Objective: To assess age, gender distribution and relative frequency of congenital heart disease (CHD) in children who underwent palliative or corrective cardiac surgery at Rehman Medical Institute, Peshawar.Methodology: This retrospective study was conducted in Department of Cardiac Surgery at Rehman Medical Institute (RMI), Peshawar from May 2008 till May 2010. One hundred and twenty three patients up to age group of 16 years with confirmed diagnosis of congenital heart disease admitted for Cardiac Surgery at Rehman Medical Institute, Peshawar were included.Results: Out of 123 patients, there were 71 males (57.7%) and 52 females (42.2%), with male to female ratio of 1.3:1. Sixty five (52.8%) of the total cases had acyanotic heart defects. Cyanotic heart defects were seen in 58 patients (47.1%). Ventricular Septal Defect (VSD) followed by Patent Ductus Arteriosus (PDA) and Atrial Septal Defect (ASD), were the commonest acyanotic heart lesions, 33.8%, 23.0% and 16.9% respectively. Tetralogy of Fallot (TOF) was the commonest cyanotic lesion.Conclusion: Majority of patients with congenital heart disease had acyanotic CHD with the commonest lesion being VSD. Tetralogy Of Fallot (TOF) was the commonest cyanotic lesion. Most of the patients were less than five years with no significant difference in sex distribution. Availability of expertise locally will lead to more patients getting surgical treatment at an earlier age thereby reducing morbidity and mortality and improving quality of life for these children. The relatively high birth rate in India, an average of 150,000 children are born with congenital abnormalities with 50,000 requiring surgery in the first year of life and only one thousand cardiac surgeries are done in the early infancy.5 The relevant high mortality rate due to CHD is due to the fact that many of the babies who could be saved by surgery do not have the chance due to high cost and inadequate facilities; the situation is the same in other South Asian countries including Pakistan. Congenital heart disease is the most common congenital problem effecting nearly 25% of all children with congenital malformation6 The presentation of children with CHD can be very variable; they may be asymptomatic and discovered only accidentally when a murmur is noted during check up for an unrelated illness or routine neonatal checkup,7 or may present with symptoms like cyanosis, clubbing of fingers nails to full blown congestive heart failure.6,7 CHD has not been studied thoroughly in Pakistan as in other western and neighboring countries. Despite vast improvements in medical field, congenital heart disease is still one of the leading cause of death and can present in different age groups from birth to adolescence. The purpose of this study was to present a single center experience in CHD at RMI, Peshawar, which is the biggest cardiac tertiary care center in the province, receiving patients not only from all over Pakistan but also Afghanistan and Central Asia and to compare it with studies done in other countries and similar studies locally. This is a retrospective chart review conducted at cardiac surgical unit from May 2008 to May 2010 at Rehman Medical Institute, Peshawar, Pakistan. All children with confirmed diagnosis of CHD admitted for corrective or palliative cardiac surgery were included. A total of 123 children were studied with age ranging from one month to 16 years. Clinical data was reviewed. Consideration was given to the total number of cases with CHD, age, sex distribution and type of CHD. Patients with multiple heart anomalies or syndromes were also included. Patients with acquired heart diseases, such as rheumatic heart disease, were not included.:1. The age ranged from one month to 16 years. Afghani patients constituted 60% of the population studied while 40% cases reported from Khyber Pukhtoonkhwa province. A total of 123 children were included. The data from these patients were evaluated regarding sex distribution, age and relative frequency of different congenital heart defects. There were 71 males (57.7%) and 52 females (42.2%), with male to female ratio of 1.3 Sixty five (52.8%) of the total cases had acyanotic heart defects. Cyanotic heart defects were seen in 58 patients (47.1%).Ventricular septal defect (VSD) followed by Patent ductus arteriosus and atrial septal defect (ASD), were the commonest acyanotic heart lesions, 33.8%, 23.0% and 16.9% respectively. While combination of VSD with other anomalies like PDA and ASD were 13(20%), there were two cases of Aortic stenosis and Coarctation of aorta. In Cyanotic heart defects TOF was the commonest 30 (51.7%), followed by Transposition of Great Arteries (TGA) 10(31.3%), complex heart disease 6(10.3%), five cases each of Atrioventricular canal defect  and VSD with RVOT obstruction. There was one case of pulmonary stenosis with total anomalous venous return and fallot’s pentology each. There was male predominance in both cyanotic and acyanotic heart lesions. However, complex heart defects and mixed cardiac lesions like VSD with Right ventricular outflow tract obstruction (RVOT obstruction) and VSD with ASD were more common in females.8 Our study is confined to Rehman Medical Institute only where not only Pakistani but Afghani patients are also treated so it does not give true incidence and prevalence of CHD in total population. CHD is an important group of diseases that cause great morbidity & mortality in children.6,8 The present study indicates that CHD is an important pediatric cardiac problem. There were 123 cases of CHD 71 were males (57.7%) and 52(42.2%) females. Male to female ratio is 1.3:1. The male predominance is similar to other studies done in Pakistan. In the study at Pediatric Dept of JPMC, Karachi by Rahimtoola males was 57% and females 43%.9 Acyanotic heart defects were present in 52.8% of cases while 47.1% had cyanotic heart disease, correlating with a study carried out in Jordan Department of Pediatrics at Prince Hashim Military Hospital Jordan-Zarka.10 It is accepted that the advancement in health sciences has helped in early diagnosis, attention and awareness among general pediatrician and early referral to pediatric cardiologists has resulted in an increase of reported prevalence of CHD.11 There was male predominance in both cyanotic and acyanotic heart lesions. However, complex heart defects and mixed cardiac lesions like VSD with RVOT obstruction and VSD with ASD were more common in females. This finding is the same as already reported in a previously done study12 but it is contradictory to the finding made by Burki MK and Babar GS13 who reported both sexes to be equally affected. This difference may be due to a number of factors such as socio-economic, cultural, ecological and genetic factors. Maximum number of children with CHD was observed in 1-5 years and 6-10 years age groups. Same was observed in the study done by AL-e-Hag, 1994.14,15 Worldwide, VSD is the most common acyanotic CHD accounting for 25-30% of all CHD.16 PDA ranked second in frequency accounting for 23% of the acyanotic heart defects which is higher than found in other studies. Similarly cyanotic heart defects were in higher percentage as compared to others studies shown in 14,15 and also to a local study by Rehman F et al.2VSD is found to be the most common acyanotic CHD (33.8%) in our study. This is in accordance to what is reported in other studies as shown in  The study gives an overview of the pattern of congenital heart disease in children admitted for cardiac surgery. In order to avoid complications, reduce mortality and improve quality of life, earlier detection and correction of disease is of utmost importance. Many lesions are amenable to surgery, availability of local expertise and awareness amongst parents and professionals will help do these at the optimal time.


Tetralogy of Fallot (TOF) repair and pulmonary valvotomy for pulmonary stenosis (PS) lead to progressive pulmonary insufficiency (PI), right ventricular enlargement and dysfunction. This study assessed whether pulmonary regurgitant fraction measured by cardiovascular magnetic resonance (CMR) could be reduced with inhaled nitric oxide (iNO).Patients with at least moderate PI by echocardiography undergoing clinically indicated CMR were prospectively enrolled. Patients with residual hemodynamic lesions were excluded. Ventricular volume and blood flow sequences were obtained at baseline and during administration of 40 ppm iNO.2 (mean ± SD), 50% were women and 75% were in NYHA class I. Right ventricular end diastolic volume index for the cohort was 157 ± 33 mL/m2, end systolic volume index was 93 ± 20 mL/m2 and right ventricular ejection fraction was 40 ± 6%. Baseline pulmonary regurgitant volume was 45 ± 25 mL/beat and regurgitant fraction was 35 ± 16%. During administration of iNO, regurgitant volume was reduced by an average of 6 ± 9% (p=0.01) and regurgitant fraction was reduced by an average of 5 ± 8% (p=0.02). No significant changes were observed in ventricular indices for either the left or right ventricle.Sixteen patients (11 with repaired TOF and 5 with repaired PS) completed the protocol with adequate data for analysis. The median age [range] was 35 [19–46] years, BMI was 26 ± 5 kg/miNO was successfully administered during CMR acquisition and appears to reduce regurgitant fraction in patients with at least moderate PI suggesting a potential role for selective pulmonary vasodilator therapy in these patients.NCT00543933ClinicalTrials.gov,  Pulmonic valve insufficiency (PI) is a well-defined problem following primary surgical repair of tetralogy of Fallot (TOF) or valvar pulmonic stenosis (PS). The early experience with surgical repair suggested that residual outflow tract obstruction led to poor short-term outcomes . Combine2 and end systolic volume index is >85 mL/m2, there is no decrease in ventricular size after valve surgery  was 34.8 [23.4 – 40.8] years. The average body mass index of the cohort was 25.8 ± 5.4 kg/mEleven patients (69%) had a history of TOF, while five (31%) had a history of isolated PS. The median age [interquartile range] for complete surgical repair among TOF and PS patients was 3.7 [1.8 – 4.6] years. Most patients had echocardiographic evidence of at least moderate PI  and all but one had mild tricuspid valve regurgitation or less . Mean estimated right ventricular systolic pressure by echocardiography was 35.8 ± 13.6 mmHg for the cohort. The mean QRS duration was 139.5 ± 28.2 ms on electrocardiography.2, right ventricular end systolic volume index was 93.0 ± 19.6 mL/m2, right ventricular stroke volume index was 63.9 ± 17.8 mL/m2 and right ventricular ejection fraction was 40.5 ± 6.2%. All parameters remained unchanged during administration of iNO .Volumetric results at baseline and with iNO are shown in Table 2, left ventricular end systolic volume was 38.5 ± 8.7 mL/m2, left ventricular stroke volume was 44.5 ± 7.7 mL/m2 and ejection fraction was 53.8 ± 5.2%. All parameters remained unchanged during iNO administration .At baseline, left ventricular end diastolic volume index was 83.0 ± 13.6 mL/m2 at baseline and did not change with iNO either (p=0.13). The forward volume across the pulmonary artery was similar before and after iNO administration  but regurgitant fraction . Aortic regurgitant fraction was minimal at baseline (4.5 ± 6.4) and did not change during iNO administration (p=0.51). Large % changes were observed in reverse volume and regurgitant volume with iNO administration but the absolute changes were minimal. Outliers in these fields were removed for improved data clarity.No significant changes in aortic flow parameters were detected during administration of iNO Table . Average2=0.01, p=0.74), right ventricular end diastolic volume , right ventricular ejection fraction , QRS duration  or the degree of pulmonary insufficiency (r2=0.13, p=0.17, Figure The length of time from complete surgical repair to enrollment in the study did not appear to be associated with NYHA function class (rThis study is the first to show that inhaled nitric oxide may be safely and effectively delivered inside a CMR suite in a cohort of adult patients with congenital heart disease and demonstrates that inhaled nitric oxide acutely reduces the severity of PI as measured by CMR which is the key determinant in late outcomes following repaired TOF and PS. It has been well established that patients with PI and increased afterload develop early right ventricular failure -18. FurtWhile significant, the absolute reductions in pulmonary regurgitant volume and regurgitant fraction were modest and the effect size did not produce significant changes in ventricular indices. The hemodynamic effects of iNO on PI might have been underestimated for a number of reasons. The half-life of nitric oxide is shorter than the typical breath hold sequence and variability likely exists in the length of breath holds between patients. The severity of PI also varied among the cohort. Two patients with echocardiographic evidence of at least moderate PI were enrolled in the study but had only minimal PI on CMR which reduced the observed effect size. Finally, it has been recently shown that pulmonary regurgitant fraction is significantly smaller when measured in end expiration as compared with other techniques Right ventricular end diastolic volume and the magnitude of PI appeared to be related in this study Figure . This reNo discernible relationship was observed between right ventricular end diastolic volume or PI and time from complete repair, which is contrary to the perceived natural history of chronic volume overload . This maThe population chosen for this study was selected to minimize confounding physiology. Patients with residual shunt lesions or with prior surgical reintervention on the RVOT were excluded when this was recognized. Patients with residual RVOT or branch pulmonary artery stenosis were also excluded, because it is unknown how these lesions might affect the magnitude of PI or influence hemodynamic changes observed with iNO.Sustained pulmonary vasodilation with a longer acting agent may possibly result in a greater effect size and more consistent results. A recent study by Babu-Narayan and colleagues, however, demonstrated no change in severity of PI after 6 months of oral ramipril therapy in a similar population of patients . AngioteThere are limitations to this study that must be considered when assessing applicability. The study was carried out at a single quaternary care medical center and is therefore subject to referral bias. The majority of patients carried the diagnosis of TOF, though 5 had only PS as their initial lesion. We did not have the power to discern significant differences between these 2 populations, though differences potentially exist. Furthermore, the degree of PI varied considerably across the cohort, with 2 patients having almost no PI on CMR. This study also lacks precise details of the primary repair and peri-operative management which have been suggested to influence late outcomes -30. DespThis study demonstrates that inhaled nitric oxide may be delivered within a CMR suite and serves as a proof-of-concept for pulmonary vasodilator therapy in patients with PI. Long term pulmonary vasodilation with oral agents such as phosphodiesterase-5 inhibitors may have similar effects to those seen following pulmonary valve repair or replacement with potentially less risk. Further studies are necessary to evaluate the effect of these agents on this complex disorder, particularly given the ever growing patient population.PI: Pulmonic insufficiency; TOF: Tetralogy of Fallot; PS: Pulmonic stenosis; RV: Right ventricle; AI: Aortic insufficiency; CMR: Cardiovascular magnetic resonance; NYHA: New York heart association; RVOT: Right ventricular outflow tract; SSFP: Steady-state free precession; iNO: Inhaled nitric oxide; ACEi: Angiotensin converting enzyme inhibitors.Dr. Krasuski serves on the scientific advisory board for Ventripoint, as a consultant to Actelion and on the speakers bureaus of Actelion and Roche. The other authors report no industry relationships.SH participated in the study design, subject recruitment, data collection, data analysis, manuscript drafting, and critical review of the manuscript. GD participated in subject recruitment, data analysis, and critical review of the manuscript. YK participated in acquiring study funding, study design, subject recruitment, and critical review of the manuscript. SF participated in the study design, study coordination, data collection, data analysis, and critical review of the manuscript. VK participated in data collection, data analysis, and critical review of the manuscript. JA participated in data analysis and critical review of the manuscript. EW participated in data analysis, statistical analysis, and critical review of the manuscript. TB participated in data collection, data analysis, and critical review of the manuscript. MB participated in data collection, data analysis and critical review of the manuscript. RS provided technical support, provided study coordination, data analysis, and critical review of the manuscript. RK conceived of the study, participated in study design, subject recruitment, data analysis, critical review of the manuscript and overall study coordination. All authors read and approved the final manuscript.


The aim of the present study was to investigate the effects of sabiporide, a potent and selective NHE1 inhibitor, on myocardial ischemia-induced arrhythmias and myocardial infarction and the possible pathways related to the cardioprotection afforded by sabiporide treatment. Anesthetized rats were subjected to myocardial ischemia via left main coronary artery occlusion for 30 minutes, followed by 2 hours of reperfusion. Administration of sabiporide (0.01–3.0 mg/kg) prior to coronary artery occlusion dose-dependently reduced ischemia-induced arrhythmias and infarct size with an ED50 value of 0.14 mg/kg. Administration of sabiporide (1.0 mg/kg) prior to reperfusion also reduced infarct size by 38.6%. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase and troponin I. In addition, sabiporide (1.0 mg/kg) given prior to coronary artery occlusion or immediately before reperfusion significantly reduced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and the expression of the inducible nitric oxide synthase (iNOS) following myocardial ischemia-reperfusion. This study demonstrates that sabiporide is a potent and effective cardioprotective agent during myocardial ischemia and reperfusion, by reducing serious ventricular arrhythmias and myocardial infarct size. The cardioprotection afforded by sabiporide is attributed in part to inhibition of ERK1/2 phosphorylation and suppression of iNOS expression. Physiologically, they extrude one intracellular proton in exchange for one extracellular sodium, thereby regulating intracellular pH. NHE1, the housekeeping isoform present in all mammalian cells, is the most predominant isoform in cardiomyocytes -3-(trifluoromethyl)-benzamide) was synthesized by Boehringer Ingelheim Pharma KG, Ingelheim, Germany [Rats were anesthetized with sodium pentobarbitone: initial induction at the 60 mg/kg dose  followed by continuous infusion at the dose of 30 mg/kg/h  throughout the experiment. The animals were maintained in a deep surgical plane of anesthesia throughout the experiment by continuous blood pressure monitor and using the pin-prick of the hind leg method to determine the degree of the anesthesia. The trachea was cannulated, and the animals were artificially ventilated (80 strokes/min) with room air supplemented with oxygen. The body temperature was maintained at 37°C with a heating pad. The right carotid artery and left jugular vein were cannulated for continuous measurement of arterial blood pressure and intravenous administration of test agents , respectively. Heart rate was derived from the blood pressure signal. A left-sided thoracotomy was performed at the level of the fifth intercostal space. A 5-0 silk suture was placed around the left main coronary artery approximately 1-2 mm from its origin. Four pieces of number 16 sewing cotton were coligated along with the coronary artery to facilitate reperfusion. The coronary artery was occluded for 30 minutes followed by 2 hours of reperfusion. Reperfusion was instituted by removing the ligature. Blood pressure and heart rate were measured continuously throughout the experiment. A lead II electrocardiogram (ECG) was recorded on a computer by Chart V3.5 program. Arrhythmias were evaluated according to the guidelines of the Lambeth conventions . VentricAt the end of the reperfusion period, the coronary artery was reoccluded. Evan's blue dye (1 mg/mL) was infused to the right ventricle to define the area of myocardium at risk. After this procedure, the heart was removed. Both atria and the roots of the great vessels were removed. The entire ventricle was cut from the apex to base into four transverse slices and incubated in 2,3,5-triphenyltetrazolium chloride (TTC) (10 mg/mL in phosphate buffer) for a period of 10 min at 37°C to visualize the infarct area. Each section was scanned by a color image scanner, and infarct size on the surface of each slice was determined by Photoshop 6.0 program. The infarct area were traced manually on the digital images and automatically measured. The infarct size was expressed as percentage of area at risk (AAR). The area at risk was similar between all animals, with an average of 62 ± 4% of LV. In some hearts (those which were not subjected to TTC staining), the free walls of the left ventricles (ischemia region or sham) were separated and snap-frozen for immunoanalysis. Saline or sabiporide  was given 10 min before coronary artery occlusion; or sabiporide (1.0 mg/kg) was administered immediately before the start of reperfusion.Blood samples were removed from carotid artery before drug treatment, before reperfusion, and at the end of experiment. They were promptly centrifuged at 12,500 rpm, 4°C, for 15 min, the plasma removed, and stored at –80°C until assayed. Creatine phosphokinase levels were determined using a CPK kit . Plasma troponin I levels were measured using a cardiac troponin I enzyme immunoassay kit .Rat left ventricle tissue lysate was prepared by homogenization in ice cold RIPA buffer. Tissue and cell debris were removed by centrifugation. Protein concentration was determined by the Bio-Rad protein assay. The protein extracts were boiled for 5 min in SDS loading buffer and loaded onto NuPAGE 4–12% Bis-Tris Gel . After electrophoresis, the separated proteins were transferred onto nitrocellulose membrane . The blots were incubated in 5% nonfat dry milk in Tris-buffered saline for 2 h at room temperature and incubated overnight at 4°C with primary antibody: extracellular signal regulated protein kinase (ERK1/2) (1: 500) , phospho-ERK1/2 (1: 2000); inducible nitric oxide synthase (iNOS) (1: 250); and GAPDH (1: 3000) . The blots were rinsed with Tris-buffered saline and incubated with HRP-conjugated donkey anti-rabbit or goat anti-mouse IgG secondary antibody for 2 hours. Immunoreactivity was detected using electrochemiluminescence autoradiography . The levels of the signals were detected by a color image scanner and quantified by densitometry with the use of the NIH Image J software. All bands were normalized against GAPDH. The intensity of the protein bands in the MI groups were expressed as percentage of the negative control tissue samples . All the relative ratio values obtained from 6 rats/groups were pooled and presented as mean ± SEM. U test. Comparisons for the incidence of VF were analyzed with Fischer's exact probability test. The results are presented as means ± SEM. P values <0.05 were considered to be significant.Data were analyzed for significance using GraphPad InStat software. Differences between groups in hemodynamic and infarct sizes were compared using ANOVA (with Bonferroni posttest) for multiple comparisons. Comparisons for the number of VPBs and duration of VT during ischemia were analyzed with Mann-Whitney Consistent with previous findings on the activities of NHE1 inhibitors, sabiporide has no direct effect on blood pressure and heart rate . All conOcclusion of the left main coronary artery for 30 minutes followed by 2 hours of reperfusion resulted in substantial injury to the myocardium. In the control group, occlusion and reperfusion produced an infarction of 49.8% (IF/AAR) . MeanwhiAs shown in Activation of ERK1/2 and induction of iNOS are known to be involved in myocardial ischemia-reperfusion injury , 12. To The effects of sabiporide on ischemia arrhythmias, myocardial infarction, ERK1/2 phosphorylation, and iNOS expression were studied in a rat model of myocardial ischemia-reperfusion injury. Administration of sabiporide prior to ischemia resulted in a dose-dependent reduction of ischemia-induced arrhythmias, including ventricular tachycardia, and ventricular fibrillation as well as reduction of myocardial infarct size. In addition, treatment with sabiporide prior to coronary artery occlusion or prior to reperfusion significantly reduced ERK1/2 phosphorylation and cardiac iNOS expression following ischemia-reperfusion. in vivo studies in rats have shown that acute myocardial ischemia with coronary artery occlusion results in severe ventricular arrhythmias [Coronary artery disease still remains the leading cause of death in the industrialized world despite considerable progress in its management. In patients with severe left ventricular dysfunction, more than 60% of deaths are attributed to the development of ventricular arrhythmias during periods of myocardial ischemia or infarction , 14. Thehythmias . Consist+ and Ca2+ overload may be the final common pathway leading to cardiac arrhythmias following myocardial ischemia by activating the transient inward current or causing electrical uncoupling of cardiac myocytes [+ and Ca2+ resulting from pH-regulated NHE1 activation  may  reviews , 21, the+ and Ca2+, leading to myocardium damage [Reducing myocardial infarct size is the primary goal in patients with coronary heart disease. Early reperfusion of an occluded coronary artery is a well-known and effective strategy to reduce ischemia-induced myocardial damage , 23. Howm damage –3. NHE1 m damage , 15, 21.Cardiac ischemia-reperfusion is associated with activation of various signaling pathways  pathway and inducible nitric oxide synthase (iNOS) mediated cellular injury pathway) that play an important pathophysiological role in the progression of ischemia-reperfusion injury and myocardial dysfunction , 12. ERK/2 pathwaκB), to elements within the iNOS promoter, as well as through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) formation [κB activation and reduces cytokines production in traumatic hemorrhage shock in pigs [Increased iNOS expression is a component of the immune response and has been demonstrated in cardiomyocytes in ischemia-reperfusion, septic shock, myocarditis, transplant rejection, dilated cardiomyopathy, and heart failure –34. Studormation –41. In aormation  have shoormation . We have in pigs . In the Collectively, the present study demonstrates that sabiporide is a very potent and effective agent for cardioprotection during myocardial ischemia and reperfusion by reducing serious ventricular arrhythmias and myocardial infarct size. The cardiac protection afforded by sabiporide is possibly in part attributed to inhibition of ERK1/2 phosphorylation and suppression of iNOS induction.In addition to the detrimental role of NHE1 activation in acute cardiac injury, studies have also demonstrated that NHE1 activation contributes to chronic maladaptive myocardial responses to injury such as postinfarction myocardial remodeling, and likely contributes to the development heart failure . Further


Cardiac magnetic resonance (CMR) offers a variety of parameters potentially suited as surrogate endpoints in clinical trials of acute myocardial infarction such as infarct size, myocardial salvage, microvascular obstruction or left ventricular volumes and ejection fraction. The present article reviews each of these parameters with regard to the pathophysiological basis, practical aspects, validity, reliability and its relative value (strengths and limitations) as compared to competitive modalities. Randomized controlled trials of acute myocardial infarction which have used CMR parameters as a primary endpoint are presented. Reductions of mortality and morbidity are the ultimate treatment goals in ST-elevation myocardial infarction (STEMI). Therefore, primary endpoints in clinical studies of new therapeutic interventions are ideally events relevant to patients such as death, reinfarction or new symptoms of heart failure. However, studies with clinical endpoints are associated with several shortcomings. The incidence of the event of interest  is increasingly low during short- or medium-term follow-up given the advances in treatment. Furthermore, some events might not be linked to atherosclerotic disease resulting in low sensitivity. As a consequence, large sample sizes and long follow-up periods are required absorbing time and financial resources. Missing data and noncompliance are also more likely in longer-lasting studies .Surrogate endpoints can overcome some of these problems allowing for a reduction in sample size and follow-up duration as well as studying pathophysiological mechanisms of disease thereby improving trial efficiency. Surrogate endpoints are alternative endpoints "used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint" . As compCardiac magnetic resonance (CMR) imaging offers a variety of parameters potentially suited as surrogate endpoints and is increasingly being used in clinical trials of STEMI. Following a short conceptual overview of surrogate endpoints, we describe several of these CMR parameters and their value in infarction trials.According to a widely known definition published by a working group of the National Institutes of Health, a surrogate endpoint is "a biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence." . A bioloAccording to the "International Conference on Harmonisation (ICH)" the strength of the evidence for surrogacy depends upon (i) the biological plausibility of the relationship, (ii) the demonstration in epidemiological studies of the prognostic value of the surrogate for the clinical outcome and (iii) evidence from clinical trials that treatment effects on the surrogate correspond to effects on the clinical outcome . The simApart from validity, surrogate markers must also prove a high degree of reliability. Reliability refers to the consistency of measurements with only minimal variability. Reliability may be estimated through a variety of methods such as intraobserver repeatability  or interobserver repeatability (degree of variability when measurements are repeated by a different observer). Reliability does not imply validity.The use of surrogate endpoints is controversial. Most importantly, surrogate endpoints are often criticized for poor validity or even a complete lack of validation studies. Another point of criticism of surrogate endpoints relates to the safety of therapeutic interventions. Since surrogate endpoint studies usually enroll fewer patients than trials with clinical endpoints , there is a substantial risk to underdiagnose rare adverse events.Myocardial infarction can be visualised and quantified using inversion recovery imaging 10 to 15 minutes after intravenous administration of gadolinium contrast (late enhancement imaging). With correct settings, the area of infarcted myocardium appears bright whereas normal myocardium appears black  .Delineation of the infarct region can be performed by manual planimetry based on visual assessment of infarct borders or by using semiautomatic analysis software. Although manual tracing might be partially subjective, it has been used extensively by many CMR centers -14. In aApart from quantitative analysis of infarct volume as described above, late enhancement imaging can also be used to measure the extent of infarct transmurality which provides additional information in predicting improvement in contractile function after myocardial infarction .When applying the above-mentioned ICH criteria, validity for infarct size as a surrogate endpoint is relatively high: The capacity of infarct size to predict various clinical endpoints has been demonstrated in several epidemiological studies ,24. It hFor manual tracing, infarct size measurement shows excellent interobserver reliability in the acute and chronic setting .Infarct size assessment by CMR offers several advantages over alternative methods. Owing to its high spatial resolution, it is possible to detect and quantify small endocardial infarcts which are often missed by single photon emission computed tomography (SPECT) imaging ,27. GiveFurthermore, SPECT imaging is associated with exposure to ionizing radiation which might become especially relevant in longitudinal studies with multiple assessments of myocardial morphology and function. It should, however, be kept in mind that most patients with myocardial infarction are relatively old and longevity will likely be limited by cardiovascular morbidity rather than the risk imposed by additional radiation.Infarct size may also be quantified through cardiac enzyme analysis by estimating the cumulative „area under the curve" or peak enzyme release in serial measurements . HoweverMyocardial salvage, which is defined as salvaged tissue following reperfusion therapy, holds promise as a surrogate endpoint. The area of high signal (edematous myocardium) on T2-weighted CMR imaging likely reflects the area at risk in acute myocardial infarction Figure  31]. By. By31]. As for infarct size, there is a lack of standardization with regard to image acquisition and analysis. Also, in the setting of multicenter trials, the potential variability of infarct size measurements between scanners from different vendors should be taken into account. Currently, most of the clinical experience in visualising myocardial edema has been obtained using inversion recovery turbo spin echo (TSE) sequences with suppression pulses for both fat and blood. Although these sequences provide useful images in most clinical cases, they have inherent limitations such as artefact susceptibility, variability in signal intensity if phased array coils are used and low contrast-to-noise ratio . Slow flAt present, there are only limited data with regard to the natural evolution of postinfarction edema by CMR. In a canine model, edema could be detected by CMR shortly after coronary occlusion . In a smMost of the techniques described for the measurement of infarct size also apply to edema assessment. However, due to the aforementioned limitations of current T2 sequences for edema assessment, image analysis can be challenging in some patients. Image interpretation depends on regional differences in myocardial signal intensity and the purely visual delineation of edema borders offers the potential for subjective error. Cut-off values for defining abnormal vs. normal tissue for semiautomated quantification are not sufficiently standardized. A quantitative T2 mapping technique has recently been introduced which offers the potential for increased accuracy in image analysis .SPECT myocardial salvage has been successfully used as a surrogate endpoint in several clinical trials -46 and tMyocardial salvage can also be assessed by SPECT ,46. HoweEarly recanalization of the infarct-related artery is the primary treatment target in the first hours after symptom onset in acute STEMI . HoweverSeveral methods for the assessment of microvascular obstruction by CMR have been proposed . Image aGiven the time dependency of presence and extent of microvascular obstruction on the time between contrast administration and image acquisition, it is important to adhere to strict methodology within the clinical trial setting.Quantitative analysis of microvascular obstruction within the infarct zone is performed in a stack of short-axis slices using either manual planimetry or semiautomatic methods. Techniques are similar to those described above for the assessment of infarct size.Microvascular obstruction is reasonably valid to be used as a surrogate endpoint in clinical trials. Numerous studies relating to pathophysiological mechanisms have been published  and the Several other modalities are available for detecting microvascular obstruction such as myocardial blush grading on invasive angiography, evaluation of electrocardiographic ST-resolution or myocardial contrast echocardiography. Microvascular obstruction assessed by CMR might be superior to myocardial blush grading and ST-resolution in predicting functional recovery after myocardial infarction ,59. In cCMR measures ventricular volumes and mass using a simple acquisition of a 3-dimensional stack of contiguous short-axis cines with full biventricular coverage. Currently, the standard technique to measure left ventricular ejection fraction and volumes is a breath-hold, SSFP sequence that provides optimal contrast between blood and myocardium. Current cine sequences use retrospective electrocardiographic gating, although prospective gating may be required in patients with irregular heart rhythm. A portion of the data is recorded during each cardiac cycle and data from several heart beats are then fused to form a continuous cine movie loop.Calculation of left ventricular ejection fraction and volumes is commonly performed in short axis images following planimetry of endocardial and epicardial contours. The borders are typically traced at enddiastole and endsystole.Left ventricular ejection fraction and volumes are important predictors for survival after acute myocardial infarction ,62. CMR Echocardiography and gated SPECT are widely available techniques available for measuring cardiac function and volumes. Gated SPECT suffers from relatively low spatial resolution. Compared to echocardiography, CMR has been shown to be significantly more accurate with less interobserver and intraobserver variability as well as superior reproducibility . NotablyA subset of patients with acute myocardial infarction display hypointense zones within the area at risk in T2-weighted spin echo sequences Figure  65]. Th. Th65]. The infarct region can be further subclassified into core and border zone depending on relative signal intensity as compared to normal myocardium . In one trial the infarct core has been defined by a signal intensity ≥ 3 standard deviations of remote normal myocardium whereas the peri-infarct border zone was classified by a signal intensity between 2 and 3 standard deviations . The borImportant limitations of CMR imaging in post-infarct patients are contraindications such as pacemakers, internal defibrillators, claustrophobia or hemodynamic and electrical instability. Also, there are concerns about the use of gadolinium based contrast agents in patients with advanced renal failure due to the risk of developing nephrogenic systemic fibrosis . When plTable CMR is a safe technique, even in the first days after infarction and offers a variety of established and novel parameters potentially suitable as surrogate endpoints in clinical trials of STEMI. It allows the evaluation of function, infarct extent, salvaged myocardium and microvascular obstruction, and can be acquired easily within 30 to 40 minutes. The choice of marker is naturally dependent on the specific question of the trial to be conducted. However, choosing the most appropriate surrogate endpoint for the question at hand cannot restrict itself to a biologically plausible association between surrogate and clinical outcome. Other qualities of validity must also be demonstrated. Furthermore, surrogate endpoints should demonstrate high measurement reliability which can be considered a specific strength of most CMR parameters. Definite proof of validity is more difficult to establish. Therefore, the use of CMR surrogate endpoints in trials of myocardial infarction mandates a thoughtful interpretation of study results. It seems reasonable to use CMR surrogate endpoint studies mainly to prove fundamental biological activity and to evaluate pathophysiological mechanisms of novel therapeutic interventions. This can ultimately guide the decision whether to conduct larger studies with endpoints truly relevant to patients. Further studies should focus to address some of the limitations of CMR endpoints in myocardial infarction.STEMI: ST-elevation myocardial infarction; CMR: Cardiac magnetic resonance; ICH: International Conference on Harmonisation; SPECT: Single photon emission computed tomography; TSE: Turbo spin echo; SSFP: steady state free precession.The authors declare that they have no competing interests.SD drafted the initial version of the manuscript. All authors made substantial contributions in critically revising the manuscript for important intellectual content, read and approved the final version.


Extracellular volume fraction cardiac magnetic resonance (ECV-CMR) enables quantitative myocardial tissue characterization. Increased myocardial ECV is correlated to myocardial fibrosis, inversely related to the left ventricle ejection fraction (LVEF), and an independent predictor of mortality. Dilated cardiomyopathy (DCM) is characterized by decreased LVEF and increased LV end-diastolic volume (EDV). We sought to determine the prevalence of increased myocardial ECV in DCM.Consecutive patients  referred for clinical CMR evaluation of known or suspected heart disease were prospectively enrolled. CMR was undertaken at 1.5T using late gadolinium enhancement (LGE) and a Modified Look-Locker Inversion recovery (MOLLI) sequence. ECV images were generated using MOLLI-derived T1-mapping before and 15 minutes after an intravenous contrast bolus , and calibrated to hematocrit. Motion correction and co-registration was performed offline using an automated dedicated algorithm. ECV images were examined and focal and diffuse lesions were identified . If the ECV in remote, LGE-negative myocardium was >30% it was said to be diffusely increased. DCM was defined as LVEDVindex >100 ml/m2 and LVEF <58%. Data are presented as mean [range].Out of 213 patients, 58 had DCM, among which 50/58 (85%) had normal myocardial ECV and 8/58 (14%) had diffusely increased myocardial ECV >30%. The patients in the diffusely increase myocardial ECV group were the same age  and male to the same extent (75 vs 72%). Of the patients with normal myocardial ECV, 30/50 (60%) had focal lesions on LGE and 15/30 (50%) of these were ischemic lesions. Out of the patients with diffusely increased myocardial ECV, 3/8 (38%) had focal lesions, and one of these was an ischemic lesion. When compared to the DCM patients with normal ECV, the group with diffusely increased myocardial ECV did not differ in LVEDVindex , had a lower LVEF  and, as expected, higher myocardial ECV .Our findings suggest that diffusely increased myocardial ECV can be found in approximately 1 in 7 patients with DCM. These patients with DCM and diffusely increased myocardial ECV had a more severe form of heart disease, manifested as lower LV systolic function compared to DCM patients with normal myocardial ECV.The study is supported (PI: MU) by the Swedish Research Council, Swedish Heart and Lung Foundation, Stockholm County Council, Swedish Society for Medical Research, Swedish Heart Assocation, Swedish Society of Medicine, Karolinska Institute, and the following foundations: Å. Wiberg, L.&H. Osterman, M. Kleberg, L.&J. Grönberg.


Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs.In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment.From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p = 0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p = 0.001). This was associated with a 27% increase in T2* (p < 0.001) and 3.1% increase in LVEF (p < 0.001). By contrast, deferoxamine showed no change in RVESV , or RVEF  whereas the T2* increased by 13% (p < 0.001), but with no change in LVEF . Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p = 0.014) and 1.16% for RVEF (p = 0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p < 0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p = 0.012).In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone. Blood transfusions are standard therapy for patients with β-thalassaemia major (TM) and prevent death in childhood, but although clinical status and short term survival improve, each unit of blood contains about 200-250 mg of iron which the body cannot eliminate, which leads to long term iron accumulation. Patients treated only with blood transfusions may die in the second and third decades of life from the complications of iron overload, in particular heart failure ,2. MyocyDeferoxamine was the first iron chelating agent for clinical use and became standard therapy in the 1970s. It is a large positively charged lipophobic molecule, is poorly absorbed by the digestive system and has a short plasma half life ,11. It iThe LA16 RCT consisted of 61 regularly transfused patients with TM from 4 centres in Greece and Italy . All patIron loading and cardiac function was assessed using CMR. The T2* sequences were installed at the local CMR facilities, Athens (GE CVi) and Cagliari (GE Signa). The technique was validated by scanning phantoms of known T2* and testing intra-site reproducibility by scanning 5 patients twice at the local centre. The same patients were scanned at the reference site in London (Siemens Sonata) for inter-site reproducibility. A coefficient of variation (CV) ≤ 15% was defined as acceptable. Site inter-study variability was 2.4% for Cagliari and 3.5% for Athens. Comparison with the reference site yielded CVs of 1.6% and 9.7% respectively. Volumetric data were acquired using a steady state free precession sequence (FIESTA). A set of contiguous short axis cines were acquired to give complete coverage of both ventricles. Care was taken to place the basal slice parallel to the atrioventricular groove. Slice thickness was 8 mm with a spacing of 10 mm. No patient had a history of, and no CMR scan showed any features of pulmonary hypertension . Patients were scanned between 3 and 10 days post transfusion at baseline, 6 months and 12 months after entering the trial. T2* values and LV volumetric data were assessed previously using a CMR viewing and analysis software package CMRtools  . LV funcContinuous variables were compared using a paired t-test. T2* values were log transformed and changes expressed as geometric mean with coefficient of variation. Between groups comparison of drug effects were assessed using a repeated measurement ANOVA. Statistical significance was set at p < 0.05. To quantify reproducibility the coefficient of variance (CV) was calculated.Full data on the LA16 study have been published including the patient demographics, but the In the current analysis, the RV mean volumetric and T2* values are detailed in table RV volumetric and functional parameters have been difficult to measure using conventional imaging techniques due to the irregular geometry of the RV chamber, the size and quantity of the RV trabeculae, and the proximity of the RV to the chest wall which impairs echocardiographic assessment. CMR suffers less from these drawbacks because of its inherent 3D nature and high blood to myocardium contrast and is therefore considered to be the most accurate and reproducible technique for assessing RV volumes and EF ,24. AtteIn the current study, we found a significant improvement in RVEF (increase) and RVESV (reduction) with deferiprone therapy. These improvements parallel the previously reported LV response . There wThere is little other data relating RV function changes with the iron chelators, but a recently published abstract relating to a longitudinal trial of the efficacy of deferasirox in myocardial siderosis, showed aData acquisition for this study was originally designed to assess the change in T2* and LV functional parameters in response to therapy. Therefore no RV long axis images were obtained to construct 3-dimentional models for volumetric analysis, but the requirement for this was removed by using direct manual planimetry for quantitative analysis of RV volumes. Pulmonary arterial pressure was not systematically measured using echocardiography of the tricuspid regurgitant jet, but here was no CMR evidence of raised pulmonary artery pressure in our patients, and pulmonary hypertension is rare in well treated thalassaemia major . Direct This study has shown that RVESV decreased and RVEF improved with deferiprone monotherapy and this beneficial response was superior to deferoxamine. RV volumetric and function parameters have in the past been neglected when reporting the efficacy of iron chelators for myocardial iron overload, and may have independent prognostic importance, as they do in other cardiac conditions with impaired cardiac function.GCS is a consultant to Novartis and has received honoraria from ApoPharma. FA has received honoraria from Novartis. JPC has received speaker's honoraria from Novartis, Swedish Orphan and ApoPharma. VB is a consultant for ApoPharma. VL has received grant support, consulting fees and lecture fees from ApoPharma and Novartis. AP has received honoraria and research funding from Novartis. RG has served on speakers' bureaus and received research grants from Novartis and ApoPharma. DJP is a consultant to and has served on advisory boards and speakers' bureaus for Novartis, ApoPharma, and Siemens; has received research funding from Novartis; and is a director and stockholder for Cardiovascular Imaging Solutions.GCS and FA participated in study design, data analysis and interpretation and manuscript drafting. JPC and MHA performed additional data analysis. VB, MK, VL, AP, AA, EDG, MAT and MAW Served as investigators on the original trial. MR performed statistical analysis. DJP conceived of the study and was responsible for the final manuscript draft. All authors read and approved the final manuscript.


Systolic circumferential and longitudinal strain are widely used to assess myocardial performance, but their afterload dependence has not been well characterized. Using geometric estimates of left ventricular (LV) circumferential and meridional wall stress as indices of afterload at the myocardial level, we compared LV CSt and LSt to estimates of CWS and MWS in normals  and patients with dilated cardiomyopathy .Breath-hold retrospectively gated SSFP cine images in short and long axis planes and cuff systolic blood pressure(P) during imaging were obtained and mid LV and "global"  CSt% and LSt% determined using feature tracking . Mid-LV CWS and MWS were estimated using Mirsky's published formulae (CWS= P(B/h)/2), B= ES midwall semiminor axis ([D + h]/2)) and MWS= PRi/(2h(1+h/2Ri) where Ri= short axis LV radius).Mean mid-LV CSt% was -22.2+/-4.8% in NL but markedly reduced in DCM  while mean mid-LV LSt% was -14.7/-+8.9 in NL and markedly reduced in DCM. Reductions in CSt% and LSt% in DCM were associated with markedly elevated CWS  and MWS. Similar results were obtained for "global" CSt% and LSt%, the means of CSt% and LSt% at basal, mid-LV and apical slice locations(Table We conclude that afterload excess is a major contributor to impaired systolic function in DCM and normalization of contractile state and myocardial composition alone may not restore normal function. Consideration of effects of afterload excess, inadequate hypertrophy and adverse remodeling on myocardial strain is essential in the evaluation of pathophysiology.This study was supported by the St. Francis Research Foundation


Although dipyridamole is a widely used pharmacological stress agent, the direct effects on myocardium are not entirely known. Diabetic cardiomyopathy can be investigated by 2D-strain echocardiography. The aim of this study was to assess myocardial functional reserve after dipyridamole infusion using speckle-tracking echocardiography.Seventy-five patients referred for dipyridamole stress myocardial perfusion gated SPECT (MPGS) were examined by echocardiography to assess a new concept of longitudinal strain reserve (LSR) and longitudinal strain rate reserve (LSRR) respectively defined by the differences of global longitudinal strain (GLS) and longitudinal strain rate between peak stress after dipyridamole and rest. Twelve patients with myocardial ischemia were excluded on the basis of MPGS as gold standard.Mean LSR was −2.28±2.19% and was more important in the 28 (44%) diabetic patients . After multivariate analyses, only diabetes improved LSR (p = 0.011) after dipyridamole infusion and was not associated with glycaemic control (p = 0.21), insulin therapy (p = 0.46) or duration of the disease (p = 0.80). Conversely, age (p = 0.002) remained associated with a decrease in LSR. LSSR was also correlated to age (p = 0.005). Patients with a LSR < 0% have a better survival after 15 months (log-rank p = 0.0012).LSR explored by 2D speckle-tracking echocardiography after dipyridamole infusion is a simple and new concept that provides new insights into the impact of diabetes and age on the myocardium with a potential prognostic value. Dipyridamole is a widely used pharmacological agent to test coronary reserve in patients referred for stress myocardial perfusion imaging. The mechanism of stress with dipyridamole implies a coronary vasodilatation, which leads to the detection of myocardial ischemia through coronary steal phenomena. Dipyridamole mainly increases the flow supply in the subendocardial layer by decreasing vascular resistance , but theThe aim of this study was to assess the effects of dipyridamole on the myocardium in a population of patients referred for myocardial perfusion imaging by gated single-photon emission computed tomography (MPGS) and to explore the myocardial functional reserve with dipyridamole by means of a longitudinal strain reserve with speckle-tracking echocardiography.Patients referred for MPGS with previous or non-coronary artery disease (CAD) and without history of myocardial infarction were prospectively included from March to September 2011. All patients underwent a complete physical exam before inclusion. Exclusion criteria were documented allergies to dipyridamole, asthma, systolic blood pressure < 90 mmHg, decompensated heart failure or acute angina, significant valvular disease, hypertrophic cardiomyopathy, atrial fibrillation and the possibility to induce stress by effort. All patients were informed of the study design and agreed to the protocol before inclusion. Patients with identified MPGS ischemia were also excluded of the analysis.All enrolled patients underwent MPGS with intravenous dipyridamole pharmacologic stress using the standardized protocols from the European Association of Nuclear Medicine / European Society of Cardiology guidelines . CaffeinEchocardiography for all patients was performed at rest and 3 minutes after the completion of the dipyridamole infusion, i.e. at peak of stress, with a Imagic KM 60  using a 2.5 MHz transducer. A complete two-dimensional grey scale echocardiography including the three standard apical views  with a frame rate > 75 frame/s was performed for each patient. Left ventricle ejection fraction (LVEF) and volumes were assessed before and after the dipyridamole infusion as diastolic parameters. Myocardial strain was measured using speckle-tracking echocardiography.The 17-segments model, as defined by the American Society of Echocardiography, was used to examine both echocardiography and MPGS . The apeFor the echocardiography, digital data of 3 consecutive heart cycles were recorded and transferred to a personal computer with My Lab Desk workstation  for offline analysis. The endocardial border was defined manually in end systole and automatically tracked frame by frame. Operator assessed optimal evaluation of both quality of tracking and region of interest. Global longitudinal strain (GLS) was obtained by averaging all segmental longitudinal strain curves computed from the conventional apical two-, three- and four-chamber views. Longitudinal strain reserve (LSR) was defined by the difference between peak systolic global longitudinal strain at the peak of vasodilatation with dipyridamole and at rest. The longitudinal strain rate was determined for the left ventricle as the maximal strain rate value  during the ejection phase. The longitudinal strain rate reserve (LSRR) was similarly obtained Figure . Left veFor MPGS studies, off-line analysis was performed on Syngo MI Applications software . The images were assessed visually and by applying automated methods. A single blinded observer interpreted echocardiographic and MPGS studies. Myocardial ischemia was defined by at least one reversible myocardial perfusion defect between stress and rest myocardial perfusion gated-SPECT and was expressed by the number of segments affected.Data about the occurrence of adverse events were obtained from medical records by direct patients’ interviews or from the referring physician. The primary end point was defined by all-cause mortality. Patients unable to be interviewed up to 6 months at the date of follow-up were considered as lost to follow-up.2 test. Linear regression analysis was used to investigate the relation between LSR-LSRR and variables. Conventional variables correlated with LSR with a p value < 0.05 at first univariate analyses were used to build the final multivariate stepwise model. Receiver operating characteristic (ROC) curves were computed to determine optimal cut-off point for longitudinal strain reserve as well as to calculate area under the curve (AUC) to determine prognostic significance. Multivariate Cox regression model was built to identify echocardiographic parameters associated with all-cause mortality. Survival curve was determined according to the Kaplan-Meier method, and cumulative event rates compared by means of the log-rank test. Differences were considered statistically significant for p-values of < 0.05. All analyses were performed on SPSS software version 20 .Data were expressed as mean +/− SD. Nominal values were expressed as numbers and percentages. Normality was tested by the Kolmogorov-Smirnov test. The association between the mean values of continuous normally distributed variables were compared using unpaired and paired Student’s t test and the Mann–Whitney rank sum test was used when the samples were not normally distributed or had unequal variances. Comparison between multiple groups was performed with a variance analysis (ANOVA). Nominal variables were investigated by the χEighty patients were prospectively included. Four patients (5%) were excluded from the analysis due to a poor resolution of 2D echocardiography as a consequence of poor ultrasonic window (obesity or pulmonary disease) that did not allow speckle-tracking imaging and 1 (<1%) due to refusal of gated-SPECT after echocardiography. Among the 75 other patients included, 12 were excluded for MPGS ischemia with at least one or more reversible defect segment  but the diabetic patients in comparison to the non-diabetics also showed a non-significant variation of systolic blood pressure . Results are similar regarding the diastolic blood pressure (p = 0.09). The mean heart rate increased from 70±14 beats/min at rest to 80±18 beats/min after the dipyridamole infusion (p < 0.001) showing the pharmacological effect of dipyridamole. No examination had to be stopped for safety reasons.The effects of dipyridamole on LSR according to baseline characteristics, coronary risk factors, dyspnea and medications are presented in Table By univariate analysis, only age was associated with a decrease of LSR after dipyridamole infusion whereas patients with diabetes, higher Body Mass Index (BMI) and current smoking showed an improvement of LSR Table . IncreasLSRR was only associated with aging (p = 0.005) and was not influenced by diabetes (p = 0.57). Moreover, longitudinal strain rate increased by 16% between baseline and peak stress in the diabetic population (p = 0.11).During a mean follow-up of 15±5 months, 6 (10%) patients reached the primary endpoint. Only one patient was lost to follow-up and was excluded for survival analysis. After multivariate analysis, only the left ventricle end systolic volume at stress  from Kontron for speckle-tracking echocardiography. However, the current study was not supported by those grants.TC researched and analyzed data and wrote the manuscript. PLV performed the statistical analysis. LD recorded follow-up information. DB, RR, MB, PM, MG, AF researched data. MG, DC, PM, IB contributed to discussion and reviewing. O.L. led the study, revised the manuscript and gave final approval of the version to be published. All authors read and approved the final manuscript.


Congenital heart diseases are broadly defined as those cardiac anomalies that are present at birth. By their very nature, such defects have their origin in embryonic development. Congenital mitral valve regurgitation is a rare disease occurring in infancy or childhood. In up to 60% of cases, congenital anomalies of the mitral valve occur in association with other cardiac lesions, and often more than one component of the mitral apparatus is involved. The true incidence of congenital mitral valve regurgitation (MVR) is difficult to determine accurately ; isolated congenital mitral regurgitation is uncommon.The Carpentier classification of congenital mitral valve disease is the most commonly used nomenclature based on a functional analysis of the mitral valve leaflet. The contemporary anatomic classification has the advantage of minimizing observer variability in the diagnosis and it offers a much better liaison between the cardiologist and surgeon. Historically, the emergence of two–dimensional echocardiography must be viewed as a milestone in the diagnostic approach to congenital heart disease. The tomographic nature of the technique and its great number of imaging planes permit the anatomy and relationships of the cardiac structures to be defined, even in the presence of complex congenital malformations. For the noninvasive assessment of cardiac structure and function, echocardiography plays a prominent role as the most accurate and widely applied method. When details of the clinical history are unavailable, the echocardiographer is often called on to determine which surgical procedures have been performed. The options for further intervention often depend on the echocardiographic results ,2.For a good and useful evaluation, echocardiographic exam must take into account the anatomic and functional aspects of mitral valve, in a tight connection. To obtain a comprehensive and accurate description of the whole mitral apparatus it is useful to have a systemic approach when performing transthoracic echocardiography and multiplane transesophageal echocardiography examination.The anatomic structure of mitral apparatus is complex and sometimes difficult to describe in echocardiographic exam .Anatomically, the mitral valve consists of an annulus, leaflets, chordae tendineae, and papillary muscles. The mitral annulus is an integral part of the fibrous skeleton of the heart. The normal mitral valve has two leaflets, anterior and posterior, that act in conjunction with the subvalvular apparatus as one functional unit. The larger anterior  leaflet attaches to 150 degrees of the annulus, and is squat and trapezoidal in shape. As a consequence of being in fibrous continuity with the aortic valve, it forms the posterior boundary of the left ventricular outflow tract. The posterior  leaflet is narrower and occupies 210 degrees of the annulus. Two natural indentations in the posterior leaflet produce three segments, which subdivide it into lateral, central and medial scallops. The mitral valve leaflets are separated by the anterolateral and posteromedial commissures. Beneath the commissures lie two corresponding papillary muscles, which are extensions of the subendocardial ventricular myocardium. Chordae tendineae from the papillary muscles insert on both sides of the corresponding commissure, so each valve leaflet receives chordae from both papillary muscles.Considerable variation can be found in the morphology of the normal mitral valve ,5. It iIt should be expected that medical and surgical practice use prevalently an anatomic classification. However, the Carpentier classification  of congThis 1976 classification is predicated on a functional analysis of the mitral valve leaflet. However, there are two limitations of this classification, which can produce observer variability, and therefore potential inconsistency in data reporting. Firstly, a purely stenotic or insufficient valvar lesion is rarely observed. Secondly, the surgical literature has generally divided, reported, and risk stratified congenital mitral valve lesions based on stenosis versus insufficiency, not leaflet function .In addition, the Carpentier classification was developed before routine two–dimensional echocardiography was available. Functional evaluation of the leaflets by direct vision in the operating room may be difficult, despite saline insufflation of the flaccid left ventricle .Accurate and thorough preoperative echocardiography becomes mandatory to define lesions based on leaflet motion and to effect the appropriate repair. Individual interpretations of the functional anatomy introduce variability, which makes the reliability and reproducibility of a classification difficult ,8,9.At present, transesophageal echocardiography provides considerable information regarding mitral valve structure and function. Intraoperative echocardiographic monitoring of mitral valve surgery has become a routine practice in most cardiac centers. Perioperative assessment of valve anatomy by transesophageal approach provides detailed anatomical imaging .Surgeons now have much more information before the valve is inspected. This permits preoperative classification, which may be enhanced by direct observation of the valve at the time of operation.Within the context of criticisms for Carpentier functional classification of congenital mitral valve diseases and from practical necessity, S. N. Mitruka et al.  Table  proposedThe adoption of an optimal standard nomenclature that could be widely utilized, consistent, and reproducible would minimize observer variability in the diagnosis. This classification makes the issues of leaflet function as a consequence of the altered valvar anatomy. This, in turn, allows a segmental and systematic approach for considering the therapeutic options ,11,15.The anatomic contemporary classification for congenital mitral valve disease is presented below .In our institution (‘Prof. C.C. Iliescu’ Emergency Institute of Cardiovascular Diseases) from March 2003 to March 2009 were admitted 60.175 patients, out of whom 8709  had mitral valve regurgitation. Congenital mitral valve regurgitation was represented by 4.08% (356 patients): 197 men and 156 women, with medium age of 48.3 years old (range: 5–89 yrs). We have to add that in our Institute, which includes a Medical Cardiology Clinic and a Department of Cardiac Surgery, Carpentier classification is used dominantly, and the prevalent surgical treatment is mitral valve replacement. However, lately, the anatomic classification has been starting to gain its place. Thus, there were cases of mitral valve disease in which anatomic classification offered a comprehensive medical and surgical approach.In virtue of this classification, we present some personal echocardiographic images with congenital mitral valve regurgitation, as it follows:Type 1 , an abnormality of the mitral valve above the level of the leaflets or annulus, is illustrated inFig 1by a mitral supravalvular ring .Type 2 , an abnormality of the mitral valve at the level of leaflets or annulus, is illustrated in: Fig 2 by isolated  mitral valve cleft,Fig 3 by leaflets with excessive tissue and Fig 4 by congenital double–orifice mitral valve.Type 3 , an abnormality of the mitral valve at the level of the chordae tendinae or the papillary muscles, is illustrated in Fig 5 by elongated chordae tendineae and in Fig 6 by shorted chordae tendineae.Type 4 (mixed), an abnormality of the mitral valve that is described as a mixture or combination of two or more of the above three types, described in Fig 7 by: annulus dilatation, excessive tissue on the leaflets and elongated chordae tendineaeThe therapeutic options for congenital mitral valve disease are somewhat limited ,13. An The echocardiography can offer preoperative important features and allows the characterizations of the lesions based on both accepted classifications: the functional and the anatomical one. Currently, Doppler echocardiography plays an important role in the early determination of the type of surgery that may be performed for the correction of the mitral valve regurgitation –16. TheThere is no truly satisfactory substitute for the mitral valve in a patient of any age. The limitations of replacing the mitral valve with a mechanical valve in infants and children are well recognized . TechniqOften, infants and children are referred for mitral valve operation in the absence of obvious symptoms. Gross cardiomegaly and dilatation of the left atrium in a seemingly asymptomatic child may provide an adequate basis for operation if the preoperative echocardiographic analysis suggests that the valve is amenable to repair.In patients with a markedly abnormal valve or in those who have previously undergone repair, mitral valve replacement may be the only option .In general, most cardiologists and surgeons wait longer before referring a patient for mitral valve replacement than they would for a first time attempt at mitral valve repair. Thus, surgical intervention is considered when symptoms become severe or when exercise limitations become unacceptable. Valve repair is the optimal course of action. Mitral valve replacement is considered a last resort .The classification for congenital mitral valve regurgitation based dominantly on anatomic considerations offers useful medical and surgical details for the most appropriate mitral valve correction . The Carpentier classification based on functional analysis of mitral valve leaflet continues to be the traditional classification, and may be used in addition to the anatomic nomenclature.


Our aim was to characterize the cardiac morphology, function and myocardium in patients with sickle cell disease (SCD) using CMR and transthoracic echocardiography (TTE).Cardiovascular complications are a major cause of death in SCD yet the mechanism remains unclear.Thirty-one stable, African-American outpatients with SCD (mean age 32±8 yrs) prospectively underwent CMR (Philips 1.5 Tesla) and TTE (Philips iE33). Retrospectively-gated cines of left ventricular (LV) 2-, 3-, and 4-chamber, and short axis cine stack were obtained using SSFP . Late gadolinium enhancement (LGE) images of the same views were obtained 10-20 minutes after infusion of Gd-DTPA (0.15 mmol/kg) using phase sensitive inversion recovery .TE2/ SITE1) where ΔTE represents time difference between the two echo times and ITE1 and ITE2 represent signal intensity at echo time one and two. Myocardial and hepatic T2* were abnormal if <20ms and <18ms, respectively.Single short-axis, mid-ventricular myocardial T2* slice and coronal, hepatic T2* slice were acquired with a single breath-hold, at six echo-times (2.3 to 14 msec) using a gradient echo sequence. Tissue T2* signal intensity was measured in LV septum and liver at two separate echo times and T2*= - ΔTE/ln , and mass were calculated using method of disks and indexed for body surface area. The presence or absence of LGE was determined. Diastolic dysfunction (DD) was identified based on echocardiographic measurements including tissue Doppler (age adjusted E/A ratio) and left atrial volumes.SCD patients had preserved LVEF with enlarged biventricular and LA volumes. DD was present in 15 (48%). LGE was noted in 7 (23%), myocardial iron overload in 2 (7%) and hepatic iron overload in 16 (52%). (Figure SCD patients had significant chamber dilation, DD, and LGE. Those with LGE had significantly more hepatic iron overload suggesting a greater disease severity requiring more blood transfusions. Women with LGE demonstrated more severe adverse remodeling. Myocardial iron overload was rare.


Cardiovascular magnetic resonance (CMR) can provide a non-invasive means of measuring the amount of tissue iron. The iron results in shortening of proton relaxation times and both CMR T2* and T2 have been validated as non-invasive means for assessment of myocardial iron overload. . We have reported that a T2* value below 20ms represents iron overload in the heart (5). This cut-off value, though proven very useful in clinical practice, was based on 15 normal volunteers in our initial report (5). There is currently little data to confirm this important cut-off value which has been widely accepted for early diagnosis of myocardial iron in patients with thalassemia major (TM).A mixture model corresponds to the mixture distribution that represents the probability distribution of observations in the overall population. We believe myocardial T2* and T2 data may contain an intrinsic pattern which can be explored for clinical diagnosis. The current study, therefore, aimed at clustering patients automatically into normal and abnormal groups by using Gaussian mixture models (6).In total 236 TM patients  were studied on a 1.5T MRI scanner All patients were scanned using the black blood T2* (3) and T2 (4) sequences, each within a breath-hold. A single mid-ventricular short axis slice was imaged with T2* and T2 measured in the left ventricular septum. The clustering algorithm using Gaussian mixture models was developed in Matlab.Figure This study confirms that T2* is a reliable tool for screening patients with iron overload. There appears an intrinsic pattern in myocardial T2* and T2 data in patients with thalassemia patients; Gaussian mixture model can automatically cluster the 2-dimensional data and the results agree well with that using a T2* cut-off value of 20ms. There are a few mismatched samples and a further study is needed to clarify and explain this phenomimen in order to provide improved myocardial tissue characterization for patients with TM.This study was supported by the UK NIHR Cardiovascular Biomedical Research Unit of Royal Brompton Hospital and Imperial College, London. Dr He was supported by Wellcome Trust Value In People (VIP) award and now holds a British Heart Foundation (BHF) Intermediate Basic Science Fellowship (FS/08/26225).


To investigate the phenotypic relationships between aortic stiffness and left ventricular (LV) stroke volume (SV) and modes of deformation  at rest and stress, with preserved and compromised contractile capacity.Increased aortic stiffness, measured by pulse wave velocity (PWV), is linked to a range of cardiovascular (CV) risk factors and acts as predictor of CV events, independently of age-related increase in pulse pressure. As an integrated marker of the pulsatile component of LV afterload, PWV has been linked to prognostically adverse cardiac phenotypes, including LV systolic dysfunction and post-infarct remodelling. Evidence suggests that longitudinal mode of deformation is particularly important to overcome the superimposed afterload. Thus, reduced LD due to myocardial ischaemia or scar may influence the capacity to offset the LV afterload in patients with increased aortic stiffness.At total of 124 cardiac patients underwent a high-dose dobutamine-stress/perfusion magnetic resonance (DS(P)MR) protocol with simultaneous late gadolinium enhancement (LGE) imaging and aortic pulse wave velocity (PWV) measurements MR/LGE outcome as negative (n=68) or positive for ischaemia (n=25), or post-infarct LV remodelling with scarring (n=31). All three groups showed a significant within-subject increase in HR and cardiac output with similar HR*BP products (p>0.05) in all 4 stages of the protocol Figure . SV incrOur findings reveal that modes of deformation to increased aortic stiffness differ at rest and dobutamine-stress and with compromised LV contractility: intact myocardium relies on longitudinal function to displace volume and offset the afterload, whereas with LV dysfunction, increased LV wall stress reveals a role for radial component.


The right ventricular (RV) apex has been the standard pacing site since the development of implantable pacemaker technology. Although RV pacing was initially only utilized for the treatment of severe bradyarrhythmias usually due to complete heart block, today the indications for and implantation of RV pacing devices is dramatically larger. Recently, the adverse effects of chronic RV apical pacing have been described including an increased risk of heart failure and death. This review details the detrimental effects of RV apical pacing and their shared hemodynamic pathophysiology. In particular, the role of RV apical pacing induced ventricular dyssynchrony is highlighted with a specific focus on differential outcome based upon QRS morphology at implant. The development of implantable pacemaker technology in the mid 20th century proved life saving for many patients with bradyarrhythmias . In the However, an increasing amount of data has recently raised questions about the safety of RV apical pacing -14. ThesThis review details the detrimental effects of RV apical pacing and its associated hemodynamic pathophysiology. In particular, the role of RV apical pacing induced ventricular dyssynchrony is highlighted with specific focus on differential outcome based upon QRS morphology at implant. Alternative and developing pacing strategies for patients with a permanent pacing indication including cardiac resynchronization therapy (CRT), alternative pacing sites, leads, programming configurations and energy sources are also discussed.For decades, RV apical pacing proved to be an effective therapy for sinus node disease , atrio-vStudies that have shown the deleterious effects of RV apical pacing can be categorized by the indication of pacemaker implantation and by the mode of pacing. Studies enrolling patients with sinus node dysfunction compared VVI with AAI pacing or DDD with AAI pacing whereas those enrolling patients with AV block compared the effects of DDD with VVI pacing.Andersen et al  investigSeveral clinical studies ,20-22 inProviding a possible mechanism for the increase in both endpoints, Nielsen et al. demonstrated that the use of dual-chamber pacing (i.e. high RV pacing) is associated with left atrial enlargement when compared to atrial pacing alone . This suSeveral studies of DDD vs. VVI only pacing in patients with AV block ,11, or bA subsequent subgroup analysis of MOST  among patients with QRS < 120 msec shed light on a possible underlying reason for the negative outcomes of these studies . It demoThe DAVID  trial further substantiated the association between RV pacing and adverse cardiovascular outcome . OperatiThe MADIT II  enrolled 1,232 patients with ischemic cardiomyopathy randomized to ICD vs. medical therapy in a 3:2 ratio. ICD configurations within the study included single chamber programmed VVI-40 (44%) and dual chamber programmed DDD-70 (56%). Steinberg et al reported the short term (median 1.5 years) follow up of RV pacing in the ICD arm dichotomized by a pacing burden of greater (high RV pacing) and less than 50% (low RV pacing) [8]. Patients with high RV pacing were older, had higher blood urea nitrogen levels, and were more likely to have wide QRS and LBBB compared with non-ICD patients or patients with low RV pacing. After multivariate adjustment, high RV pacing patients were at significantly increased risk of new or worsened HF  and appropriate ICD therapy for VT/VF . However, the mortality rates were similar for high (13%) and low (10%) RV pacing groups  [8].Most recently, we have analyzed the association between percent RV pacing and long term mortality in MADIT II during an 8-year follow-up [9]. Patients were categorized into three subgroups: low RV pacing , high RV pacing , and no ICD (n = 490). During the first 3 years after enrollment, the benefit of the ICD was prominent both in patients with low RV pacing  and in those with high RV pacing ; In contrast, during the late phase of the extended follow-up period (4-8 years) ICD therapy was associated with a significant survival benefit among patients in the low RV pacing subgroup  but not in the high RV pacing subgroup . In addition, during the total 8 year follow up, high RV pacing was shown to be associated with a significant adjusted 40% (P = 0.01) increase in the risk of death compared with low RV pacing . Thus, tThe deleterious effects of RV apical pacing have been attributed to the abnormal electrical and mechanical activation induced secondary to this form of pacing. During RV apical pacing, the electrical wave front propagates through the myocardium, rather than through the His-Purkinje conduction system. As a result, the electrical wave front propagates more slowly and induces heterogeneity in electrical activation of the myocardium, comparable but not identical to left bundle branch block. This is characterized by wave front breakthrough at the interventricular septum and latest activation at the infero-posterior base of the left ventricle -26.Similar to the changes in electrical activation of the ventricles, the mechanical activation pattern is altered during RV apical pacing. Importantly, not only does the anatomic onset of mechanical contraction differ, but also the resulting pattern of mechanical contraction . Badke eBeyond the hemodynamic effects of ventricular dyssynchrony, it has become clear that long-term RV pacing may also result in structural changes and adverse LV remodeling. Originally reported in1986 in an RV pacing dog complete heart block model , three mIt has long been known that native LBBB can have profound hemodynamic effects due to ventricular dyssynchrony, particularly among patients with HF . As detaWe explored the effects of RV pacing on ICD benefit according to LBBB at enrollment in MADIT-II during an extended long term follow-up of 8 years . We founIn contrast to these findings, Hayes et al  in a subReconciling the stark differences among these studies remains difficult. The primary differences between the MADIT-II substudy and the DAVID substudy include different study endpoints (death in MADIT II vs. HF or death in DAVID), duration of follow up and indication for pacing. DAVID specifically randomized patients based upon pacing programming where the focus of MADIT II was the efficacy of primary prevention ICD therapy in ischemic cardiomyopathy. Within the MADIT II sub-analysis the primary limitation was the clinical differences between high and low RV pacing subgroups. We cannot completely exclude the possibility that sicker patients required more pacing and had poorer outcomes as a result. Furthermore, data on percent RV pacing were collected only among 79% of the 720 patients who received an ICD in MADIT II. Patients who were not included in this data analysis due to missing pacing information appeared to be sicker with an elevated in-trial mortality rate of 42% compared with 12% in patients analyzed in our study. The DAVID analysis was limited by size and follow up duration.Methods to avoid the detrimental effects of RV pacing include device programming to minimize RV pacing, alternative pacing sites, and biventricular pacing. The current mainstay of programming based methods to avoid RV pacing includes AV search or MVP (managed ventricular pacing) mode. Such programming was evaluated in the SAVE PACe (Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction) trial, where 1,065 patients with sinus node disease and intact AV conduction were randomized between conventional dual-chamber pacing and dual-chamber minimal ventricular pacing . RV paciWhen RV pacing is inevitable, the His bundle ,43, righFor RV apical pacing dependent patients with abnormal LV function -56 or RVThe PACE trial  directlyRight ventricular apical pacing is an integral part of the treatment of brady-arrhythmias for the majority of patients receiving pacemakers. Right ventricular apical pacing is, however, an often pathologic substitute for intrinsic ventricular activation over the His-Purkinje system. Several reports indicate that this form of pacing is detrimental potentially increasing the risk of heart failure episodes and death, particularly in patients with abnormal LV function. Further studies are needed to clarify the mechanisms underlying the deleterious effects of RV pacing, RV apical pacing burden to be avoided, and the specific risk factors for poor outcome among patients with high RV pacing burden. In the meantime, alternative pacemaker programming and configurations are available that can minimize the frequency and detrimental nature of ventricular pacing in many pacemaker patients. Additional research will determine if different forms of ventricular pacing, such as right ventricular outflow tract, RV septal pacing, or biventricular pacing will improve outcomes in patients who require ventricular stimulation.


Left atrial volume (LAV) and emptying fraction (LAEF) are phasic during cardiac cycle. Their relationships to left ventricular end diastolic pressure (LVEDP) have not been fully defined.max), LV end diastole (LAVmin) and late LV diastole prior to LA contraction (LAVac). LAEF was assessed as global LAEF , passive (LAEFPassive) and active LAEF (LAEFContractile). The relationships of phasic LAV and LAEF to LVEDP were assessed using Receiver operating characteristic comparing areas under the curves (AUC).Forty one patients undergoing clinically indicated left heart catheterization were recruited for same day cardiovascular magnetic resonance (CMR). LAV and LAEF were assessed in cine images using biplane area and length method. Three phasic LAV was assessed at LV end systole (LAVmin had the strongest association with LVEDP elevation (>12 mmHg) , as compared to LAVmax  and LAVac . Among three phasic LAEF assessed, LAEFTotal had the closest association with LVEDP elevation , followed by LAEFContractile  and LAEFPassive .The mean age of the patients was 59 years. A history of heart failure was present in 16 (39%) with NYHA functional class III or IV in 8 (20%) patients. Average LV ejection fraction was 49 ± 16% ranging from 10% to 74% and LVEDP by catheterization 14 ± 8 mmHg ranging from 4 mmHg to 32 mmHg. LAVmin and decreased LAEFTotal have the best performance in identifying elevated LVEDP among three phasic LAV and LAEF analyzed. Future studies should further characterize LA phasic indices in clinical outcomes.Increased LAV Left atrial (LA) dilatation is found in many conditions, including atrial fibrillation, left ventricular (LV) systolic and diastolic dysfunction, congestive heart failure, and valvular heart disease -4. IncreThe standard method of determining phasic LA volumes (LAV) is based on a time-volume curve depicting LAV over the entire cardiac cycle. A simpler alternative, which is commonly used in clinical studies, assesses LAV in single-phase analyses characterized by mitral valve position -13. But We sought to assess the relationship of phasic LAV and LA function to LV filling pressure and to compare the single-phase LAV method to the standard multi-phase method using cardiovascular magnetic resonance (CMR) in a group of patients who underwent clinically indicated right and left heart catheterization.2; claustrophobia; pacemaker/defibrillator implantation; or other metallic hazards.The study protocol was approved by the St. Francis Hospital Institutional Review Board. All subjects were prospectively recruited with written consent. There were 41 patients undergoing clinically indicated right and left heart catheterization. Exclusions included atrial fibrillation, impaired renal function with glomerular filtration rate < 45 mL/min/1.73 mLV end diastolic pressure (LVEDP) was obtained during left heart catheterization following standard clinical protocol. Hemodynamic tracings obtained during quiet respiration were recorded and stored electronically. Two experienced cardiologists reviewed tracings and the values of LVEDP were determined by consensus. To match the inspiration breath-hold during CMR image acquisition LVEDP at inspiration was used.All subjects underwent CMR in a 1.5 T Avanto scanner (Siemens) using 8-element phased array surface coil. Steady-state free precession (SSFP) cine images were acquired during inspiratory breath-holds with retrospective ECG gating in long axis 2-, 3- and 4-chamber views. A stack of 8-mm thick short axis images was obtained with 2-mm gaps. The average field of view was 240 mm, echo time 1.3 ms, repetition time 3.1 ms, flip angle 70°, matrix 192 × 154 yielding an in-plane resolution of 1.6 × 1.3 mm and temporal resolution of 30–40 ms. The average number of phases was 20 to 30, varying by heart rate to reach consistent temporal resolution.max), at LV late diastole just before LA contraction (LAVac) and LV end diastole (LAVmin) , passive LAEF (LAEFPassive) and active LAEF (LAEFContractile) were defined as fractional volume changes as follows. LAEFTotal = (LAVmax-LAVmin)/LAVmax, LAEFPassive = (LAVmax-LAVac)/LAVmax and LAEFContractile = (LAVac-LAVmin)/LAVmax, respectively [Volumetric short axis cine images were analyzed using commercially available software . Left and right ventricular volumes, ejection fraction and myocardial mass were assessed and normalized to body surface area. LAV were calculated using a biplane area and length method following the formula: 0.85×A1×A2/L, where A1 and A2 were areas measured by planimetry in 2- and 4-chamber views, respectively and L was the length of LA perpendicular to the center of mitral annulus in the 4-chamber plane . Bland-Altman plots were used to compare LAV measurements derived using single-phase and multi-phase methods. For all statistical analyses, p < 0.05 was considered significant. Statistical analysis was performed using MedCalc 11.3  and SPSS 17 .Categorical variables were expressed as proportions and continuous variables as means ± standard deviations (SD). Categorical variables were compared using Fisher’s exact test and continuous variables using Student’s The mean age of the patients was 59 years. A history of coronary artery disease was present in 27% of patients and history of congestive heart failure in 39%. NYHA functional class III or IV was present in 20% of patients. Average LV ejection fraction was 49 ± 16% ranging from 10% to 74% with 32% of patients having LV ejection fraction < 50%. Mean LVEDP was 14 ± 8 mmHg ranging from 4 mmHg to 32 mmHg. The most prevalent significant valvular dysfunction (≥2+) was aortic insufficiency (17%) followed by mitral regurgitation (12%) . Each was significantly larger in subjects with elevated LVEDP (>12 mmHg) than in those with normal LVEDP (≤12 mmHg) . Similar to phasic LAV, all three phasic LAEF indices were lower in subjects with elevated LVEDP than in those without  [min taken at LV end diastole is superior to LAVmax as a marker of clinical outcome risk [End systolic LAV failure ,5,14-16. failure . Therefore [max) ,14,17-19ome risk . Few stuWith the growing interest in LA assessment in clinical and epidemiological studies it is important to delineate the pros and cons of alternative evaluation methods ,9. The mThere are limitations to our study. As expected the chronicity of increased LV filling pressures is a variable which may influence the extent of LA remodeling and LA active contraction and could not be easily determined in this clinical population. Mitral regurgitation was present in some patients and can further complicate the relationship of LA size and function to LV filling pressure. While all participants were reportedly stable small variation in hemodynamics are inevitable given that CMR was performed within 5 hours of catheterization. Contrast or sedatives commonly given during left heart catheterization may reduce LV filling pressure rendering a possible underestimation of the relationship of the LA indices with LVEDP. We also assessed LAV using the biplane area length method rather than the gold standard Simpson’s rule method. However, the biplane method has been well validated and is of the most relevant approach because of its speed, simplicity and widespread use in both clinical and epidemiological studies.min and decreased LAEFTotal were most closely associated with elevated LVEDP in ROC analysis. Single-phase LA volume and function indices are good alternatives to the multi-phase volume curve methods.In conclusion, increased LA volumes at multiple time points in the cardiac cycle and decreased LA functional indices were all associated with increases in LVEDP. Among them increased LAVCMR: Cardiovascular magnetic resonance; LV: Left ventricle; RV: Right ventricle; LVEDP: Left ventricular End Diastolic Pressure; LA: Left atrium; LAV: Left atrial volume; LAVmax: Left atrial volume at left ventricular end systole; LAVmin: Left atrial volume at left ventricular end diastole; LAVac: Left atrial volume at left ventricular late diastole before left atrial contraction; LAEF: Left atrial emptying function; LAEFTotal: Global left atrial emptying fraction; LAEFPassive: Passive left atrial emptying fraction; LAEFContractile: Active left atrial emptying fraction; ROC: Receiver operating characteristics.The authors declare that they have no competing interests.KP, Analysis and interpretation of the data, image analysis, and drafted manuscript. JM, Patient recruitment and clinical data management. PR, Patient recruitment and clinical data collection. LL, Image analysis. JC, Image acquisition. WS, Image acquisition. RG, Hemodynamic data collection. AB, Hemodynamic data collection. GP, Hemodynamic data collection. NR, Critical review of the manuscript. JJC, Conception and design of study, data review and analysis, critical review of the manuscript, and final approval of submission. All authors read and approved the final manuscript.


Patients with RVI complicating AMI suffer from increased morbidity and mortality, but it is unclear which patients are in risk of developing RVI. Cardiovascular magnetic resonance (CMR) can identify patients with RVI and might add important information for risk stratification, prognosis and treatment.We aimed to determine the predictors of right ventricular involvement (RVI) assessed by wall motion abnormalities, edema, myocardial salvage and delayed enhancement in acute reperfused myocardial infarction (AMI) and the prognostic significance of RVI.We studied 431 patients 1-4 days after primary angioplasty for ST-elevation AMI. T2-weighted and delayed enhancement (DE) CMR was used for visualizing edema and scar to calculate myocardial salvage (MS). Cine-imaging was used for wall motion analysis. Patients with RVI were compared to matched patients with isolated left ventricular (LV) infarction. The primary endpoint was the occurrence of a major adverse cardiac event (MACE): a composite of death, reinfarction and congestive heart failure.RVI with localized wall motion impairment and edema was found in 69 patients, of which 41 showed myocardial necrosis in DE imaging. In multivariate linear regression analysis predictors of RVI were a low TIMI-flow grade before angioplasty , a high RV myocardial mass  and a low ST segment resolution . In Cox regression the strongest predictor of MACE was RVI .RVI detected by CMR is a strong and independent predictor of clinical outcome after acute reperfused AMI.