heart.Fourteen acute anterior myocardial infarction models were made from healthy dogs (mean weight 17.6 ± 2.5 kg). Six out of 14 dogs with old myocardial infarction were sacrificed, and their hearts were harvested after they survived the acute anterior myocardial infarction for 3 months. Each heart was dissected into ventricular myocardial band (VMB), morphological characters in infarction region were observed, and infarct size percents in descending segment and ascending segment were calculated.Six dog hearts were successfully dissected into VMB. Uncorresponding damages in myocardial fibers of descending segment and ascending segment were found in apical circle in anterior wall infarction. Infarct size percent in the ascending segment was significantly larger than that in the descending segment (23.36 ± 3.15 (SD) vs 30.69 ± 2.40%, P = 0.0033); the long axis of infarction area was perpendicular to the orientation of myocardial fibers in ascending segment; however, the long axis of the infarction area was parallel with the orientation of myocardial fibers in descending segment.We found that damages were different in both morphology and size in ascending segment and descending segment in heart with myocardial infarction. This may provide an important insight for us to understand the mechanism of heart failure following coronary artery diseases. Postinfarct ventricular remodeling (PIVR) is the major cause of heart failure following coronary artery disease . MicrocoFourteen dogs received humane care in compliance with the 1996 NRC Guide for the Care and Use of Laboratory Animals. They were offered by Animal Experimental Center of PLA General Hospital. 14 dogs (16.5 to 19.0 kg) were premeditated with Ketamine hydrochloride (15 mg/kg) and diazepam (0.5 mg/kg) intramuscularly and were anesthetized with Pentobarbital sodium (10 mg/kg) and Norcuron (0.03 mg/kg). Support with a volume-controlled ventilator  was maintained after tracheal intubation. The left femoral artery was cannulated for arterial pressure measurement. The electrocardiogram was monitored. Each dog underwent thoracotomy through the fifth intercostal space and the heart was exposed with pericardial incision. The left anterior descending branch was ligated by a 4-0 Prolene thread at the site between the first and second diagonal branch. Asynersis was found in the left ventricular anterior wall which appeared dark and the electrocardiogram showed classic acute myocardial infarction. Chest was closed after the vital signs were observed for an hour. Dietary activities were observed every day after surgery. Postoperative echocardiography was performed, and cardiac morphology and function were measured at 3 months.Six surviving dogs were sacrificed and their hearts were harvested at 3 months. Each heart was treated and dissected by hand with the method described by Torrent-Guasp .Double helical VMB was unfolded. Morphologic characteristics were determined. In addition, to measure the infarct size more exactly, we calculated infarct size percents of descending segment and ascending segment respectively with a new method which was designed based on Torrent's double helical VMB theory rather than a traditional method.As the VMB was unfolding naturally, it was photographed with a digital camera and the pictures were fed into the computer. The infarct sizes in descending segment and ascending segment were measured using picture processing software (Sichuang Company). Then, the infarct size percents of descending segment and ascending segment were calculated respectively as follows:ISPDS: Infarct size percent of descending segment; IADS: Infarct area in descending segment; ADS: area of descending segment; ISPAS: Infarct size percent of ascending segment; IAAS: Infarct area in ascending segment; AAS: area of ascending segment.SPSS 10.0 was used for statistical analysis.  Infarct size data were compared by t-test between two segments and were reported as mean ± standard deviation (mean ± SD). P-values < 0.05 were considered statistically significant.Echocardiography confirmed that old myocardial infarction was successfully established in the 6 dogs, in which dyskinesia was found in the left anterior wall and apex. Postinfarct left ventricular end-diastolic dimension (LVEDD) was larger than that of normal heart (34.3 ± 7.8 (SD) vs 25.6 ± 7.3 mm, P = 0.106). Postinfarct ejection fraction (EF) was significantly smaller than that of normal heart (45.7 ± 4.5 (SD) vs 59.8 ± 5.2%, P = 0.0018.)Six hearts were successfully dissected into ventricular myocardial band (VMB) Figure , which wAnterior wall infarction mainly involved apical loop, but the damages in ascending and descending segments appeared uncorresponding Figure . InfarctPostinfarct ventricular remodeling (PIVR) is the major pathologic basis of chronic heart failure following myocardial infarction. It always occurs regardless of the degree of infarction and involves myocardial fibers in both infarct and non-infarct regions. Its main macropathologic changes are ventricular wall attenuation, chamber dilation and ventricular wall hypertrophy in non-infarct region and so on. In addition, these changes can lead to chronic heart failure and ventricular aneurysm. Torrent -7 descriMeasurement of infarct size percent is one of the important methods for evaluating PIVR. In present study, we found that anterior wall infarction led to uncorresponding damages in the apical loop. Infarct size percent of ascending segment was significantly larger than that of descending segment and we found that long axis of infarction region was perpendicular to the orientation of myocardial fibers in ascending segment, where the major myocardial fibers were broken and long axis of infarction region was parallel with the orientation of myocardial fibers in descending segment, where only partial myocardial fibers disappeared. We found that damages were different in both morphology and size in ascending segment and descending segment in heart with myocardial infarction.It has been recently reported that postinfarcted filling function decrease was an independent risk factor of congestive heart failure and death in patients with myocardial infarction ,14. HoweIn present study, we conclude that damages were different in both morphology and size in ascending segment and descending segment in heart with myocardial infarction. This may provide an important insight for us to understand the mechanism of heart failure following coronary artery diseases.The authors declare that they have no competing interests.Gao C: Study design, development of methodology, collection and analysis of data, writing the manuscript and supervision. WHY: Completion of the experiment. LBL: Completion of the experiment. All the authors have read and approved the final manuscript.Professor Changqing Gao is Chairman and professor of the Department of Cardiovascular Surgery, Director of the Minimally Invasive and Robotic Cardiac Surgery Center, PLA General Hospital, Beijing, China, and Director of the Institute of Cardiac Surgery, and chief surgeon. His professional interests include acquired heart disease, mitral and aortic valve repair/replacement, aneurysms of the thoracic aorta, and heart transplantation. He has a special interest in complex coronary artery bypass, off-pump coronary artery bypass, left ventricular aneurysms, and minimally invasive cardiac surgery


The majority of children awaiting heart transplantation require inotropic support, mechanical ventilation, and/or extracorporeal membrane oxygenation (ECMO) support. Unfortunately, due to the limited pool of organs, many of these children do not survive to transplant. Mechanical circulatory support of the failing heart in pediatrics is a new and rapidly developing field world-wide. It is utilized in children with acute congestive heart failure associated with congenital heart disease, cardiomyopathy, and myocarditis, both as a bridge to transplantation and as a bridge to myocardial recovery. The current arsenal of mechanical assist devices available for children is limited to ECMO, intra-aortic balloon counterpulsation, centrifugal pump ventricular assist devices, the DeBakey ventricular assist device Child; the Thoratec ventricular assist device; and the Berlin Heart. In the spring of 2004, five contracts were awarded by the National Heart, Lung and Blood Institute to support preclinical development for a range of pediatric ventricular assist devices and similar circulatory support systems. The support of early development efforts provided by this program is expected to yield several devices that will be ready for clinical trials within the next few years. Our work reviews the current international experience with mechanical circulatory support in children and summarizes our own experience since 2005 with the Berlin Heart, comparing the indications for use, length of support, and outcome between these modalities. Most pediatric patients listed for heart transplantation eventually require a high level of cardiac support before transplantation. Currently, over 85% patients undergoing heart transplantation within the Pediatric Heart Transplant Study (PHTS) were United Network of Organ Sharing status 1 (heart failure requiring intravenous inotropes) . This siPediatric MCS in the United States has been limited until recently to ECMO, the Bio-pump , and adult systems adapted for pediatric support. New devices in the United States available for children are the implantable MicroMed DeBakey VAD Child  and the Berlin Heart VAD  which were granted Humanitarian Device Exemption (HDE), and compassionate use exemption, by the Food and Drug Administration (FDA), respectively. The purpose of this review is to discuss the use of MCS in the critically ill child awaiting heart transplantation, and describe our own experience with the Berlin Heart VAD.et al. [et al. [Implantation of MCS devices in children as a bridge to heart transplantation is not uncommon -7. Both et al. , early a [et al.  document1.ECMO is still the most common type of MCS used in infants and children. Indications for ECMO include the pre and postoperative support in congenital heart disease, as well as cardiogenic shock associated with cardiomyopathies, acute myocarditis, and intractable arrhythmias . In pati2.The BCP  is a constant speed, nonpulsatile device which can be used in children of all ages. Compared with roller pumps, there is less hemolysis and less significant inflammatory response . A flow The use of a single BCP in the setting of postoperative cardiac arrest is suboptimal since severe biventricular failure in these children is expected. Intaoperative placement of this type of a centrifugal pump is more common for patients who cannot be weaned from CPB due to isolated left ventricular failure, such as in children with anomalous left coronary artery arising from the pulmonary artery, transposition of the great arteries following arterial switch, and donor heart dysfunction following transplantation . When glThe operating room provides a controlled environment which allows assessment of BCP versus ECMO support. In this setting, a venous cannula is placed in the left atrium while clamping the right atrial or caval cannulae used for CPB. Right heart hemodynamic profile is monitored at 150 ml/kg/min pump flow. If right atrial pressure, pulmonary artery pressure, and right ventricular function are satisfactory, the patient is placed on full ventilatory support, while gas exchange in the oxygenator is temporarily interrupted. If gas exchange, metabolic balance, and hemodynamic profile are adequate, left BCP may be utilized. ECMO or biventricular BCP are required if right sided failure is observed during this assessment . Advantaet al. [Both modalities are limited to similar short-term periods of support, which is largely responsible for the nearly identical hospital outcomes reported in 1999 by Duncan et al.  in a sinet al. . The sur3.One of the most common MCS devices in adults with left ventricular failure associated with ischemic heart disease is IABP. IABP uses the concepts of systolic unloading and diastolic augmentation. Its use in children remains limited due to technical considerations related to small patient and blood vessel size which complicates insertion and renders the IABP less effective. Early concerns about whether effective counterpulsation was achievable in the highly elastic and distensible aorta of young children have proven unfounded . Its clinical efficacy in adults with left ventricular failure was established in 1973 through a multicenter trial . They su1.2 [2 , respectively. Overall survival in this cohort (71%) was similar to survival in adults supported by this device (58%-71.6%) with a comparable average duration of support. Statistical analysis exposed congenital heart disease as a strong independent risk factor for death. Another concerning finding was that 27% of the subjects had neurologic complications, substantially higher than the 5-12% neurological complications in adults supported by the Thoratec VAD.These adult FDA approved extracorporeal MCS devices have been used successfully in older children whose body surface area is greater than 1.4 m2 -26. A re2  in child2.Child system consists of four subsystems: an implantable pump system, an external controller system, an external Clinical Data Acquisition System and an external Patient Home Support System. The blood pump, intended to provide mechanical assistance to the failing left ventricle, is a miniaturized, implantable, titanium, electromagnetically actuated axial flow pump. The pump is 1.2 inches (30.5 mm) in diameter, 3.0 inches (76.2 mm) in length and weighs 95 grams. A titanium inflow cannula connects the pump to the ventricular apex and a Vascutek Gelweave vascular graft (outflow conduit) connects the pump to the aorta. Blood flow from the pump is measured by an ultrasonic flow probe placed around the outflow conduit. The flow probe's wiring is bundled with the pump motor's wiring in a polymer-coated assembly. The cable assembly exits the skin superior to the iliac crest on the right frontal portion of the body and attaches to the VAD's external controller system.The DeBakey VAD 2 and < 1.5 m2) who are in NYHA Class IV end stage heart failure, are refractory to medical therapy, and who are listed for heart transplantation. Its use in children has been limited to date. A recent report by Fraser et al. [Child. The average age of the patients was 11 years  with a BSA of 0.8 to 1.7 m2. The average duration of support was 39 days, with 84 days being the longest duration of support. Three of these patients were successfully transplanted, whereas three died during support before transplantation.The DeBakey VAD Child was authorized by the U.S. FDA (February 2004) for use in providing temporary left side mechanical circulatory support as a bridge to heart transplantation for pediatric patients . They provide a long term bridge to heart transplantation while allowing extubation, ambulation, and active physical therapy, unlike ECMO or centrifugal pump VADs. While the Berlin Heart EXCOR system has been used successfully in Europe since 1991, the U.S. FDA has only recently approved the use of the Berlin Heart EXCOR Pediatric VAD under a limited investigational device exemption in the USA. These extracorporeal systems have provided successful MCS in children of all ages . The pump is made of a translucent, semirigid housing of polyurethane divided into a blood chamber and an air chamber by a three layer flexible diaphragm. Available pump stroke volumes are 10, 25, 30, 50, 60, and 80 mL. The blood flow is directed by trifleaflet polyurethane valves mounted in the pediatric pumps , whereas either tilting disc valves  or trileaflet polyurethane valves are available for the adult pump sizes . All blood-contacting surfaces inside the pump, including the polyurethane valves, are coated with heparin by the Carmeda process . Cannulae are designed in various configurations to allow biventricular support for all age groups. They are made of silicone rubber with a smooth internal surface. The outside of the cannulae is covered with a Dacron  velour surface at the contact site with the abdominal wall to encourage scar tissue ingrowth, thereby minimize ascending infections . The cannulae are designed to produce a considerably reduced afterload to the native heart in comparison with conventional CPB cannulae. All Berlin Heart EXCOR cannulae are made to exit the body through the upper abdominal wall. Inflow cannulation for the left ventricular assist device is typically completed via the left ventricular apex and outflow cannulation is to the ascending aorta. Right atrial to main pulmonary artery cannulation is the preferred method for right-sided support. The driving subunits apply negative pressure to facilitate inflow and positive pressure to drive outflow. There are three compressor subunits. Two are driving the right and left pumps and the third is a backup unit which will take over in case of a subunit failure. The backup unit is designed to allow adequate biventricular positive/negative pressures at a constant rate of 90 per minute should both subunits malfunction simultaneously. Manual operation of the pump is possible in case of complete electrical failure. The maximum positive driving pressure is 350 mm Hg, and the maximum negative driving pressure is minus 100 mm Hg. The available biventricular operating modes are synchronous, where both ventricles are filled and emptied in concert, asynchronous, where one ventricle is filled while the other is emptied, and separate, where each ventricle is cycling independently [The Berlin Heart VAD  consists of a paracorporeal, pneumatically driven pump . Whereas in period 1 there were no survivors in the group of children younger than 1 year old, during period 2, survival in this age group was similar to that of the two groups of older children (p =0.024). There was a significant improvement in the discharge rate in period 2 in patients with cardiomyopathy  and postcardiotomy heart failure . The significant difference in outcomes is reflected in the experience accumulating worldwide in MCS for children.A recent retrospective analysis performed by Hetzer and associates in Berlin  comparedet al. at Stanford, California have described their experience in 8 children, aged 4 to 55 months [The first child implanted with the Berlin Heart EXCOR in North America  was a 9 year old child with tricuspid insufficiency . Over 165 months . All patWe have implanted Berlin Heart BiVADs in 13 patients from April 2005 to August 2008  The medi1.Our experience, albeit limited, demonstrates the feasibility of routine use of biventricular (BiVAD) support in pediatric patients. Children, unlike adults, tend to have significant biventricular involvement as well as increased pulmonary vascular resistance associated with severe decompensated heart failure. The pediatric sized hardware facilitated the implantation, and other than slightly longer operative times, we have not encountered significant disadvantages to the addition of the right VAD. We propose that BiVAD support simplifies postoperative management by elimination of the adverse pathophysiological consequences of right ventricular dysfunction. Another significant benefit is improved liver synthetic function contributing to better control of postoperative coagulopathy as well as intravascular oncotic pressure. Adequate oncotic pressure may promote optimization of extravascular lung water as well as better renal perfusion and diuresis. These beneficial physiological consequences may facilitate earlier extubation and therefore more expeditious recovery.et al. [et al. [Criteria to guide decision making in regards to the need for biventricular support are not clear-cut. Studies performed by Farrar et al. , and Kor [et al.  in adult2.et al. in 2002 [Current studies support the use of MCS as a bridge to transplantation . Both in in 2002 . With in3.et al. [et al [According to the experience of Hetzer et al.  which waet al.  had no n. [et al , and the4.et al. [et al. [Patients with implantable VAD are at risk for developing antibodies to HLA during support. HLA sensitization is defined as didithiotreitol-treated T-cell panel-reactive antibody (PRA) titer greater than 10% immediately before transplantation. Data presented by McKenna et al.  suggest  [et al. , alloimu [et al. .5.2 unresponsive to pulmonary vasodilator therapy alone, Rpi decreased to 1.4 and 4.6 WU x m2, after 33 and 41 days of support, respectively. Pulmonary vascular resistance remained normal without pulmonary vasodilators in these patients within 3 months after heart transplant.Based on our experience ,even chiThe need for pediatric miniaturized long-term MCS devices fit for use in all age groups including neonates led the U.S. National Heart, Lung, and Blood Institute (NHLBI) to provide funding for their development . The NHL


Patients with heart failure and ischaemic heart disease may obtain benefit from revascularisation if viable dysfunctional myocardium is present. Such patients have an increased operative risk, so it is important to ensure that viability is correctly identified. In this study, we have compared the utility of 3 imaging modalities to detect myocardial scar.Prospective, descriptive study.Tertiary cardiac centre.35 patients  with coronary artery disease and symptoms of heart failure (>NYHA class II).99Tc-Sestamibi (MIBI), 18F-flurodeoxyglucose (FDG) and cardiac magnetic resonance (CMR).Assessment of myocardial scar by The presence or absence of scar using a 20-segment model.More segments were identified as nonviable scar using MIBI than with FDG or CMR. FDG identified the least number of scar segments per patient . The strongest agreement between modalities was in the anterior wall with the weakest agreement in the inferior wall. Overall, the agreement between modalities was moderate to good.There is considerable variation amongst these 3 techniques in identifying scarred myocardium in patients with coronary disease and heart failure. MIBI and CMR identify more scar than FDG. We recommend that MIBI is not used as the sole imaging modality in patients undergoing assessment of myocardial viability. Coronary artery disease is the most common cause of heart failure in the Western world.99Tc-Sestamibi (MIBI), 18F-flurodeoxyglucose (FDG) and CMR, with a particular emphasis on the identification of scar by each imaging modality.Patients with impaired left ventricular function represent a higher operative risk group than patients with normal LV function. Recent reports indicate that the perioperative mortality after CABG in patients with advanced LV dysfunction varies between 2.5%–8%. This is compared to standard CABG mortality of less than 2%. In addition, LV dysfunction is a variable on standard scoring systems for assessing likely mortality such as the Euroscore/Parsonnett systems.Subjects were referred for viability assessment if the assessing clinician felt that the patients might benefit from intervention for coronary artery disease in the context of clinical heart failure. Medical management was optimised and all were clinically stable prior with at least NYHA class II symptomatic heart failure. Forty six patients were studied over a 24 month period. MR scans were not undertaken in 4 subjects with implanted devices (pacemakers or defibrillators) and 3 were too large for the modified gamma camera. The images obtained from four of the FDG scans were not of diagnostic standard and were classed as technical failures such that complete data from all three imaging techniques was available for 35 patients. The baseline characteristics are shown in Assessments were undertaken on separate days according to the standard clinical protocol described below. None of the subjects reported a clinical event during the period of testing. The studies were reviewed by at least two cardiologists/ radiologists blinded to clinical data. A 20-segment model was used with 2 apical segments, and 3 radial layers of 6 segments at apical, mid and basal levels using short axis slices. This model was chosen as the software package for SPECT studies in our institution generates a 20 segment model and the AHA consensus statement supports a 20 segment model for this technique.99mTc MIBI (400 mBq) was administered for both the rest and the stress studies and images acquired with gated SPECT on a dual headed gamma camera (GE Millenium VG) at least 90 minutes post administration of radiopharmaceutical. Acquisition was performed over a 360 degree arc using a standard parallel hole collimator. Subsequent data reconstruction and analysis was performed with QPS/QGS software  for production of bulls-eye plots/gated EF assessment respectively, on a dedicated Entegra workstation . Ejection fraction was obtained from the gated rest images. Viability was defined as uptake >60% of maximal pixel intensity on the resting image as described in the CHRISTMAS trial.12A two-day protocol was used with stress and rest scans at least 24 hours apart. Adenosine was used in the majority of cases as the stress agent at a dose of 140 mcg/kg/min for a period of 6 minutes, with tracer being injected at 3 minutes. Dobutamine was used as an alternative stress agent in subjects with significant airways disease. Sublingual nitrates were administered in all cases prior to the isotope injection during the rest study. 18F-fluorodeoxyglucose (FDG) uptake. The average glucose infusion rate during the equilibrium phase of the clamp was 4.2+/−1.7 mg/kg/min. At least 80 minutes after commencement of insulin (during clamp steady state), FDG (185 MBq) was injected and scanning performed 30 minutes after injection of isotope. Images were acquired on the same gamma camera as the MIBI studies using high energy collimators to facilitate coincidence mode, and corrected for attenuation using X-rays. Images were analysed using an Entegra workstation and Cedars-Sinai software . A segment was considered viable if uptake was >50% of the maximum pixel intensity.13Subjects were fasted for at least 6 hours. A hyperinsulinaemic euglycaemic clamp was performed to standardise metabolic conditions and to maximise myocardial Patients were imaged using a 1.5T GE Signa CV/i scanner  with a four channel cardiac phased array coil. Cine images were acquired by steady state free precession imaging in the short axis, 2 chamber and 4 chamber cardiac planes . Technical parameters: TR 3.5, TE 1.3, flip angle 45 degrees, 0.75 NEX, matrix 224 × 128, FOV 36 × 36 cm, 75% phase field of view.Viability imaging (“delayed enhancement”) was performed 10–30 minutes following a total bolus of 0.2 mmol/kg of gadolinium chelate  using an inversion recovery-prepared gradient echo pulse sequence. The optimal inversion time was individually adjusted for each patient. Images were acquired in matching locations to the cine images. Technical parameters: TR 7.2, TE 3.2, flip angle 15 degrees, matrix 256 × 192, trigger delay 500 msec, 75% phase field of view, inversion time individually matched to patient (range 180–220 msec).Polar viability maps were constructed based using the same 20 segment model as above, and viability defined as wall thickness >6 mm without delayed gadolinium enhancement.15Volumetric measurements from the MR data set were made by importing the short axis steady state free precession cine images into a dedicated off line workstation with appropriate software .Statistical calculations were performed using Statview 4.5 . Numerical values are presented as mean +/− standard deviation. Comparisons between group means were carried out by analysis of variance (ANOVA). The agreement between the 3 imaging modalities to detect cardiac scar on a segment by segment basis was assessed using κ statistics. K values of less than 0.4, of 0.4 to 0.75 and greater than 0.75 were considered to represent poor, moderate to good and excellent agreement respectively on the basis of the Fleiss classification.The total number of scarred segments per patient for each imaging modality is shown in A significantly higher number of segments were identified as scar by MIBI than by either FDG or CMR. The over-estimation of scar by MIBI was independent of site within the left ventricle as shown in The best agreement between modalities was seen in the anterior wall with virtually no difference in the number of scar segments seen by MIBI, FDG and CMR. The worst agreement occurred in the inferior wall with an 87% difference between MIBI and FDG. An example of this discrepancy is shown in The patients were divided into tertiles on the basis of resting ejection fraction determined from the gated MIBI scan. As might be expected, those patients with more marked left ventricular dysfunction demonstrated significantly more scar than those with more preserved ventricular function . Again tThere is an increasing evidence base to support revascularisation in the context of viable ischaemic myocardium.per se. Only 2 out of 35 patients were diabetic and excellent suppression of myocardial FFA utilisation was achieved in all patients with the insulin clamp method. Whilst preserved myocardial metabolic activity using FDG during hyperinsulinaemia is often regarded as the gold standard to assess viability, our findings suggest that there is no clinically significant difference between FDG imaging and CMR for viability assessment. We chose to define non viability at CMR primarily by end diastolic wall thickness and used presence of delayed enhancement as a secondary criterion. This is because there remains some controversy about the exact degree to which trans-mural extent of scar identified by gadolinium correlates with non recoverability of function. It can also be difficult to accurately delineate quartiles of transmurality in regions of severely thinned myocardium where an overall measurement of end diastolic wall thickness is potentially more reliable and reproducible. Although delayed enhancement at CMR may reflect uptake into an expanded interstitial space in addition to delayed washout from scar following acute myocardial infarction, this consideration was not relevant to our sample since no patients were studied within 6 months of an acute coronary event and the majority were suffering from chronic ischaemic cardiomyopathy.There is a relatively close agreement between FDG and CMR although variation exists between these two modalities that may reflect the limited spatial resolution and/or partial volume effects associated with FDG imaging using a modified gamma camera that would tend to limit delineation of scar.One aspect of this work requiring consideration is the homogeneity of our patient population. A small number of patients had minor atheroma or only single vessel disease raising the question of whether they were incorrectly classified as ischaemic rather than dilated cardiomyopathy. However it is well accepted that infarction frequently occurs on low grade stenoses and a subendocardial pattern of infarction characteristic of coronary disease was seen by delayed enhancement CMR in all but one of these patients. The ability of CMR to distinguish between heart failure secondary to coronary disease from that due to other forms of cardiomyopathy has been well described previously.In this study we used end diastolic wall thickness (EDWT) as our major determinant of viability by MRI. It is generally accepted that transmural extent of late gadolinium enhancement (LGE) is the gold standard for determining myocardial viability. However, the LGE technique is more challenging in the severely breathless heart failure patient due to altered blood pool kinetics and limited achievable spatial resolution (due to impaired patient breath hold ability) in areas of myocardial thinning. A navigated free-breathing approach to LGE image acquisition was discounted because of the length of time necessary to acquire a full volume data set in these enlarged left ventricles. Nonetheless EDWT is a reasonable surrogate that has been used many times in earlier literature and remains a valid measure.The limitations of this study also include the relatively small number of patients assessed and the lack of attenuation correction as discussed above. This is likely to increase the agreement between MIBI and the other imaging modalities but should not influence the agreement between FDG-SPECT and CMR. This can only be clarified by defining the extent of functional recovery following revascularisation, which we believe is the most significant limitation of this study.In summary we present data obtained in a clinical service using three common imaging techniques in a group of patients. We suggest that technetium MIBI should not be used to define myocardial viability where more accurate methods exist. Local resource availability and patient characteristics may well dictate the use of FDG-PET or CMR and our data suggest that there is little practical difference between these two modalities.


The purpose of this study was to measure regional contractile function in the normal rat using cardiac cine and tagged cardiovascular magnetic resonance (CMR) during incremental low doses of dobutamine and at rest.Five rats were investigated for invasive left ventricle pressure measurements and five additional rats were imaged on a clinical 1.5 T MR system using a cine sequence  and a C-SPAMM tag sequence . For each slice, wall thickening (WT) and circumferential strains (CS) were calculated at rest and at stress .Good cine and tagged images were obtained in all the rats even at higher heart rate (300–440 bpm). Ejection fraction and left ventricular (LV) end-systolic volume showed significant changes after each dobutamine perfusion dose (p < 0.001). Tagged CMR had the capacity to resolve the CS transmural gradient and showed a significant increase of both WT and CS at stress compared to rest. Intra and interobserver study showed less variability for the tagged technique. In rats in which a LV catheter was placed, dobutamine produced a significant increase of heart rate, LV dP/dtmax and LV pressure significantly already at the lowest infusion dose.Robust cardiac cine and tagging CMR measurements can be obtained in the rat under incremental dobutamine stress using a clinical 1.5 T MR scanner. The clinical hallmarks of hibernating myocardium in chronic ischemic patients include regional contraction deficit while retaining an inotropic reserve during a low dose dobutamine challenge. Experimental models on rodents aiming to reproduce myocardial hibernation require an accurate quantification of the contractile reserve measured after low dose of dobutamine. Currently, two modalities echocardiography  and cardCine CMR consists in the acquisition of the same slice position at different phases of the cardiac cycle. It allows the assessment of left ventricle (LV) size and shape as well as global LV function and wall thickening -6. In noIntra-myocardial mechanisms including wall motion strains and/or torsion angle, can be measured when presaturation tag pattern (CMR-tagging) is added to cine imaging. The basic principle is to tag the myocardium physically using spatially selective saturation pulses and to track the displacement of the tagged myocardium. CMR-tagging has been well demonstrated in normal rats -10. MyocThe purpose of the present study was to evaluate the effects of low dose dobutamine on the myocardium contraction in rat using tagged and cine CMR on a 1.5 T clinical system.Sprague-Dawley rats (weighing 385 ± 30 g) were included in the protocol approved by the ethical committee of our institution. Five rats were used for MR imaging, and five additional rats were investigated for invasive LV pressure measurements.Ten normal adult 2: 0.4). The rats were placed in a cradle in prone position. A rectal thermal probe with a heating system maintained the rat's temperature constant (37.0–37.5°C). A respiratory pillow was placed under the abdomen to monitor respiratory rate. Subdermal electrodes recorded an electrocardiogram (ECG) that was used to trigger the MR system. The monitoring devices were connected with optical fibers to a computer during the MR acquisitions , Stony Brook, NY, MR-Compatible Model 1025 Monitoring and Gating System). Using this set-up, the physiological parameters of the rats were continuously measured in real time during the whole experiment.All images were acquired on a clinical scanner at 1.5 T with a microscopic surface coil (47 mm diameter) . Anesthesia was induced and maintained with isoflurane 3% administered by a facemask, with animals breathing spontaneously oxygen enriched air  30°, 288 × 288 matrix sampled on a Cartesian grid, 80 mm FOV and 2 mm slice thickness yielding an acquired voxel resolution of 0.28 × 0.28 × 2 mm. Eleven to twenty cardiac phases were acquired per R-R cycle depending on the heart rate. 2 short axis levels and two- and four-chambers were realized at rest and for each dobutamine dose.Tagged CMR was obtained by using a C-SPAMM tag preparation segmented cine fast field echo sequence, TR/TE 7.8/3.6 ms, tag spacing 1.25 mm, acquired voxel size 0.63 × 1.79 × 3 mm, FA 10°. The inter image was about 8 msec yielding to 18–25 phases per cardiac cycle. 2 short axis levels were realized at rest and for each dobutamine doseDobutamine 0.5%  diluted to a final concentration of 50 μg/ml with isotonic saline was consecutively administered for 20 min as a continuous intravenous infusion at 2.5, 5 and 10 μg/min/kg rate of injection by means of a continuous infusion pump : CMR image acquisition started once the heart rate was stabilized (between 5 and 10 min after start of drug infusion).2, 0.4) at a tidal volume of 7 ml/kg body weight and a respiratory rate of 70 bpm with a constant volume-cycled rodent ventilator . A positive end-expiratory pressure of 2.5 cm H2O was applied. Anesthesia was maintained with 1.4% isoflurane. Respiratory gases and airway pressure were continuously monitored. A 3-lead ECG was recorded on a Hewlett-Packard monitor using subcutaneous electrodes. The femoral vein was cannulated for drug infusion and the carotid artery for continuous arterial blood pressure monitoring using a calibrated pressure transducer . Through a left thoracotomy, the heart was exposed and a 20-cm long polyethylene catheter  connected to a second calibrated pressure transducer was placed into the LV through the apex for continuous LV pressure measurement. The transducers were further connected to a pressurized continuous normosaline filled flushing system . Meticulous care was taken to ensure that the catheters and pressure transducer systems remained free of air bubbles during the experimental protocol. The thorax was then closed.Animals were conditioned similarly as for imaging and anesthetized with isoflurane by facemask, intubated and mechanically normo-ventilated with oxygen-enriched air  on an Acer microcomputer for further off-line analysis. Rectal temperature was maintained constant with a heating pad.2: 0.4) and documentation of normal pH and PaCO2 concentration by arterial blood gas analysis, the stress study was started. Systolic, diastolic and mean arterial pressure, heart rate, LV systolic and end-diastolic pressures, the maximal rate of pressure development (LV dP/dtmax), and peak LV pressure were measured during baseline conditions and during a dobutamine challenge identical to the protocol used during the MR sessions.After a stabilization period of 30 min under stable isoflurane anesthesia (0.85%) with animals breathing spontaneously oxygen enriched air (FIO. Left ventricle ejection fraction (LVEF) was assessed for each animal with MR cine images according to: LVEF(%) = (Vdiast - Vsyst)/Vdiast. End-diastolic (Vdiast) and end-systolic (Vsyst) volumes were calculated by manually drawing endocardial contours and long axis length at end-diastolic and end-systolic phases for each axis. End-diastolic and end-systolic volumes were calculated according to the Simpson's modified method [basal+2/3 × Aapex) with Abasal, diastolic or systolic basal area; Aapex, diastolic or systolic area and length, diastolic or systolic long axis length.Image analysis was performed using the open source software OsiriX d method : Volume Regional contraction analysis was performed by measuring myocardium thickness changes between diastolic and systolic phases on cine images. Endocardium and epicardium boundaries were manually segmented on end-diastolic and end-systolic phase images. The myocardial slices were then divided in 128 evenly spaced radial sectors and then averaged into six main sectors. The wall thickening was obtained by subtraction of diastolic and systolic radii lengths.syst - CSdias). We defined CSepi, CSmid and CSendo at epicardial, midwall and endocardial levels respectively by dividing the wall thickness in thirds.The tag analysis was performed with the Extrema Temporal Chaining (ETC) algorithm. ETC algIntra and inter observer study: three observers were blinded of dobutamine administration and pathological status of rats. Two rats were analyzed in this way including 2 short axis levels per animal, at rest and under stress (3 doses), yielding 16 slices per sequence. Each observer performed three measurements with at least a one week interval between each measurement.Value per sector of the three observers or different measurement were averaged and the ratio of the standard deviation by this mean was obtained for each sector to compare the intra and inter observer variability percentage in cine and tagged images.All data are presented as means ± standard deviation. Data from the invasive hemodynamic studies were averaged over the last 10 heart beats before switching to the next dobutamine dosage. The difference between doses groups and modalities were determined by using an one-way ANOVA with repeated measures design followed by post hoc Newman-Keuls multiple comparison test. All data are expressed as means ± standard deviation. A p value less than 0.05 was considered statistically significant.In rats in which a LV catheter was placed, dobutamine produced the well known expected chronotropic and inotropic effects fig. . Both heRegarding the imaging study, high image quality of both cine and tagged CMR was obtained in all the rats at rest and after dobutamine as shown in figure Dobutamine induced a progressive and proportional decrease in the end systolic volume of the left ventricle p < 0.001) without any significant changes in the end diastolic volume (p > 0.05) as presented in table  without According to both intra and interobserver studies, tag analysis was less variable and more reproducible than the wall thickening measurements from the cine table . At restThis study demonstrates that cine and tag CMR acquired on a 1.5 T clinical MR system are sensitive enough to detect the effects of a low dose dobutamine challenge on the cardiac function of normal rats. Even at the lower dobutamine dose of 2.5 μg/min/kg a positive inotropic effect can be measured by CMR in small animals.Both cine and tag sequences allow to obtain a high image quality with high spatial and temporal resolution. Either in rest or stress conditions, regional and global cardiac function changes were well depicted by cine or tagged methods. Especially, the cine sequence had a superior spatial resolution compared to the C-SPAMM sequence, but a lower temporal resolution (inter-image 15 msec vs. 8 msec for tag sequences). According to our CMR sequence, the inter-image delay was equal to the TR. Due to the gradient limits of our MR system, it was not possible to decrease the minimum TR at the FOV needed to image rodent. According to the Nyquist-Shannon sampling theorem, a time series must be sampled at least twice as fast as its largest frequency component for an exact reconstruction. At a cardiac heart rate of 350 bpm, 6 harmonics are sampled during a cardiac cine with an inter-image delay of 15 msec. As deduced from the simulations of Setser et al , less thWe observed a good agreement between the global function measured with CMR cine images and hemodynamic parameters. The absence of change of the LVEDV and the decrease of the LVESV are well correlated with the LV end-diastolic pressure and the peak LV pressure respectively. The contractility expressed as the dP/dt value is in accordance with the MR regional contraction measurement using wall thickness measurements from the cine CMR. The increase of wall thickening by dobutamine as measured by cine CMR was similar to previous studies performed by Nahrendorf et al ,19. The The intra and inter-observer analysis reveal a powerful advantage of the use of tagged images for the regional contractile function assessment in rat. Both intra and inter observer variability are around 10% for midwall circumferential strains whereas variability increased to 25% for wall thickening. Consequently, tagged images appear more suitable for regional contraction measurement as already published . In partCine CMR seems to be more affected by operator. The main difficulty in wall thickening measurement remains the myocardium segmentation. Endocardial and epicardial boundaries were manually drawn since no accurate automatic tools are available. The absence of contrast between myocardium and thoracic muscle increases the difficulty to well delineate epicardium. Since wall thickening is dependant of four contour drawings, an error of only one contour will directly be reported on wall thickening measurement. Cine images are however suitable for a global function evaluation. Due to a high contrast to noise ratio between left ventricle cavity and myocardium, endocardium segmentation is easily performed and left ventricle end systolic and end diastolic volumes can be accurately assessed. The results of ejection fraction variability (less than 3%) which is consistent with previous published results in rat  confirm The modified Simpson's method was used to measure the left ventricle end systolic and end diastolic volumes instead of a summation of continuous short axis slices covering the entire left ventricle. This choice resulted from the time constraint induced by the dobutamine challenge. The modified Simpson's method requires the acquisition of only 3 slices instead of 5 to 7 slices needed to cover the entire ventricle resulting in a significant time savingThe modified Simpson's method yields a small underestimation of the left ventricle volumes without significant difference in the ejection fraction estimation . TherefoIn conclusion, cardiac cine and tagging CMR with dobutamine stress are feasible in rat at 1.5 T on a clinical system. Both sequences offer consistent measurements of regional cardiac function by comparison to a haemodynamic study. Significant changes were observed with incremental doses, even at the lowest dose tested (2.5 μg/min/kg). A 18% increase of the EF was observed with the cine CMR for a global function evaluation at high dobutamine dose whereas the increase was 33% for the tagging method in regional contractile function assessment. In addition, tag CMR permits a sub-endocardial examination and appears to be an excellent tool to quantify accurately and rapidly the heart function with a low observer variability that could particularly valuable to monitor pharmacological interventions.The authors declare that they have no competing interests.JLD carried out the design of the study, MR acquisition and analysis, wrote manuscriptJPJ developed the tag analysis software. JNH participated in the MR acquisition, sequence development and results discussion. PC participated in the design of the study and helped to draft the manuscript. KMA carried out the animal sacrifice and post mortem analysis. SR and DB participated in the intra and inter observer study. MLC participated in the MR acquisition and in the intra and inter observer study. DM carried out the hemodynamic studyJPV carried out the design of the study and its coordination, participated in manuscript writing. All authors read and approved the final manuscript.


We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed 165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGFOur data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood. Epidemiological studies have shown that intrauterine stress, reflected by intrauterine growth restriction and low birth weight, increases the risk of developing cardiovascular diseases later in life In experimental models of embryonic hypoxia, it has been found that chronic hypoxia results in growth restriction, aortic remodeling, sympathetic hyperinnervation, and left ventricular (LV) pump dysfunction in the embryo We report that chronic hypoxia in chick embryos resulted in LV dilatation and several other structural and functional hallmarks of cardiomyopathy. Left ventricular dilatation and signs of cardiomyopathy persisted into adulthood and were, at least partly, secondary to increased VEGF levels.2 throughout embryonic development displayed lower arterial blood PO2 levels, elevated hematocrit, and lower total body, liver and heart weights as described previously Chick embryos that had been exposed to 15% Oin vivo by echocardiography revealed reduced LV ejection fractions and confirmed the presence of LV dilatation in hypoxic embryos . LV dilatation was accompanied by increases in myocardial collagen content . To achieve competitive antagonism of VEGF165 binding to NRP1, muscle bundles were co-incubated with Sema3A 165  in hypoxic embryonic hearts provided us the rationale for studying the role of this hypoxia-responsive cytokine. We show in vivo that both conditions of increased and decreased VEGF-A levels have an essential role in the origin of the cardiac disease. First, exposing normoxic embryos to rhVEGF165 initiated LV dilatation and loss of wall mass. Vice versa, scavenging VEGF-A with sFlt-1 in hypoxic embryos prevented LV dilatation and loss of wall mass, and restored LV ejection fraction and muscle bundle contractility to levels resembling normoxic embryos. In contrast, diastolic properties remained unchanged in E20 hypoxic embryos after sFlt-1 treatment, suggesting separate mechanisms for systolic and diastolic dysfunction. It has been reported that reduced cardiac VEGF signaling interferes with myocardial angiogenesis, resulting in local ischemia, which triggers cardiomyocyte damage and heart failure The increased expression of large VEGF-A isoforms  or 15% O2  throughout embryonic development as described previously 2. Structural and functional analysis of adult hearts was performed at 8 months after hatching. Chick embryos and adult chickens were sacrificed by decapitation.Fertile White Leghorn eggs were incubated at 21% O2. LV cross-sectional area was measured on formalin-fixed sections . Consecutive paraffin-embedded 5-µm sections were stained with hematoxylin and eosin (HE), PAS, and trichrome Masson to visualize tissue fibrosis. The area of fibrotic tissue was quantified by computer software . Ultrastructural analysis of epoxy resin embedded hearts was performed on 70-nm sections.Hearts were fixed during diastole using 100 mmol/L CdCl2-EDTA; pH 7.4). Leupeptin (0.5 mmol/L) was added to prevent protein degradation. Protein content was determined by the Micro BCA method . Samples (20 µg protein) were loaded on a 2% SDS-polyacrylamide slab gel reinforced with agarose and electrophorized using a Mini-PROTEAN II electrophoresis system . Fairbanks running buffer was used for electrophoresis and the conditions were 7.5 mA/gel for 30 min and 15 mA/gel for 5 hours Hearts from normoxic and hypoxic E20 embryos were excised, snap-frozen, and stored at −80°C. Left ventricular tissue samples were homogenized in 4 mL SET-buffer , and heating was adjusted to maintain a body temperature between 36 and 38°C. All feathers were removed from the abdomen by gentle shaving. Pre-warmed gel was applied to the precordium as an ultrasound coupling medium . Chick embryo hearts were imaged transcutaneously using the ultrasound biomicroscope (UBM) and a 30 MHz or 40 MHz transducer operating at 30 frames/s . Generally, the heart was first imaged in the two-dimensional (2-D) mode in the short-axis view. Images from this view were used to measure left ventricular (LV) cross-sectional area. Images were stored on harddisk for review and analysis. LV end-diastolic diameter (LVEDD) was measured from the M-mode tracings of the maximum chamber cavity. All measurements were performed from leading edge to leading edge according to the American Society of Echocardiography guidelines. Ejection fraction was calculated from the LV cross-sectional area (2-D short-axis view) using the equation EF (%) = [(LVDA−LVSA)/LVDA]×100; where LVDA is LV diastolic area and LVSA is LV systolic area. All primary measurements such as LV wall thickness, dimensions, and cross-sectional areas were traced manually and digitized by goal-directed, diagnostically driven software installed within the echocardiograph. Three beats were averaged for each measurement.2+-free solution . A thin subendocardial LV muscle bundle was excised in parallel with fiber direction, mounted in an organ bath with HEPES buffer  between a rigid hook and a force transducer connected to a micromanipulator for length adjustment, as described Hearts were in situ perfused with 0.2 mL heparin (5000 U/mL), and immediately after surgical resection placed in a Camax. Generated force was defined as peak systolic minus diastolic force and normalized to cross-sectional area (mN/mm2) by optical measurement of the smallest diameter of the bundle assuming cylindrical geometry. Muscle bundles were stretched until the fiber length was reached which provided maximal active force generation (100% Lmax). For standardization purposes, all further experiments were performed at 100% Lmax after a resting period of 5 minutes. Isometric contractile force development was measured in response to increasing extracellular calcium (2–12 mmol/L). Relaxation properties of the LV muscle bundles were assessed by measuring the time to 50% relaxation during diastole in these experiments.After an equilibration period of 10 minutes, the muscle bundle was paced by external field stimulation with rectangular pulses  at a frequency of 1 Hz. This resulted in isometric contraction of the fiber. Subsequently, the muscle was stretched in steps of 218 µm. Passive tension (mN) was determined by measuring force during diastole, i.e. unstimulated force, at incremental bundle lengths 165121165+130 ng/mL sFlt-1, 100 ng/mL rhVEGF165+130 ng/mL rhSema3A , 100 ng/mL rhVEGF165+50 µmol/L SU5416 (Sigma), or HEPES buffer alone.In separate experiments, contractility of LV muscle bundles from normoxic E20 chick embryos was measured after 4 hours incubation with: 100 ng/mL rhVEGFin vitro by measuring fractional shortening of isolated rat cardiomyocytes in response to rhVEGF165 or rhPlGF-1 (500 ng/mL) using a Ionoptix Contractility System  The effect of VEGF was further defined in vivo molecular imaging using annexin-V Real-time PCR for atrial natriuretic factor (ANF), VEGF, VEGFR-2, and NRP1 was conducted using the My iQ iCycler and iQ SYBR Green Supermix (both Bio-Rad) . Semi-qu165 in hypoxia-induced LV dilatation, normoxic chick embryos received a daily systemic dose of rhVEGF165  between E10 and E19. Vice versa, hypoxic embryos were treated with sFlt-1  between E10 and E19 To test the involvement of VEGFData are expressed as mean±SE. The term n refers to the number of animals. Multiple comparisons were made using the non-parametric Mann-Whitney U test. Statistical significance was defined as P<0.05.


Left atrial size is an important marker for adverse cardiovascular events. There is general consensus that left atrial volume index (LAVI) is the best measurement of size. The current LAVI measurement techniques are laborious. Semi-automated measurement with a 3-dimensional echocardiography (3DE) system may be a practical clinical alternative to measure LAVI, but it has not been adequately evaluated against Magnetic Resonance Imaging (MRI) gold standard. The aim of this study was to compare the accuracy of a commercially available 3D algorithm for measurement of LAVI against LAVI obtained from MRI and Area Length Method (ALM).In 27 consecutive subjects referred for cardiac MRI , LAVI was measured using 3 imaging modalities: 3DE, ALM, MRI and the results were correlated. ALM was measured using standard American Society of Echocardiography guidelines. The time required to measure LAVI by 3DE and ALM were compared.P < 0.0001 for all). There was also significant correlation of diastolic volumes between 3DE and ALM . The time to obtain LAVI was shorter using 3DE versus ALM .There was a significant correlation in systolic and diastolic LA volumes and left atrial ejection fraction between 3DE and MRI (r = 0.86 for systole, r = 0.76 for diastole, r = 0.88 for ejection fraction, Three-dimensional echocardiography with semiautomatic border detection is a practical alternative for obtaining the left atrial volume in a time-efficient manner compared to the current standard. Left atrial (LA) size is an independent marker of adverse clinical outcomes in conditions such as atrial fibrillation, myocardial infarction and heart failure -6. AlthoThis study was approved by the Medical College of Wisconsin's Institutional Review Board. From April to December 2006, subjects who were referred for cardiac MRI for any indication were asked to participate in the study consecutively. Other inclusion criteria were age 18 years or older and willingness to provide informed consent. Exclusion criteria were presence of prosthetic valves, supraventricular or ventricular tachyarrhythmias at the time of image acquisition, known congenital heart disease and inability to complete cardiac MRI study due to claustrophobia. All consenting subjects were included and no subjects were excluded due to suboptimal image quality.Patients were positioned in the left lateral decubitus position. The echocardiogram was either obtained immediately following MRI or within 48 hours before or after the MRI. All measurements were performed off-line using Xcelera, QLAB and 3DQ-Advanced software . The real-time 3D images were acquired using an X3-1 matrix transducer on Phillips IE33 . Apical full-volume images were acquired over 4 cycles. The image was aligned in order to obtain the optimal border delineation of the left atrium in the far field. The 3D longitudinal axis was aligned parallel to the left atrium's axis. The 3D transverse axis was placed at the level of the left atrium where it crossed the 3D longitudinal axis approximately at the left atrium's geometric center point Fig . MaximumThe time required to measure the LA volume by ALM and 3D techniques were compared. The 3D measurement time period included the interval from launching the 3D application, aligning the image for LA volume calculation in atrial diastole and then marking the 5 points until the border tracing algorithm was completed and then indexed manually to body surface area. Timing of the ALM began with area and length measurements, and included the time to enter the measured values and body surface area into the custom calculator. The measurements were performed independently by authors (RA and LH) who were blinded to MRI results.Left atrial volume index was measured using cardiac gated steady state free precession cine pulse sequence of contiguous short axis slices . The left atrial border was manually traced . Clinical characteristics are detailed in Table 2 (P < 0.0001) for diastolic volumes, r = 0.86, Δ -18 ± 11.8 ml/m2 (P < 0.0001) for systolic volumes, and r = 0.88, Δ 11.3 ± 8.2, (P < 0.0001) for left atrial ejection fraction. The diastolic volumes measured by ALM showed significant correlation with MRI as well   .There was a significant correlation between left atrial volumes obtained by 3DE and MRI  Fig. . There wm2) Fig. . When thP < 0.0001). When the 3DE measurements were manually corrected, the time to calculate LAVI was 64 ± 15 sec (P < 0.0001 compared to ALM). The intra- and interobserver variability among the different methods is demonstrated in Table P = 0.006) and 0.893 for ALM (P = 0.002). Using likelihood ratio analysis (sensitivity/(1-specificity)), LAVI of 31 mL/m2 (for 3DE) and 33 mL/m2 (for ALM) had the highest sensitivity (86%) and specificity (80%) to detect left atrial enlargement based on MRI gold standard.The time to calculate LA diastolic volume was shorter using 3DE versus ALM (56 ± 8 sec vs. 135 ± 55 sec, In this study we compared for the first time the LA volume measured by a commercially available 3-dimensional echocardiography system that utilizes semiautomated border detection, to an MRI gold standard and demonstrated good correlation. This technique has furthermore proven to have favorable intraobserver and interobserver variability compared to MRI and ALM.Measurement of LA volume by 3D echocardiography in adult patients has been attempted in the past by Keller and Rodevand in 2 separate studies ,9. The cThe accuracy of MRI measurement of left atrial volume has been validated against water displacement of cadaveric atrial casts by Järvinen and coworkers . Our finIn this study we demonstrated that time to obtain LAVI was significantly shorter using 3DE even with manual correction as compared to ALM measurements when measured off-line. Measurements using both techniques were performed off-line to replicate best clinical-practice guidelines. Although many modern ultrasound systems permit on-line ALM calculation of LAVI, a critical shortcoming is the inability to adjust sonographers' left atrial area tracings by the interpreting physician off-line. In our multi-vendor clinical laboratory, we have overcome this limitation by performing all measurements off-line on images already transferred to the digital reporting system.Our findings suggest that in laboratories equipped with 3D matrix-array transducers and an off-line quantification application, the 3DE is the most time-efficient method of LA volume quantification. This finding, along with good MRI correlation and reproducibility, implies this may be the preferred method of LAVI measurement except in cases when poor image quality prevents automated border detection. Given the prognostic implication of LA size, the ease of 3D derived volume and ejection fraction calculation will allow more routine acquisition of these parameters. In a busy echocardiography imaging laboratory the time saved by the sonographers and readers to calculate such parameters might have significant impact on the efficiency of the lab as well as better patient care.This study was limited by a relatively small sample size. Although we did not have normal subjects, the use of subjects with suspected heart disease makes this study applicable to clinical practice. The study population was biased towards subjects who are undergoing MRI. All subjects had adequate echocardiography acoustic windows and no one was excluded due to poor echocardiographic image quality. Therefore, the study is not biased in terms of echocardiographic imaging quality limitation. The group studied more closely reflects the referral of a tertiary institution with a higher proportion of patients with advanced cardiac disease. The findings should be validated in a larger and more general population reflecting the continuum of left atrial size. In this study we used commercially available software that was originally designed for assessment of left ventricular volume and function and applied it to the measurement of LA volume which explains the ellipsoid shape of the left atrium illustrated in Figure Three dimensional echocardiography with semiautomatic border detection is a practical alternative for obtaining the left atrial volume in a time-efficient manner compared to the current ASE standard and has good correlation with MRI measurements.3DE: 3 dimensional echocardiography; ALM: area length method; ASE: American Society of Echocardiography; LAVI: Left atrial volume index; MRI: magnetic resonance imaging.The authors declare that they have no competing interests.RA was responsible for the conceptualizing and the design of the study, echocardiographic measurements, the statistical analysis and preparation and submission of the manuscript. RQM was responsible for MRI image acquisitions, measurement and had a substantial contribution in finalizing of the manuscript and the statistical analysis. LH was responsible for the coordination of the study, echocardiographic image acquisition and measurement and reviewed the manuscript for relevant intellectual content, MB was responsible for MRI measurements and reviewed the manuscript for relevant intellectual content, TDW was the principal investigator, responsible for conceptualizing and the design of the study and had substantial contribution in finalizing the manuscript.


First-pass perfusion cardiovascular magnetic resonance (CMR) is increasingly being utilized in both clinical practice and research. However, the reproducibility of this technique remains incompletely evaluated, particularly in patients with severe coronary artery disease (CAD). The purpose of this study was to determine the inter-study reproducibility of adenosine stress CMR in patients with symptomatic multi-vessel CAD and those at low risk for CAD.Twenty patients  underwent two CMR scans 8 ± 2 days apart. Basal, mid and apical left ventricular short axis slices were acquired using gadolinium 0.05 mmol/kg at peak stress  and rest. Myocardial perfusion was evaluated qualitatively by assessing the number of ischemic segments, and semi-quantitatively by determining the myocardial perfusion reserve index (MPRi) using a normalized upslope method. Inter-study and observer reproducibility were assessed--the latter being defined by the coefficient of variation (CoV), which was calculated from the standard deviation of the differences of the measurements, divided by the mean. Additionally, the percentage of myocardial segments with perfect agreement and inter- and intra-observer MPRi correlation between studies, were also determined.The CoV for the number of ischemic segments was 31% with a mean difference of -0.15 ± 0.88 segments and 91% perfect agreement between studies. MPRi was lower in patients with CAD (1.13 ± 0.21) compared to those with low risk CAD (1.59 ± 0.58), p = 0.02. The reproducibility of MPRi was 19% with no significant difference between patients with CAD and those with low risk CAD (p = 0.850). Observer reproducibility for MPRi was high: inter-observer CoV 9%, r = 0.93 and intra-observer CoV 5%, r = 0.94. For trials using perfusion CMR as an endpoint, an estimated sample size of 12 subjects would be required to detect a two-segment change in the number of ischemic segments .Adenosine stress CMR, by qualitative and semi-quantitative normalized upslope analyses are reproducible techniques in both patients with multi-vessel CAD and those without known CAD. The robust inter-study reproducibility of perfusion CMR supports its clinical and research application. First-pass perfusion cardiovascular magnetic resonance (CMR) allows non-invasive, rapid and ionizing-radiation-free evaluation of myocardial perfusion and, in combination with other CMR techniques, provides a comprehensive assessment of ischemic heart disease. Stress CMR has high diagnostic accuracy with 91% sensitivity and 81% specificity reported for the detection of coronary artery disease (CAD) -4. In paHowever, despite the appeal and anticipated future application of perfusion CMR in both clinical and research arenas, its reproducibility remains incompletely evaluated, particularly in the severe CAD patient-population. Reproducibility is a measure of the ability of a test to produce the same result when applied under similar conditions. Thus, reproducibility affects test precision, reliability and is particularly important for tests that are used in serial examinations to evaluate response to therapy or for clinical monitoring. Knowing the inherent variability of a technique is critical for interpreting the significance of changes in measurements. For research applications, tests with poor reproducibility require increased sample sizes to reduce statistical error, which would unfavorably increase study duration and costs.R = 0.80-0.85) and inter-observer (R = 0.83-0.88) agreement for good quality images, using the quantitative Fermi deconvolution method. In another study of the qualitative analysis of dobutamine stress CMR in patients with severe Canadian Cardiovascular Society class III-IV angina, an inter-observer agreement, K, of 0.70, and low intra-subject variability were reported [Thus far, only three small studies have reported the reproducibility of perfusion CMR -9. In a The study was conducted between January and September 2009 with the approval of the St Vincent's Hospital Human Research Ethics Committee and with written informed consent from all patients.Patients underwent two CMR scans that were performed on two separate occasions up to two weeks apart. CMR scans were analyzed in random order by two reporters (JM and SC) who were blinded to patients' details. Qualitative analysis was performed by consensus reporting and semi-quantitative analysis was performed by a single reporter (SC). Inter-study reproducibility was assessed by comparing each patient's first and second scans. Additionally, a single short-axis slice (SA) was chosen from 20 randomly selected scans (10 case and 10 control) and semi-quantitative analysis repeated by the same observer (SC) and by a second observer (JM) to assess intra- and inter-observer reproducibility, respectively.Subjects were recruited into one of two groups: CAD (case) or low risk CAD (control). Patients with CAD had angiographically documented multi-vessel CAD (≥70% stenosis in ≥2 major coronary vessels (>2 mm diameter)) and Canadian Cardiovascular Society class II-IV angina. Classification of patients in the low risk CAD group was based on them having a Framingham estimated 10 year coronary heart disease risk of <10% [CMR was performed at St George Hospital (Kogarah) and Specialist Magnetic Resonance Imaging (Camperdown), New South Wales on a 1.5 Tesla scanner  using a five channel cardiac phased-array coil, cardiac gating and repeated breath holds. Each examination involved an assessment of resting ventricular function, first-pass perfusion imaging and late gadolinium enhancement (LGE) imaging for infarct delineation.Cardiac functional imaging was assessed by steady-state free precession cine imaging  in the long and short axis (SA) planes. The basal SA slice was positioned at the level of the atrioventricular valve in end-diastole, with all subsequent cines acquired in 8 mm steps towards the apex. Parameters were: echo time = 1.82 ms, repeat time = 3.6 ms, field of view = 350 × 280 mm, read matrix = 192, phase matrix = 131, frames = 18 heart phases, flip angle = 70°.Myocardial perfusion assessment was performed using a T1-weighted single shot gradient echo sequence with a saturation recovery pre-pulse. Parameters were: echo time = 1.06 ms, repetition time = 3 ms, field of view = 360 × 360 mm, read matrix = 128, phase matrix = 97, reconstruction matrix = 240, voxel size = 2.8 mm × 3.6 mm × 8 mm, flip angle = 20°. Images were acquired over 50 dynamic scans in standard basal, mid and apical SA slices Figure . LGE imaFirst-pass perfusion was assessed using three 0.05 mmol/kg boluses of gadolinium , administered at peak stress, 10 minutes later at rest Figure  and immeImage analysis was performed offline on a Philips View Forum workstation using cardiac analysis software. Segmental analysis was based on an 18-segment model: radial division of each of the three SA slices into six segments with positioning of segment 6 at the insertion of the right ventricle into the inferior septum of the LV Figure . Image qLV volumes, function and mass were derived by manual tracing of epicardial and endocardial borders of contiguous SA slices at end-diastole and end-systole. The end-systolic phase was visually determined as the one with the smallest cavity area and this was then used for all LV levels. Papillary muscles and trabeculae with visible borders in continuity with the endocardium were included in both mass and volume analyses. Perfusion was assessed qualitatively and semi-quantitatively. An automated image stabilizer was applied to correct for gross cardiac motion and images were windowed appropriately to optimize visualization of perfusion defects, with the same parameters used for both stress and rest images. Qualitative analyses were performed by visual assessment of myocardial signal enhancement in each segment. A perfusion defect was defined as any visible hypoenhancement appearing after maximum signal intensity in the LV blood pool  and persisting for at least four dynamics. Perfusion defects were graded by their transmural extent  and degree of hypoenhancement , 2 = probably abnormal (grey defect), 3 = definitely abnormal (black defect)). Segments affected by artefact were graded as 0. An artefact was defined as a defect present at rest but absent at stress, matching stress and rest defects without evidence of infarct on LGE, or segments in the basal SA slice obtained through the left ventricular outflow tract. Transmural and hypoenhancement ischemia indices, reflecting the degree of reversible ischemia, were calculated as a ratio of summed segmental stress-to-rest scores, thus resulting in a grading scale of 1 = no ischemia, >1 and <3 = mild ischemia, and 3 = severe ischemia. Abnormal ischemic segments were defined by segmental transmural ischemia index >1. Myocardial perfusion ratio index (MPRi) was derived from maximal upslopes of stress to rest myocardial contrast signal intensity time curves, normalized to LV input Figure . Myocardhttp://hedwig.mgh.harvard.edu/sample_size/size.html). All data were analyzed on SPSS for Windows, release 17.0 .Within group differences in adenosine dose, hemodynamic parameters and baseline CMR measures were assessed using paired Student's t-test, and differences in symptomatic response using Fisher's exact test. Reproducibility was defined by the coefficient of variation (CoV) . This waTwenty patients (10 low risk CAD controls and 10 patients with CAD) were recruited. Patient characteristics are shown in Table Adenosine-related side effects were reported by the majority of patients Table . The adeThere were no significant differences between control and case patients for baseline LV function, volumes or mass Table . As expeThe two CMR studies were performed at a mean of 7.7 ± 2.2 days apart. A total of 40 scans were performed, providing 104 slices (624 segments) for analysis with equal numbers from case and control groups. In four patients, only two slices were analyzable due to a high heart rate preventing acquisition of all three slices (n = 2), breath-holding problems resulting in the apical slice being positioned too distally (n = 1) and LV outflow tract affecting the basal slice (n = 1). In two patients, only a single slice was analyzed due to a combination of high heart rate and LV outflow tract acquisition in one patient, and gating difficulties in another patient. Overall, image quality for perfusion analysis was considered adequate in all patients with a mean grading of 2.7 ± 0.5 for the first study and 2.8 ± 0.4 for the second study. No significant differences in image quality were detected between case and control groups or between the two studies within each group.As shown in Table Reproducibility for all qualitative measures of myocardial perfusion was high, as demonstrated by consistently low CoVs, high percentage of perfect agreement between studies, and small mean difference between studies Table . ReproduThe inter-study reproducibility for MPRi is shown in Table There was good agreement for MPRi between and within observers, with low CoVs and moderate to high correlation coefficients Table . ReproduWithin-subject variability estimates for the number of ischemic segments, transmural ischemia index and MPRi are shown by the standard deviation of between-study differences for these parameters Table . As showThis study demonstrates that adenosine stress perfusion CMR has good reproducibility for both qualitative and semi-quantitative analyses and in both patients with and without CAD. There is limited published data available for the reproducibility of serial myocardial perfusion imaging modalities, especially for CMR. The inter-study reproducibility of CMR has been demonstrated for LV volumes, ejection fraction and mass ,12, but The reproducibility of qualitative analysis was better than that for semi-quantitative analysis by MPRi: global CoV for all subjects - 19% for MPRi, 8% for transmural ischemia index and 9% for hypoenhancement ischemia index. As fully automated techniques remove observer variability, improved accuracy and uniformity of measures are expected for quantitative compared to qualitative techniques. MPRi by normalized upslope analysis, however, is at best semi-quantitative as it is dependent on the operator to discern endocardial and epicardial borders accurately throughout the cardiac cycle. Furthermore, the occurrence of certain types of artefacts  may impede semi-quantitative analysis but may be overcome by an experienced reporter on visual inspection.In comparison to control subjects, patients with known CAD were expected to have lower inter-study reproducibility for a number of reasons, including increased myocardial scarring from prior infarction, previous coronary interventions (PCI and CABG) generating artefacts, and also poorer clinical condition affecting testing due for example, to an increased susceptibility to ischemia induced arrhythmias or to an inability to breath-hold. As expected, LGE was not detected in the control group but was present in 29% of myocardial segments analyzed in the CAD group. The mean infarct index was comparable across all three coronary artery territories. Mean differences between studies were higher, and the proportion of myocardial segments with perfect agreement was lower for the CAD compared to the control group. However, despite the presence of moderate scar burden in the CAD compared with control group, there was no significant difference in MPRi reproducibility between the two groups (p = 0.850). This suggests that the presence of scar may affect qualitative but not semi-quantitative analysis. Intra-observer reproducibility was similar between the two groups p = 0.733) and there was only a trend (p = 0.056) towards lower inter-observer reproducibility for MPRi in patients with CAD versus controls: CoV 5% vs. 13% for control and CAD, respectively. Elkington et al. [33 and thThe small differences observed between the CAD and control groups in this study may be secondary to a lower than expected reproducibility in the control group. Our control group was selected on the basis of low estimated risk for CAD as defined by a Framingham risk score of <10%. Therefore, patients in this group may have had undiagnosed underlying CAD. Notably, the mean MPRi was 1.59 ± 0.58 for the control group and 1.13 ± 0.21 for the CAD group. Previous studies have reported an MPRi of >2.0 in normal patients. Al-Saadi et al.  showed tSmall SDs for between-study differences were detected for perfusion parameters, resulting in small sample size estimates for studies using adenosine stress CMR as a primary endpoint. Syed et al.  reportedCommonly used reproducibility measures have potential shortcomings and require cautious interpretation. We used the CoV to define reproducibility, a measure that is expressed as a percentage and not in specific units, thereby allowing comparison of variables using different units or scales. The CoV is calculated from the SD of the differences in measurements divided by the average. Given that, the denominator is dependent on the average value of measurements, the CoV loses utility when the average of measurements approximates zero. This limitation was evident when calculating the CoVs for the number of ischemic myocardial segments in the control group in whom this was, as expected, close to zero. The calculated high CoV of 76% reflects this drawback and should not be interpreted as poor reproducibility. Inter-study variability for the number of ischemic segments in control subjects is in fact low, as shown by the very small mean difference (-0.10) and SD (0.57), as well as the high percentage of perfect agreements (96%) between studies.There are several limitations to this study. Currently, CMR does not permit assessment of the entire myocardium. Reproducibility may differ in different myocardial regions and variation in SA slice acquisitions due to variable patient positioning and breath holding can, therefore, affect reproducibility. Furthermore, other groups have performed studies for reproducibility assessment using shorter periods between studies, to minimize physiological variation . SimilarThis study demonstrates that adenosine CMR is a reproducible technique with low inter-study and observer variability. Our data provides valuable information for designing adequately powered trials to assess the efficacy of interventions by CMR perfusion and, thus, support the clinical and research applicability of this technique.The authors declare that they have no competing interests.SC and JAM conceived the study. All authors participated in its design. SC and JAM coordinated the study and performed the CMR analysis. SC and ML performed the statistical analysis. SC, JAM, PSM and RMG helped to draft the manuscript. All authors read and approved the final manuscript.


Previous events evidence that sudden cardiac death (SCD) in athletes is still a reality and it keeps challenging cardiologists. Considering the importance of SCD in athletes and the requisite for an update of this matter, we endeavored to describe SCD in athletes. The Medline (via PubMed) and SciELO databases were searched using the subject keywords "sudden death, athletes and mortality". The incidence of SCD is expected at one case for each 200,000 young athletes per year. Overall it is resulted of complex dealings of factors such as arrhythmogenic substrate, regulator and triggers factors. In great part of deaths caused by heart disease in athletes younger than 35 years old investigations evidence cardiac congenital abnormalities. Athletes above 35 years old possibly die due to impairments of coronary heart disease, frequently caused by atherosclerosis. Myocardial ischemia and myocardial infarction are responsible for the most cases of SCD above this age (80%). Pre-participatory athletes' evaluation helps to recognize situations that may put the athlete's life in risk including cardiovascular diseases. In summary, cardiologic examinations of athletes' pre-competition routine is an important way to minimize the risk of SCD. Athlete is defined as who participates in individual or collective sports (any age) as well as training programs of systematic and regular competitions -7.Recent events in all parts of the world show that sudden cardiac death (SCD) of athletes is still a reality and it continues to challenge experts in cardiology which works with athletes -13. SCD SCD in athletes is rare , however, it is still 2-4 times more often when compared to non athletes. Several mechanisms are proposed: myocardial ischemia, repolarization due to potassium channel downregulation and it may also be explained by the presence of multiple factors such as cardiac hypertrophy (athlete's heart) and/or hypertrophic cardiomyopathy, increased sympathetic tone, genetic defects, drugs, doping agents or food ingredients. These factors together may increase the repolarization homogeneity which sometimes leads to risk of arrhythmias and SCD .In not selected population the incidence of SCD is 0.001-0.002% per year. Nevertheless, in absolute value it generates a significantly higher number. In selected populations such as athletes the absolute value of deaths decreased but the relative risk increases .In Brazil and in the rest of the Latin American continent, the only statistic of SCD tracked over the years is from the Institute of Cardiology Dante Pazzanese. More than 25 years they have monitored SCD in athletes. The statistics of this institution shows that in children and adolescents mild abnormalities risks ranged from 17.7 to 21.0% while in active amateur athletes and in professionals younger than 35 years old it was 8.2%, this only for cardiac factors. The results of the Italian Olympic Committee regarding removal of athletes for heart disease were only 3% .We believe that cardiologic evaluation of athletes' pre-competition routine is the only way to minimize the risk of SCD in this selected population. In view of the importance of SCD in athletes and the necessity for an update of this issue, we aimed to describe SCD in athletes through a systematic review.The Medline (via PubMed) and SciELO databases were searched using the subject keywords "sudden death, athletes and mortality". We also used the "related articles" function on PubMed and SciELO with the references of the studies. Publications were included in our review if their titles or abstracts were available in English or Portuguese and described SCD in athletes. The review was completed on June 2010. Publications were excluded if the treatment was limited to a particular technique.Each publication was reviewed in order to identify the author(s), study period and data source.In the review which we made in the mentioned databases we found a total of 694 manuscripts. We excluded investigations where the management was limited to a particular method.We summarized the main studies in Table The prevalence of SCD is estimated in one case for each 200,000 young athletes -19. On tThe most common cause of sudden death is cardiovascular origin according to the literature, with incidence and nature of the subject areas. For example, the family hypertrophic cardiomyopathy is more common in the U.S., while right ventricular arrhythmogenic dysplasia have a greater effect in the region of Veneto in Italy . In BrazFrom 1966 to 2004 it was reported 1,101 cases of sudden death in athletes younger than 35 years, 90% were due to cardiovascular diseases, 50% presented anatomic congenital cardiac diseases and cardiomyopathies, 10% presented early coronary atherosclerotic disease, 40% occurred in athletes younger than 18 years and 33% below 16 years old, the ratio of female/male was 1/9. SCD was reported for almost all sports, the majority involved soccer (30%), basketball (25%) and runners (15%) .Sadaniantz and Thompson  demonstrJeresaty  and SadaWhen we investigate the causes of sudden death in soccer players, we may describe two groups: The first includes congenital cardiac abnormalities , and the second due to coronary artery disease. In the both groups it is observed fatal arrhythmias (SCD).Several electrophysiological mechanisms may be responsible for SCD, however, in general it is resulted of complex interaction of factors such as arrhythmogenic substrate, regulator and triggers factors: arrhythmogenic substrate: it may be represented by a fibrotic or infiltrative myocardial process, myocardial necrosis, ventricular aneurysm, myocardial hypertrophy, myocardial inflammation and electrocellular changes; regulator factors: autonomic nervous system, renin-angiotensin system, hydro-electrolyte disturbances, hypoxia, drug action, hemodynamic factors, ischemia and blood pH and; trigger factors: extra-systole and abrupt increases of heart rate .The arrhythmogenic substrates alone do not produce fatal arrhythmia. It is necessary trigger factors acting on it in a favorable context for the sustenance of the arrhythmia - modifying factors . Over 90In general, the most common triggers for sudden death are excessive physical effort, stress and the transition period from sleep to wakefulness on the first hours of the morning. In these situations there is a peak of sympathetic activity which promotes sudden increase of myocardial demand and/or changes in vasomotor tone of coronary arteries. These conditions may lead to rupture of a plaque with subsequent thrombus formation, leading to myocardial ischemia which may be manifested as unstable angina, myocardial infarction or its complications . Abrupt Although a rare event, sudden death in athletes generates great social and emotional impact throughout society, especially when the victim is a young athlete, it arises questions from the midia: Would be the sport detrimental to health? Sudden death could be prevented?There is evidence that sports, including soccer, are healthy to body and mind, except for a small group of practitioners who have undiagnosed heart disease and which it would not be recommended. However, at least one of them could be prevented through pre-participatory evaluations recommended to all practitioners of physical activities in order to identify their conditions that would lead to the final event .In all types of sports it has been considered older ages in which the athletes are classified as "masters". These ages are apparently arbitrary and vary according to the sports. For instance, in water polo the age is 25 years old and in bowling it is 50 years old. In soccer the age is 35 years old and it is not reported in the literature the objective criteria regarding these ages' limits. Similarly, the national and international publications follow this categorization and in the world all these ages are referred to as watershed between young athletes and "masters" .For the vast majority of deaths caused by cardiovascular disease in athletes younger than 35 years old the literature relate congenital abnormalities of the heart, i.e., diseases at birth. Among them the most commons are: hypertrophic cardiomyopathy (36%), coronary artery anomalies (19%) and increased ventricular mass (10%). The remaining percentage is caused by other diseases such as right ventricular arrhythmogenic dysplasia, Marfan syndrome, the long QT syndrome, Brugada syndrome and catecholaminergic familiar tachycardia ,34. UnfoA large number of congenital cardiac anomalies may be found and listed as a cause of SCD during exercise; however, the most prevalent according to literature references are anomalous origin of left coronary artery from pulmonary artery and hypertrophic cardiomyopathy .It represents 0.25-0.5% or 4 per 1000 of all congenital heart disease , it occuThis pathological condition is not the only coronary anomaly that causes SCD. In fact, this entity is rather uncommon in adult population. The clinical and pathological profile may be divided into child and adult . The chiThe electrocardiogram (ECG) contributes to the most of clinical diagnosis achievement, especially in symptomatic infants. In children and adults the electrocardiogram may be normal or almost normal , howeverHypertrophic cardiomyopathy may be defined as myocardial involvement without definitive etiology, characterized by left ventricle hypertrophy (rarely right ventricle), with myofibrillar disorder, increased left ventricular ejection fraction and decreased cardiac output, which depends on the functional impairment degree -47. The The asymmetric septal hypertrophic cardiomyopathy is the most prevalent and may occur in non-obstructive or obstructive outflow of the left ventricle and it is revealed at rest or with stress. Hemodynamically, it is noted pressure gradient between the left ventricle and the aorta, resulted from septal hypertrophy, which avoids the flow through the left ventricle outflow. Due to the Venturi effect, during ventricular systole the anterior leaflet of the mitral valve come close to the interventricular septum (MSA) and anguishes the left ventricle outflow. The mitral valve becomes incompetent allowing blood reflux into the left atrial cavity due to the lacinia movement. Regardless of the obstruction, there is hipodiastole by impaired ventricular relaxation, which contributes to cardiac output decrease .It is estimated that cardiomyopathy may affect between 0.001 and 0.2% of the population . On the Considering that septal hypertrophy may be totally asymptomatic, this disease may be not diagnosed. A detailed investigation in family history is of great value, since this disease has a pattern distribution of dominant autosomal genetic  in at leThe natural history of hypertrophic cardiomyopathy leads to heart failure and/or sudden death. It is difficult to evaluate the prognosis of this disease because studies examined only symptomatic patients treated at major centers. Some manifestations are held for most of the authors as worse prognosis: early diagnosis (particularly children); large ventricular thickness, family history of sudden death, personal history of resuscitated sudden death, sustained (or not) ventricular tachycardia and exercise-induced hypotension -55.According to the literature, athletes older than 35 years old may die due to complications of coronary heart disease often caused by atherosclerosis. Myocardial ischemia and myocardial infarction are responsible for most of SCD above this age (80%) ,56-60.This review does not allow us to surely identify the preference causes of SCD in athletes. Although this etiology tends to prevail in older subjects, it seems that in competitive sports there is insufficient evidence regarding this matter. Acceptance of this premise may reduce the preventive approach to SCD just aiming to exclude congenital heart in young and just deal with coronary risk factors in the elderly, considering as secondary level the prevention of other possible etiologies for the athletes, including masters in football. The qualification by age implies that as a result of age the athletes would present limitations that would hamper their performance. Moreover, ages above 35 years old puts a real stigma in these athletes, thus, compromising physical performance, beyond the psychological involvement resulting on SCD risk.The authors declare that they have no competing interests.All authors participated in the revision of the manuscript. All authors conceived of the study, determined the design, performed the statistical analysis, interpreted the data and drafted the manuscript. All authors read and gave final approval for the version submitted for publication.