To investigate to what extent cardiac MRI derived measurements of right ventricular (RV) volumes using the left ventricular (LV) end-systolic and end-diastolic frame misrepresent RV end-systolic and end-diastolic volumes in patients with tetralogy of Fallot (ToF) and a right bundle branch block.Sixty-five cardiac MRI scans of patients with ToF and a right bundle branch block, and 50 cardiac MRI scans of control subjects were analyzed. RV volumes and function using the end-systolic and end-diastolic frame of the RV were compared to using the end-systolic and end-diastolic frame of the LV.2, interquartile range −1.9 to −5.6 ml/m2; p<0.001) and close to unchanged in control subjects. Using the RV instead of LV end-systolic and end-diastolic frame hardly affected RV end-diastolic volumes in both groups and ejection fraction in control subjects , while increasing ejection fraction from 45±7% to 48±7% for patients with ToF (p<0.001). QRS duration correlated positively with the changes in the RV end-systolic volume (p<0.001) and RV ejection fraction obtained in ToF patients when using the RV instead of the LV end-systolic and end-diastolic frame (p = 0.004).Timing of the RV end-systolic frame was delayed compared to the LV end-systolic frame in 94% of patients with ToF and in 50% of control subjects. RV end-systolic volume using the RV end-systolic instead of LV end-systolic frame was smaller in ToF (median −3.3 ml/mFor clinical decision making in ToF patients RV volumes derived from cardiac MRI should be measured in the end-systolic frame of the RV instead of the LV. Evaluation of right ventricular (RV) volumes and function is crucial in the management of patients with congenital heart disease To acquire accurate CMR derived volume measurements, correct selection of the RV end-systolic and end-diastolic frame may be important. In normal hearts, contraction of the RV lags slightly behind that of the left ventricle (LV) The present study is the first to quantitatively document the influence of independent selection of the end-systolic and end-diastolic frame for the RV and LV, on RV volume measurements in a large group of patients with ToF and control subjects.Our institution’s CMR database was searched to collect 65 of the most recent CMR scans of patients with ToF and 50 normal CMR scans performed in patients suspected for myocardial infarction (control subjects). Normal CMR scans were defined as normal anatomy, normal LV and RV contraction, normal LV and RV volumes and ejection fraction with no signs of infarction, and no valvular dysfunction RBBB is defined as complete when the QRS duration≥120 ms and defined as incomplete when the QRS duration is ≥100 ms and <120 ms This retrospective study was approved by the University Medical Center Groningen review board. Informed consent was not required according to the Dutch Medical Research Involving Human Subjects act.All subjects were examined on a 1.5-Tesla MRI system  using a 2×6 channel body-coil. After single-shot localizer images, for function analysis short axis cine loop images with breath holding in expiration were acquired using a retrospectively gated balanced steady state free precession sequence. Short axis slices were planned in end-diastole from two slices above the mitral valve plane to the apex. The following parameters were used: TR 2.7 ms, TE 1.1 ms, flip angle 80°, field of view 320 mm, matrix 192×192 mm, 25 frames per cycle, slice thickness 6 mm, interslice gap 4 mm, voxel size 1.7×1.7×6 mm.Image analysis was performed using commercially available software . The end-systolic and end-diastolic frame was defined as the frame with the smallest and largest volume, respectively.These frames were selected by visual assessment independently for the LV and RV. LV and RV contours were drawn manually by tracing the endocardial borders in every slice in the end-systolic and end-diastolic frame of the LV. Contour tracing was aided by reviewing the multiple phase scans in the movie mode. The papillary muscle and trabeculae were considered part of the cavum. Additionally, RV contours were drawn in the end-systolic and end-diastolic frame of the RV.The basal slice was selected with aid of long-axis cine view images. The basal slice of the LV was defined as the most basal slice surrounded for at least 50% by the LV myocardium. When the pulmonary valve was visible in the RV basal slice, only the portion of the right ventricular outflow tract below the level of the pulmonary valve was included. For the inflow part of the RV, the blood volume was included when the ventricle wall was trabeculated and thick compared to the right atrium wall Stroke volume was defined as end-diastolic volume minus end-systolic volume. Ejection fraction was defined as stroke volume divided by end-diastolic volume.RV contours were first drawn in the visually selected end-systolic and end-diastolic frame of the RV. To minimize intraobserver variability, RV contours drawn in the end-systolic and end-diastolic frame of the RV were copied to the LV end-systolic and end-diastolic frame and then adjusted to this frame.To obtain intra- and interobserver reproducibility, contours were drawn independently twice by the first observer and once by the second observer in 25 scans of patients with ToF and 25 scans of control subjects. The end-systolic and end-diastolic frame was selected independently twice by the first observer and once by the second observer. There were at least two weeks between repeated contour drawing by the first observer. Both observers had more than 2 years experience with RV contour drawing.Descriptive statistics were calculated for all measurements as mean and standard deviation for normally distributed continuous variables, median with interquartile range (IQR) for skewed continuous variables and absolute numbers and percentages for dichotomous variables. Reproducibility was evaluated with the intraclass correlation coefficient (ICC). For normally distributed continuous variables a paired-samples Student’s t-test and for skewed continuous variables a Wilcoxon test was used to compare RV volumes measured in the LV end-systolic and end-diastolic frame with RV volumes measured in the RV end-systolic and end-diastolic frame. For normally distributed continuous variables an independent Student’s T-test and for skewed continuous variables a Mann-Whitney test was used to compare the difference in RV volumes between normal scans and scans of patients with ToF when measuring RV volumes in the end-systolic and end-diastolic frame of the RV instead of the LV. The relation between QRS duration and change in RV volume and function when using the end-systolic and end-diastolic frame of the RV instead of the LV was analyzed using linear regression. The Statistical Package for the Social Sciences version 16.0  was used for all statistical analyses. All statistical tests are two-sided and a P-value of less than .05 was considered statistically significant.Between January 2008 and January 2011, 65 CMR scans of patients with ToF  and 50 normal CMR scans of control subjects were collected. Patients with ToF  were younger than control subjects , p<0.001. QRS duration was longer in patients with ToF (145±25 ms) than in control subjects (93±9 ms), p<0.001. Heart rate during the CMR scan was similar in patients with ToF (70±12 bpm) and control subjects (73±15 bpm), p = NS.The difference in frame selection of end-systole and end-diastole between the RV and LV is shown in 2 (p<0.001) while ejection fraction and stroke volume increased from 45 to 48% (p<0.001) and from 62 to 66 ml/m2, respectively (p<0.001). ToF patient’s changes in RV end-diastolic volume and the changes in any of these four parameters in the controls were very small, though still significant in paired data analysis. 2 = 0.190, p<0.001), and RV ejection fraction  when using the end-systolic and end-diastolic frame of the RV instead of the LV.The increase of RV ejection fraction is mainly the result of decrease in end-systolic volume when using the end-systolic frame of the RV instead of the LV. Using the end-systolic frame of the RV instead of the LV resulted in a relative increase in ejection fraction of 7%, from 45±7% to 48±7%, in patients with ToF and of 1%, from 54±4% to 54±4%, in control subjects. The relative increase in ejection fraction and stroke volume by using the end-diastolic frame of the RV instead of the LV was <1% in both patients with ToF and control subjects.In 17 (26%) patients with ToF the absolute increase of ejection fraction exceeded 5% (range 5–8%), Intra- and interobserver ICC for RV end-systolic volume, end-diastolic volume and ejection fraction was .98, .91, .87 and .98, .97, .95 in patients with ToF and .94, .93, .88 and .95, .97 and .89 in control subjects, respectively.Our study is the first to quantitatively demonstrate the difference in RV volumes and function between using the RV and LV end-systolic and end-diastolic frame. Performing cardiac MRI derived measurements of RV volumes using the LV end-systolic and end-diastolic frame, misrepresent RV end-systolic and end-diastolic volumes in many patients with ToF, especially in the frequent case of a complete RBBB. These findings can be of clinical importance in the evaluation of the RV in patients with ToF.Previous echocardiographic and cardiac MRI studies reported on the electromechanical delay of the RV compared to the LV in patients with congenital heart disease and normal subjects One small (N = 12) cardiac MRI study indicated that measuring RV volumes in the two frames preceding RV end-systole causes no clinically significant volume changes despite the observation that end-systole of RV and LV occur in different frames 22According to the guidelines of the ESC and ACC/AHA, indication for replacement of the pulmonary valve in patients with ToF and moderate/severe pulmonary regurgitation is based on several parameters including RV function Identifying tricuspid valve opening and closing in a 4-chamber or RV 2-chamber view may allow for more accurate selection of the end-systolic frame. However, in the 4-chamber view the opening and closing of the tricuspid valve was not always clearly visible and RV 2-chamber views were not acquired.There are possible confounders for the difference in timing of end-systole between the studied groups, such as the difference in age, pulmonary stenosis and regurgitation, RV end-systolic and end-diastolic volume and underlying disease. However, it is unlikely that the difference in age will have influenced our results as age does not affect timing of contraction of the right and left ventricle Although we have shown that end-systolic volume of the RV in patients with ToF should be measured in the end-systolic frame of the RV instead of the LV, it is uncertain whether this applies to all patients with congenital heart diseases involving the RV and a RBBB.Independent selection of the end-systolic and end-diastolic LV and RV frame instead of using the LV end-systolic and end-diastolic frame for RV determinations, results in more accurate end-systolic RV volumes in patients with ToF and a RBBB. The differences are significant and correlate with QRS duration. For clinical decision making in patients with ToF and a RBBB, RV volumes should be measured in the end-systolic frame of the RV instead of the LV.


With current surgical techniques and postoperative immunosuppression, 1-year survival after HT is ≈90%, 5-year survival is ≈70%, and median survival exceeds 10 years.These improved outcomes have also affected the natural history of arrhythmia occurrence in the HT patient, and arrhythmias are increasingly recognized as significantly affecting quality of life, morbidity, and survival. Besides the effects of surgical healing, the increasing longevity of the HT patient allows for new and progressive alterations in the donor heart as well as the neurohumoral milieu, resulting in a spectrum of arrhythmias with clinical implications. The Table provides a summary of the unique mechanisms of arrhythmias in the transplanted heart.5 Risk of chronic rejection secondary to enhanced activation of the graft vessel endothelium may also be increased when myocardial preservation is not adequate.Prolonged graft ischemia time can predispose to conduction system injury in both early and late postoperative periods. Perioperative ischemic damage and subsequent endocardial fibrosis likely play a mechanistic role in many cases. Patients with prolonged graft ischemia >4 hours are classified as high risk and have greater 30-day and 1-year mortality rates.6The most commonly used technique of donor-to-recipient anastomosis is the bicaval method, in which anastomoses are made at the level of the two vena cavae, the great vessels, and the left atrial cuff around the pulmonary veins. Few centers continue to use the original biatrial method described by Shumway, where part of the recipient right and left atria are retained and sutured to the respective atria of the donor. With the latter method, the recipient sinus node is preserved but is not functional because of disruption of blood supply and denervation. Moreover, there is complete conduction block across the suture line in the right atrium. With the bicaval method, there is less sinus nodal injury, tricuspid regurgitation, and atrial dilatation.7 Reestablishment of conduction across the atrial anastomosis may produce tachycardia because of fibrillatory activity or flutter activity in the recipient atrium.12 Sinus activity from the recipient atrium may intermittently escape into the donor atrium and manifest as frequent atrial ectopics or an atrial parasystole. The scars in the atria act as conduction barriers and can also predispose to atrial flutters—cavo-tricuspid isthmus dependent as well as mitral annular flutters. Thus, the biatrial method is likely associated with greater risk of reentrant tachycardia and flutter .15When the biatrial method is used, activation of the recipient atrial tissue may be reflected on the ECG. In combination with graft P waves, the native P waves may mimic atrial flutter, though close examination will reveal nonconducted atrial parasystole rather than atrial flutter.16The exclusion of the pulmonary veins and the posterior left atrium is thought to be responsible for the very low incidence of atrial fibrillation (AF) with either surgical method, compared with other major cardiac surgeries including bilateral lung transplantation.The donor heart is completely denervated during transplantation. In the balance, lack of parasympathetic activity has greater effects, and most HT patients have higher than average resting heart rate and significantly reduced heart rate18 Studies have correlated changes in the corrected QT interval to sympathetic reinnervation and have postulated that there may be a subset of patients with increased ventricular arrhythmia and mortality risk associated with heterogeneous reinnervation.20 Autonomic denervation may partially account for several unique electro-physiological findings in HT patients, beginning with the low incidence of AF after HT. Denervation is also an intriguing possible factor in the lower incidence of ventricular fibrillation (VF) as the terminal rhythm among HT patients who have sudden cardiac death (SCD).21 Finally, hypersensitivity to adenosine as a result of denervation is the likely mechanism for exaggerated sinus node and AV node suppression with adenosine after HT.variability. Over time, both sympathetic and parasympathetic reinnervation will occur, but the degree of reinnervation is incomplete, nonuniform, variable between patients, and heterogeneous within the same patient.22 Ischemia resulting from vasculopathy or atherosclerosis is a likely precipitant of ventricular arrhythmias and SCD. Ischemia and infarction can lead to left ventricular (LV) dysfunction, with consequent increased risk of SCD. Progressive LV dysfunction, sustained ventricular arrhythmias, unexplained syncope, and progressive conduction system disease are indications for unscheduled coronary angiography in many transplant programs. Selected patients with severe coronary artery disease and LV dysfunction may receive implantable cardioverter defibrillators (ICDs) with the hope of preventing SCD, although the exact mechanisms and benefits are unclear.Cardiac allograft vasculopathy is a relatively common occurrence and an important prognostic indicator late after transplantation.23 such patients can go on to develop severe LV dysfunction and terminal arrhythmia manifesting as pulseless electrical activity (PEA) and asystole.23When progressive LV dysfunction occurs without evidence of epicardial coronary narrowing or evidence of rejection by biopsy, it is labeled as nonspecific graft failure. Although the exact relationship to incident arrhythmias is not clear,5 Many arrhythmias, especially AF and flutter, have been attributed to acute rejection.25 Although some studies observing high incidence of atrial arrhythmia reported no association with rejection,28 other studies have shown an association of sustained AF and atrial flutter with rejection episodes.29 The occurrence of persistent or paroxysmal AF should prompt evaluation for rejection.15 In HT patients, atrial flutter can occur in the setting of rejection30 or can be a manifestation of remodeled and scarred atria that can be associated with cardiac allograft vasculopathy.16 Repeated rejection episodes may lead to cumulative damage as a mechanism of atrial flutter.25 However, no clear relationship has been established between ventricular arrhythmias/SCD and rejection episodes. Myocardial injury due to infiltration of inflammatory cells, edema, and subsequent scarring and ventricular dysfunction may predispose to arrhythmias. Patients with severe acute rejection can have SCD. Routine monitoring of the ECG is not recommended for acute allograft rejection.31Over time, the incidence of rejection has decreased to 20% to 30% in the first posttransplantation year but can occur at any time period after HT.34 Some of these patients have tachycardia-bradycardia syndrome, and drugs for treatment of atrial arrhythmia may worsen the bradycardia.28 A potential association of bradycardia with increased likelihood of rejection or graft vasculopathy is controversial. Complete AV block has been reported late after HT, with multiple possible etiologies, including postoperative injury, progressive conduction system disease associated with coronary artery disease, LV dysfunction, chronic rejection, and injury from endomyocardial biopsies.37 The available retrospective series are not able to provide an exact prevalence of bradycardia episodes and AV block, but risk increases with time after transplantation.38Sympathetic denervation, ischemic injury to the sinus node, graft ischemia, and drug effects are the common underlying causes of posttransplantation bradycardia.38 Permanent pacemakers are generally indicated only for bradycardia that does not resolve and is associated with symptoms. Implantation of pacemaker is usually delayed until after the third week after transplantation. In most large series, permanent pacemakers were implanted in <10% of patients,39 with a few studies documenting a higher prevalence of >20%.38 In a large retrospective series, biatrial anastomosis was the major risk factor for permanent pacemaker implantation, though older donor age may contribute, and graft ischemic time has been associated in some series.40 Early after HT, sinus node dysfunction is the most common reason for pacemaker implantation; after 30 days, AV conduction disease and sinus node dysfunction are equally prevalent indications.41 However, biatrial anastomosis or need for permanent pacemaker implantation is not associated with decreased survival.42 A large series of patients with pacemaker implantation after HT reported that only 14.5% of patients are pacemaker dependent 6 months after implantation.42 Even with AV nodal disease, only 20% are pacemaker dependent.42 Usually AV block is intermittent, and permanent complete heart block is rare.41 A more recent series, however, showed that the majority of patients who had pacemakers implanted for late-onset AV block were pacemaker dependent on follow-up.40 A generally accepted management strategy for postoperative and late-onset bradycardia is shown in In the perioperative period, bradycardia should be managed with temporary pacing in order to maintain heart rates higher than 90 per minute. Alternatively, isoproterenol, theophylline, or terbutaline can be used to maintain heart rate while awaiting return of normal sinus node function.43 but larger series do not support this observation.42 However, late complete heart block or high-grade AV block has been associated with rejection in several reports and series and is associated with worse prognosis.44 Progressive first-degree AV block with bundle branch block may portend a poor prognosis and increased risk of SCD.45 Pseudo AV block can be observed in cases where there is no atrial activity from the donor atria but where atrial activity in the recipient atria gives rise to the ECG appearance of nonconducted P waves.46Bradycardia was associated with acute rejection in a small series,Many patients may have been maintained on amiodarone before HT. Residual effects of the drug may affect the new allograft and contribute to posttransplantation bradycardia that may persist for several weeks.48; a recent retrospective series showed a lower incidence of right bundle branch block of 20% and no association with mortality rate.48 However, progressive bundle branch blocks on serial ECGs were associated with increased risk of mortality and SCD.49Incomplete and complete right bundle branch block are common ECG findings in various retrospective series29 Most large series consistently noted a smaller incidence of AF and atrial flutter.29 Other arrhythmias, such as atrial tachycardia, AV nodal reentrant tachycardia, and AV reentrant tachycardia, have also been reported. AF is the most common early arrhythmia, whereas atrial flutter or macroreentrant atrial tachycardia is more common late after HT.50The incidence of atrial arrhythmias after HT ranges between 0.3% and 24% for AF and 2.8% and 30% for atrial flutter.26 The mechanism of AF after HT is similar to other settings of postoperative AF—manipulation of the heart, pericardial inflammation, use of inotropes, and the autonomic changes after the surgery. However, AF within 2 weeks of surgery can also be associated with rejection.24 Interestingly, however, recent series show a much lower incidence of AF after HT compared to coronary artery bypass grafting, valve surgery, or even bilateral lung transplantation.16 In addition to the major mechanisms discussed above, the reduced incidence may also be due to the healthier donor heart compared to patients with chronic cardiac ischemia/infarction, severe valve disease, or severe lung disease. Moreover, although >75% of postoperative AF occurs within 7 days in the case of major thoracic surgery, only 50% of postoperative AF after HT occurs within the first 2 weeks. The management strategy for early atrial arrhythmias is similar to other settings. 31 or vasculopathy because AF is otherwise a rare occurrence in the stable transplant patient.15In the immediate postoperative period, many factors predispose to AF, and a high incidence has been reported.51 Dronaderone, because of its significant interaction with the calcinuerin inhibitors, is generally contraindicated in this setting. Rate control can be achieved with β-blockers and calcium channel blockers, but these should be used with caution because of risk of bradycardia and interaction with immunosuppressants, respectively. Adenosine should be administered only if strongly indicated and at low dose  because of the risk of significant sustained bradycardia or asystole.52 Warfarin can either increase or decrease cyclosporine levels, and monitoring of both prothrombin time and cyclosporine levels is required on a more frequent basis. Anticoagulation in the early phase after HT is problematic because of the need to perform frequent endomyocardial biopsies. Patients may be maintained on subcutaneous low-molecular-weight heparin during this period. The recent availability of direct thrombin inhibitors  may represent a more feasible alternative because of rapid onset of action.Most HT series report that after treatment of the initial episode of AF, the majority of patients are free of recurrent AF. Thus, prolonged antiarrhythmic drug therapy is generally not indicated. Standard antiarrhythmic drugs include amiodarone and less commonly procainamide and flecainide. Antiarrhythmic agents are rarely prescribed for >3 months and the choice is narrow, especially because of increased risk of drug interactions in the heart transplant patient. Amiodarone may be used after HT but is associated with significant drug interaction with cyclosporine or tacrolimus, requiring close monitoring of immunosuppressant levels, which can become elevated. Because of amiodarone's long half-life, close monitoring of immunosuppressant levels is also required for several weeks after discontinuation of the antiarrhythmic drug. As in other situations, amiodarone is not a preferred drug for long-term use because of its side-effect profile.44 For this reason and because of the relative rarity of AF after HT, late AF occurrence should prompt evaluation for LV dysfunction, cardiac allograft vasculopathy, or acute rejection,16 as outlined in AF after HT, especially when occurring >30 days postoperatively is a marker of higher long-term mortality rate.44 Atrial flutter is the most common arrhythmia associated with rejection.50 Late-onset flutter or reentrant tachycardia may reflect remodeling of the atria.25 Typical isthmus-dependent flutters may be easily identified, but atypical macroreentrant tachycardia may be difficult to differentiate from ectopic atrial tachycardia in the donor heart or atrial activity conducted from the recipient atrium when the biatrial method is used.54 Risk of atrial flutter is increased by use of the biatrial method and older donor age.27Atrial flutter is the most common sustained atrial arrhythmia late after HT, and beyond 3 weeks of surgery, atrial flutter episodes outnumber AF.25 When sustained atrial flutter occurs after HT, radiofrequency ablation is a viable option after primary etiologies such as acute rejection, LV dysfunction, and cardiac ischemia have been excluded. The altered anatomy of the transplanted heart often makes catheter placement challenging for ablation of right atrial isthmus flutter.55 Mitral isthmus flutter can be ablated using standard techniques used in the non-HT context.Patients with atrial flutter are more likely to have LV dysfunction and earlier mortality.50 However, symptomatic nonsustained VT occurring late after HT can be associated with severe cardiac allograft vasculopathy and may warrant ICD placement.56 Sustained VT is infrequent after HT and when observed should prompt both coronary angiography and cardiac biopsy.31 Sustained VT in the immediate postoperative period may indicate impending hyperacute rejection.Nonsustained ventricular tachycardia (VT) can be relatively common in the early postoperative period, and possible associations with rejection or early graft failure have been variable.57 Many die because of noncardiac causes such as malignancy. Most deaths after HT, however, are attributed to severe cardiac allograft vasculopathy and ventricular dysfunction. Approximately 25% of such patients may suffer SCD. The reported incidence varies depending on the nature of the study, whether hospital based or autopsy based, and how SCD was defined.58 The proximate causes for sudden death include acute ischemia, rejection, and severe LV dysfunction. Primary arrhythmic death is diagnosed when no attributable anatomic cause is identified and is described in around 25% of sudden deaths after HT.58The mortality rate in the later years after HT is ≈4% per year, substantially higher than the age-matched general population.21 Acute ischemia was identified as the cause of SCD in the majority of cases. In patients with acute ischemia dying suddenly, asystole was observed in 50%, PEA in 44%, and VF in only 6% of cases.21 Lack of sympathetic innervation is a possible explanation for the low rates of VF in SCD after transplantation.In a large retrospective analysis, the first recorded terminal rhythms in patients with SCD were asystole in 34%, PEA in 20%, and VF in only 10%.59 Less commonly, episodes of acute cellular rejection lead to LV dysfunction and have also been identified as an important cause of SCD, probably contributed to by the less-vigilant surveillance for rejection late after HT.62 Those with progressive conduction system disease and bundle branch block have also been reported to have higher risk of SCD. Other risk factors noted in smaller studies include frequent rejection,24 older donor age,1 myocardial hypertrophy,58 and abnormally prolonged corrected QT interval in the donor heart.19 Patients with a history of syncope are also at higher risk and merit electrophysiological study, coronary angiography, and possible biopsy. Notwithstanding the current guidelines that recommend pacemaker for syncope after HT, such patients may be at risk of serious ventricular arrhythmia (see below). If detailed evaluation identifies no reversible cause, ICD implantation may be considered because of the possibility of SCD, although this is not clearly supported by evidence.63Heart transplant patients with significant ventricular dysfunction and cardiac allograft vasculopathy have the highest risk of SCD.63 The most common situations in which ICDs are implanted include cardiac allograft vasculopathy with LV dysfunction, nonspecific graft failure, unexplained syncope, and high nonsustained ventricular arrhythmia burden. The role of the electrophysiology study in the presence of syncope is also not clear.63 There are reports of SCD in patients with an ICD, which were presumably due to PEA because no VT or VF was documented at the time of death.64 There are also concerns that there is increased risk of infections and lead-related complications in such patients. However, a multicenter registry of posttransplantation patients implanted with ICDs showed that nearly one third of the patients had appropriate ICD therapy, almost all of them having significant cardiac allograft vasculopathy. Syncope or previous cardiac arrest did not predict increased risk of appropriate therapy.63 Therefore, multicenter studies with prolonged follow-up are warranted that will evaluate the exact role of ICDs for the long term. In our practice, we use ICDs for SCD prevention among HT patients in several contexts: (1) patients who meet conventional criteria for SCD , (2) patients with sustained VT, (3) patients with frequent nonsustained VT with significant graft vasculopathy, (4) patients with syncope with inducible VT at time of electrophysiology study, and (5) patients with syncope without reversible cause or strong evidence for bradycardia as etiology .The prevention of mortality and SCD in post-HT patients revolves around prevention of progressive cardiac allograft vasculopathy and early detection and treatment of rejection. Although there are no clear guidelines on ICD implantation, some clinical observation data are available.As survival continues to improve after HT, enhanced management of posttransplantation arrhythmias has become important for reduction of morbidity and to improve quality of life. Arrhythmias can also serve as markers of otherwise unrecognized pathologies in the transplanted heart. Therapeutic electrophysiological procedures such as pacemaker implantation and radiofrequency ablation can be effective. With better postoperative care and reduction in number of rejection episodes, the incidence of some arrhythmias such as AF has decreased. However, arrhythmias in late posttransplantation follow-up are associated with worse outcomes due to acute rejection, LV dysfunction, and SCD. From retrospective studies, the mode of SCD manifestation in the vast majority of HT patients appears to be PEA as opposed to VF. At the same time, registry data suggest that appropriate shocks were received by nearly 30% of HT patients implanted with ICDs for various indications. Given the predominance of PEA over VF as a mode of presentation, prospective evaluation is necessary to determine whether there is any role for ICDs for SCD prevention in HT patients.


Evaluating the systolic function of the left ventricle (LV) is important in the hemodynamic management of the critically ill patients with circulatory failure. Echocardiography is considered the standard monitor for estimating the LV function at the bedside in the intensive care unit. However, it requires a trained operator and is not a real-time monitoring tool. For monitoring of the systolic function, the pulmonary artery catheter has been the gold standard for a long time. However, now there are alternatives to this device, with transpulmonary thermodilution being one of them. This paper provides an overview of the usefulness of the transpulmonary thermodilution-derived indices for assessing systolic function at the bedside. Cardiovascular monitoring is essential for diagnostic and therapeutic management of critically ill patients and assessing the systolic function of the left ventricle (LV) is a key component in this strategy. Echocardiography has become the standard tool for measuring LV ejection fraction (LEVF) at the bedside in the intensive care unit (ICU). This type of monitoring gives the physician a rapid and accurate etiologic diagnosis of the cause of hemodynamic instability in the critically ill patient. Thus, a hemodynamically unstable patient is a good reason to perform a cardiac ultrasound . HoweverThe pulmonary artery catheter (PAC) has been the gold standard for monitoring of systolic function for decades, but concerns have been raised about its safety and the clinical usefulness of the data it provides –4; thus,More recently, the transpulmonary thermodilution technique with single thermal indicator  was proposed as a “less invasive” hemodynamic monitoring system for critically care patients. The system provides intermittent (transpulmonary thermodilution-derived) and continuous (pulse contour-derived) assessment of cardiac output and estimations of intrathoracic volumes . Accuracy of cardiac output calculation using the PiCCO system has been demonstrated in several clinical studies –9 and inThe PiCCO system also provides two transpulmonary thermodilution-derived indices of cardiac systolic function: the cardiac function index (CFI) and the global ejection fraction (GEF) which are automatically calculated by the monitor.A thermistor placed into a femoral, brachial, or axillary arterial catheter measures the downstream temperature changes induced by the injection of a cold saline bolus into the superior vena cava. The monitor calculates cardiac output (CO) from the thermodilution curve, using the Stewart-Hamilton algorithm, and also the mean transit time (MTt) and the exponential down slope time (DSt). The result of the product of CO times MTt is the intrathoracic thermal volume (ITTV): And the product of CO times DSt is the pulmonary thermal volume (PTV):The difference between ITTV and PTV is the global end-diastolic volume (GEDV) which represents the volume of blood contained in the four chambers: CFI and GEF are, therefore, global ejection phase indices since they are the ratio of CO or stroke volume to the global end-diastolic volume of the heart. Therefore the difference between the two indices is that GEF takes into account the heart rate and stoke volume, and the GEF only considers the stroke volume. These indices are obtained very easily by the physician at the bedside while only an experienced operator can get similar information using echocardiography .  The purpose of this paper is to review the different studies that assess the accuracy of these transpulmonary thermodilution-derived indices for the estimation of left ventricular systolic function in the ICU patients at the bedside.r = 0.87, n = 30, P < 0.0001) or GEF . The mean differences between LVFAC and LVFAC estimated with CFI or GEF were 0.8 ± 8.5% (range −17 to 14%) and 0.8 ± 9.0% (range −21 to 19%), respectively. Area under the receiver operating characteristics curves for the estimation of LVFAC ≥ 40% using CFI or GEF was 0.92. Values of CFI > 4 and GEF > 18% estimated LVFAC ≥ 40% with respective sensitivities of 86 and 88% and specificities of 88 and 79%. Additionally, significant correlations were found between changes of LVFAC and CFI and GEF over time. The authors concluded that in mechanically ventilated ICU patients, GEF and CFI provide reliable estimations of LV systolic function, but may underestimate it in cases of isolated right ventricular failure.In 2004, Combes et al. used transesophageal echocardiography to compare these indices with left ventricular fractional area of change (LVFAC) . They stn = 24); (2) it was not altered by fluid loading ; (3) it correlated with the echocardiographic left ventricular ejection fraction (LVEF). The authors simultaneously measured LVEF (monoplane or biplane Simpson method) and CFI at baseline, and after saline and dobutamine administration. Volume expansion altered neither LVEF (47 ± 11% to 47 ± 11%) nor CFI (4.5 ± 2.2 to 4.5 ± 2.1 min−1), dobutamine infusion significantly increased LVEF (percentage of change: 32 ± 28%) and CFI (percentage of change: 29 ± 22%). Considering the effects of dobutamine, there was a significant correlation between the changes in CFI and the changes in LVEF . Finally, a CFI < 3.2 min−1 predicted an LVEF of ≤35% with a sensitivity of 81% and specificity of 88%. The authors concluded that CFI fulfilled the criteria required from a clinical indicator of left ventricular global systolic function and accurately tracked the effects of inotropic therapy.Five years later, Jabot et al. conducted a prospective study in 48 medical ICU patients with acute circulatory failure, to assess whether CFI could actually behave as an indicator of left ventricular systolic function . For thir = 0.79, P < 0.001) and the CFI . The mean differences between LVEF and LVEF estimated with GEF or CFI , and pulmonary vascular permeability index (PVPI), but higher pulmonary artery occlusion pressure (PAOP). The mean values in the groups for sepsis and AHF were, respectively: CI (PiCCO) 4.2 versus 2.9 L·min−1·m−2, CI (PAC) 4.3 versus 2.7 L· min−1·m−2, CFI 6.2 versus 2.7 min−1, GEF 23 versus 13%, SmvO2 69 versus 54%, PVPI 2.8 versus 2.6 and PAOP 17 versus 20 mmHg. There were no significant differences between the two groups in the extra lung water index : 16.7 versus 15.5 mL·kg−1. Additionally, PAOP did not correlate with ELWI and PVPI either in septic shock or in AHF patients. In 2009, Ritter et al. designed an observational study comparing the cardiac function of patients with acute heart failure (AHF) or sepsis using the pulmonary artery catheter and the PiCCO technology . Twelve −1 had a SmvO2 not greater than 70%. In both groups, the CFI show a weak but statistically significant correlation with the left ventricular stroke work index  and the cardiac power . The authors concluded that in critically ill medical patients, assessment of cardiac function using the transpulmonary thermodilution technique is an alternative to the PAC. Furthermore, a low CFI identifies cardiac dysfunction in both AHF and septic patients.All patients with a CFI less than 4.5 minThe transpulmonary thermodilution-derived indices, cardiac function index (CFI) and global ejection fraction (GEF), can be considered as useful indicators of left ventricular global systolic function. In fact, both could help the physician identify, easily and at the bedside, alterations in the left ventricular ejection fraction. On the other hand, normal values of these indices indicate a good systolic function and could avoid the need for immediate echocardiographic evaluation.


By cardiac MRI we investigated the relationship of resting myocardial blood flow (MBF) in hypertrophic cardiomyopathy (HCM) patients to important parameters of disease. MBF was quantified on pixel-by-pixel basis in 804 segments in 70 patients. Relative MBF negatively correlated with left-ventricular (LV) wall thickness (p<0.001), extent of myocardial delayed enhancement , edema , T2 dark signal (p<0.001) and age (p=0.032), but not LV outflow gradient (p=0.901). Different perfusion patterns in segments with reduced and elevated resting perfusion were observed, which may represent different stages of HCM.Myocardial perfusion abnormalities are common in patients with hypertrophic cardiomyopathy (HCM) and seem important for patient prognosis. The purpose of this study was to quantify the distribution of resting left ventricular (LV) myocardial blood flow (MBF) by MRI and to determine its relationship to important parameters of disease such as LV wall thickness, myocardial delayed enhancement (MDE), T2-signal abnormalities, LV outflow tract obstruction and age.Seventy patients (mean age 52 years) with HCM underwent cardiac MRI . For perfusion imaging a bolus of gadopentetate dimeglumine was injected at a dose of 0.04 mmol/kg bodyweight. Two short axis views at the basal and mid-ventricular level were acquired using a saturation preparation SSFP sequence. Cine, T2-weighted dark blood turbo spin echo and MDE images were obtained in the short axis view, matching the slice location of the cardiac perfusion sequence. The LV myocardium was divided into 6 segments in each short-axis slice. Extent of MDE and the presence of T2 signal abnormalities were scored semiquantitatively for each myocardial segment: Edema and T2 dark signal, defined as focal increase or respectively decrease of T2-signal when compared to remote T2-signal of the myocardium, were scored as absent or present. MDE was scored from 0 to 4 based on the percentage area with hyperenhancement. Quantitative MBF maps were generated on a pixel-by-pixel basis using the Fermi function model. Relative perfusion was calculated for each myocardial segment by referring to segments with an LV wall thickness <20mm and MDE ≤25% in the same patient. Simple and multiple linear regression models with repeated measures were used to determine the association of relative resting MBF with LV wall thickness, MDE score, T2 bright signal score, T2 dark signal score, LV outflow gradient and age. Furthermore, T2-signal changes and MDE patterns were described in myocardial segments with elevated and reduced perfusion.804 segments in 70 patients were included in the analysis. In a simple linear regression model LV wall thickness p<0.001), extent of MDE (p<0.001), T2 bright signal (p<0.001), T2 dark signal (p<0.001) and age (p=0.032) negatively correlated with relative resting MBF. The LV outflow gradient did not show an effect on resting perfusion (p=0.901). Multiple linear regression analysis revealed that MDE (p<0.001), T2 bright signal (p=0.026) and T2 dark signal (p=0.019) were independent predictors of relative resting MBF. Different MDE patterns in segments with reduced and elevated resting perfusion were observed  and dark (confluent/chronic fibrosis) signal changes and age. Different myocardial resting perfusion patterns could be defined, which may represent different stages of disease.None.


This is because of the central regulatory role that galectin-3, a member of an evolutionarily conserved family of soluble β-galactoside-binding lectins, plays in several diverse biological processes and disease states.10Journal of the American Heart Association, Gopal and colleagues extend what is known about the association between galectin-3, the etiology and acuity of heart failure, and renal function.r=−0.75, P<0.001) or absence  of heart failure, as the curvilinear relationships demonstrated between galectin-3 and renal function were superimposable for patients with and without heart failure. Among patients with heart failure, estimated GFRs (eGFRs), rather than age, sex, and LVEF, were predictive of galectin-3 levels. These results suggest that the prognostic role of galectin-3 in heart failure may be related as much to renal impairment as to cardiac dysfunction.Although galectin-3 has graduated rapidly from the bench to the bedside, the mechanisms by which elevated levels influence prognosis in heart failure require further study, especially if galectin-3 is to be viewed as a “disease mediator” rather than simply a “disease marker.” In this issue of the 2). In prior studies, the prognostic value of galectin-3 has generally persisted despite adjustment for GFR, suggesting that the influence of renal dysfunction does not preclude an important prognostic value for galectin-3.The strong association between galectin-3 level and renal dysfunction has been previously reported in studies of patients with both acute and chronic heart failure.Do the current results shed light on the mechanism of galectin-3 elevation in heart failure? Given the role of galectin-3 in a diverse set of pathophysiological conditions, ranging from inflammatory bowel disease to stroke, it is likely that elevations of galectin-3 in heart failure patients signify an incompletely understood systemic inflammatory and profibrotic response. Whether this adverse biochemical milieu potentiates end-organ injury caused by known risk factors such as hypertension and diabetes or directly causes it remains to be clarified. The relationship with renal impairment shown in the current study may be a single piece of a much larger puzzle.How do these findings inform clinical use of galectin-3 in heart failure? To address this question, we must view galectin-3 within the broader framework of how biomarkers are used in cardiovascular disease. Biomarkers can be used for diagnosis , to provide prognostic information , and to influence selection of treatment strategies .Continued investigations into the relationship between galectin-3 and heart failure appear to have led to more questions than answers. Moving forward, well-designed studies are needed to answer some key questions. Is galectin-3 a marker or mediator of worsening heart failure? Why are galectin-3 levels elevated in renal disease, and do they contribute to continued renal impairment? How do the prognostic consequences of galectin-3 elevations differ in heart failure patients with and without concomitant renal dysfunction? Can galectin-3 levels identify patients who may or may not derive benefit from specific heart failure therapies? Can pharmacological blockage of galectin-3 attenuate decline in cardiac or renal function? Although much about the details of galectin-3 in heart failure remains vague, continued efforts at increasing precision may uncover a new chapter in our understanding of heart failure pathophysiology.


Cardiovascular disease is one of the commonest causes of mortality post-renal transplantation (RT), often in patients with no known cardiac disease. The cardiac phenotype in these patients is not clearly defined. Multi-parametric cardiovascular magnetic resonance (CMR) imaging enables concurrent assessment of myocardial function, perfusion and irreversible injury. We hypothesized that myocardial perfusion reserve would be impaired in asymptomatic post-renal transplant patients when compared with hypertensive controls.Twenty-two asymptomatic RT patients (3 months to 5 years post-transplant) with, no known history of ischemic heart disease) and 12 hypertensive controls underwent CMR scanning at 1.5 T. Myocardial function, late enhancement, and first-pass perfusion at rest and stress was performed. Myocardial Perfusion Reserve Index (MPRI) was calculated as the ratio of hyperemic to resting myocardial blood flow by dividing the myocardial perfusion at stress by rest perfusion (corrected to rate pressure product). All analyses were performed using multivariate linear regression.2 RT vs 127 +/- 33 g/m2 HT, p>NS) . Rate Pressure Product (RPP) was similar in both groups. Global MPRI was significantly lower in the renal transplant group compared to the hypertensive control group (1.32 ± 0.56 vs 2.00 ± 0.53, P= 0.002, Figure Baseline clinical characteristics as well as left and right ventricular ejection fraction and volumes were similar for both RT and HT control groups. Mean interventricular septal thickness and LV mass were similar in both renal transplant and hypertensive control groups (LV septum: 1.1 +/- 0.3 cm RT vs 1.1 +/- 0.3 cm HT; LV mass index 127 +/- 35 g/mAsymptomatic patients post renal transplantation have global reductions in myocardial perfusion compared to hypertensive controls, independent of the degree of LVH. This may reflect both severe coronary microvascular disease and/or undiagnosed epicardial coronary artery disease, and may in part explain the poorer cardiac outlook in these patients.Flinders Medical CentreFlinders Research Centre


Background. Rheumatic heart disease (RHD) is a leading cause of heart failure in children and young adults worldwide. B-type natriuretic peptide (BNP) is a useful marker of critical pediatric heart disease, and its N-terminal peptide, NT-proBNP, is elevated in congenital and acquired heart disease in children. Aim. To measure NT-proBNP levels as a marker of carditis in children with acute rheumatic carditis, as compared to children with quiescent RHD and healthy controls. Methods. 16 children with acute rheumatic carditis, 33 children with quiescent RHD, and a cohort of 30 healthy children were studied. Transthoracic echocardiography was performed to assess valve and cardiac function. Tissue Doppler echocardiography was performed for E/E′  and systolic strain. Results. NT-proBNP levels were significantly higher in children with acute rheumatic carditis and dropped with its resolution. Strain and E/E′ values were comparable among the three groups. Conclusion. NT-proBNP is significantly elevated in children with acute rheumatic carditis in the acute stage compared to children with quiescent RHD and healthy subjects, in the presence of comparable echocardiographic indices of LV systolic and diastolic function. Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) continue to be a major health problem in developing countries, and RHD is the leading cause of heart failure in children and young adults worldwide, resulting in disability and premature death ; 80–85% Late diagnosis is prejudicial since a bout of ARF is a therapeutic emergency. While polyarthritis is the initial and most common major manifestation, carditis is the most serious manifestation of ARF  and occuNo diagnostic method exists that detects onset of carditis prior to appearance of full-blown clinical or echocardiographic abnormalities . The JonIn 2012, the World Heart Federation published updated criteria for echocardiographic diagnosis of RHD. However, these guidelines are not intended for the diagnosis of carditis in the setting of ARF. Whilst echocardiography is valuable in confirming established valve disease, the assessment of its severity, and screening for valve disease in geographic locations with a high prevalence of RHD , its rolBrain-type natriuretic peptide (BNP), a member of the natriuretic peptide family, is produced in cardiac myocytes and secreted into the circulation in response to cardiac volume load, causing diuresis, natriuresis, and vasodilatation, as well as inhibition of the renin-aldosterone system and sympathetic activity . BNP is Recently, normal values for NT-proBNP concentrations in a large cohort of healthy 8-year-old school children followed over a 4-year period have been published . The present study was designed to evaluate plasma NT-proBNP as a marker of carditis in patients with acute rheumatic fever, as compared to controlled quiescent RHD and healthy controls. This prospective follow-up study was performed over a 2-year period. The study was ethically approved by the Pediatric Department, and consent was obtained from the all children and their parents/carers before enrollment. Seventy-nine children were studied in 3 groups: 16 patients with acute rheumatic carditis who were studied during the acute phase of their illness and after its resolution; 33 patients with known RHD not in activity ; and a cohort of 30 healthy children as a healthy control group.The diagnosis of acute rheumatic carditis was based on the Jones criteria. ARF was diagnosed when two major or one major and two minor manifestations plus evidence of preceding GAS infection were present. Carditis was defined as the presence of a new murmur, pericardial rub, tachycardia out of proportion to fever, gallop rhythm cardiomegaly, recurrent arrhythmia, and/or congestive heart failure. We excluded patients with infective endocarditis and children who had undergone previous surgical valve repair or replacement of cardiac valves.http://www.bmgrp.com) was performed on venous blood samples. All study candidates underwent a thorough medical history, physical examination, routine investigations , 12-lead ECG, and plain chest X-ray. Enzyme immunoassay of plasma NT-proBNP  for all study participants included M-mode measurements, LV end-diastolic and end-systolic volumes, ejection fraction (biplane modified Simpson method), assessment of the degree of mitral regurgitation and aortic regurgitation by colour flow Doppler, and mitral inflow velocities. Pulsed wave tissue Doppler echocardiography was also performed and t-test and Mann-Whitney test for comparison of parametric and nonparametric data, respectively, and Pearson and Spearman's tests for detection of correlations in parametric and nonparametric data, respectively. The performance of NT pro-BNP as a predictor of acute rheumatic carditis and the optimal cut-off level were assessed by the ROC curve. A P value of less than 0.05 was considered significant.Data were collected and analyzed using Student's The demographic, clinical features, routine laboratory data, medical treatment, and type and severity of valve lesions of the three studied groups are shown in P > 0.05). Patients in acute rheumatic carditis had significantly higher end-diastolic volumes and end-systolic volumes  and the PWTDI lateral mitral annulus E′ wave (cm/sec)) was significantly increased in the acute carditis group (10.7 ± 5.3) and quiescent RHD group (7.6 ± 4.2) compared to controls (5.2 ± 1.7) (P < 0.01).The P > 0.05)  .P < 0.001). Similarly, patients with quiescent RHD had significantly higher NT-proBNP values than controls (P < 0.001) (P > 0.05).Patients in acute rheumatic carditis had significantly higher NT-proBNP values than patients with quiescent RHD and controls (< 0.001) . There wE/E′ ratio , EDV  and ESV .We found a significant positive correlation between NT proBNP levels and P < 0.001), but was still significantly higher than the control group (P < 0.001). An NT-proBNP plasma level of 265 fmol/mL had a sensitivity of 93% and a specificity of 92.9% in detecting acute carditis in patients with acute rheumatic fever using the ROC curve. The area under the curve was 0.978  secondary to rheumatic carditis and worsening valve lesions, with resultant volume overload as evidenced by significantly increased EDV and ESV. NT-proBNP levels dropped significantly after resolution of the acute carditis and improvement of heart failure and volume overload secondary to treatment. Natriuretic peptide levels are known to be reduced by treatment .E/E′ with invasively determined mean LV diastolic pressure regardless of LV ejection fraction, rhythm, and heart rate [E/E′.Similar to other studies, the various conventional echocardiographic parameters measured in this study did not help to differentiate between acute rheumatic carditis and established chronic rheumatic heart disease without carditis. Clinical studies using spectral tissue Doppler for recording mitral annular velocities have produced convincing evidence of a positive, linear relation of art rate –27. In oLV strain has been hailed as a very sensitive and volume-independent modality for assessment of myocardial function. Strain imaging has been used to assess myocardial function in a wide range of cardiac conditions. It is useful in detecting early left ventricular (LV) dysfunction in the setting of systemic diseases with cardiac involvement, in differentiating transmural from nontransmural infarction and in identifying LV contractile reserve in regurgitant valve lesions . There wMeasurement of natriuretic peptides, used in conjunction with other clinical information, has been proven useful as a diagnostic marker to aid in the recognition of pediatric critical heart disease in the acute care setting . RheumatWe found that a cut-off level of 265 fmol/mL had a reasonable high sensitivity and specificity for detecting acute carditis in the setting of RF and RHD; however, there was wide overlap in NT-proBNP values between the acute carditis group and the quiescent RHD group. Whilst elevated NT proBNP might also be a consequence of worsening mechanical heart failure or complicating infective endocarditis in a patient with established rheumatic valvular disease, it could potentially be highly suggestive of acute carditis in patients without history of rheumatic heart disease but presenting with one of the major noncardiac criteria of rheumatic fever. Given the paucity of investigations that detect early carditis in this patient population, the absence of any specific echocardiographic findings prior to onset of valve regurgitation, and the potential value of treatment in early rheumatic carditis , this ca


Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia.Na) reduction in the structurally normal heart unmasks a regionally heterogeneous substrate for the induction of sustained arrhythmia by premature ventricular contractions (PVCs).We sought to determine whether sodium current (Ims), INa reduction , and post-PVC sinus rhythm (arrested or persistent). Geometric characteristics and source-sink mismatch were quantitatively analyzed by calculating ventricular wall thickness and a newly formulated 3D safety factor (SF), respectively.We conducted simulations in rabbit ventricular computer models with 930 unique combinations of PVC location (10 sites) and coupling interval  for ectopic wavefronts propagating from thin to thick tissue. In the same simulations but with 40% of normal INa, PVCs did not induce reentry because the volume of tissue with SF<1 was >95% smaller. Likewise, when post-PVC sinus activations were persistent instead of arrested, no ectopic excitations initiated sustained reentry because sinus activation breakthroughs engulfed the excitable gap.Reducing INa reduction precipitates source-sink mismatch, creating a potent substrate for sustained arrhythmia induction by PVCs originating near regions of ventricular wall expansion, such as the RV outflow tract.Our new SF formulation can quantify ectopic wavefront propagation robustness in geometrically complex 3D tissue with impaired excitability. This novel methodology was applied to show that I Na) density Na, including ischemia The effects of macroscopic structure on impulse propagation in cardiac tissue are well understood, having been characterized in tissue wedges and geometrically simple computer models Na unmasks an arrhythmogenic substrate in the structurally normal ventricles by promoting source-sink mismatch in regions of thin-to-thick tissue expansion, such as the RVOT. To achieve our goal, we conduct simulations in an anatomically- and biophysically-detailed rabbit ventricular model with different degrees of INa reduction. We systematically characterize vulnerability to reentry induction by ectopic stimuli from several locations using a novel, quantitative evaluation of source-sink mismatch distribution in the whole heart.This study aims to test the hypothesis that global reduction of INa loss-of-function . Other ionic current heterogeneities were deliberately omitted since our aim was to explore effects of global INa reduction in the absence of other potentially arrhythmogenic factors. Additional model parameters, including anisotropic tissue conductivities, are provided in Table S2 in Reentry induction experiments were conducted in a detailed model of the rabbit ventricles incorporating realistic geometric structure and fiber orientations Na), we pre-paced the ventricles with 10 sinus-like activations evoked by stimulating 53 LV and RV endocardial sites. We made this choice because closely coupled premature ventricular contractions (PVCs) are a well-known reentrant trigger, particularly in BrS patients Na  were adjusted to ensure capture at all 53 sites regardless of INa level.For both electrophysiological conditions  were located near the insertion points of the RV into the LV, which is the most prominent example of disparity in tissue thickness in the structurally normal heart; sites E1–E4 were situated at points on the thin (RV) side of this structure, including the RVOT (E1), while E7–E9 were on the thick (LV) side. The remaining sites were located on the RV (E5–E6) and LV free walls. The coupling interval (CI) of each PVC was calculated with respect to the time from the start of the preceding sinus beat. All ectopic pacing stimuli lasted 10 Na, we delivered ectopic stimuli from each of the 10 sites with CIs in the range 250–400 ms  and monitored for the establishment of sustained arrhythmia (reentry lasting ≥1000 ms after stimulus delivery). These experiments were conducted without post-PVC sinus stimuli (arrested sinus) to provide a long temporal window for analyzing source-sink mismatch. The same set of experiments was then repeated in simulations with 40% of normal INa. Finally, a third set of simulations was performed with INa set to 30% and with continued sinus stimuli (basic cycle length of 400 ms) after each PVC (persistent sinus); the purpose of these experiments was to test whether such stimuli would initiate reentry or disrupt reentrant circuits observed in the initial (arrested sinus) protocol.In simulations with 30% of normal IA) during which upstream activity depolarized a particular downstream membrane patch; then, SF at that location was calculated as the ratio between the net charge delivered during this interval and the estimated threshold charge (Qthr) to elicit an AP by a stimulus of duration tA in an isolated membrane patch in the same kinetic state.We developed a methodology to quantitatively evaluate the spatial distribution of possible source-sink mismatch in realistic 3D geometries during complex excitation sequences, such as ectopic beats. Our approach was based on a novel formulation for calculating cardiac safety factor (SF). SF was initially developed to quantify the robustness of AP propagation in 1D thr. Second, the end of the tA interval was defined as the instant when the total transmembrane current per unit area (Im) crossed below zero after an initial positive deflection; this condition (Im<0) does not always occur during sub-threshold excitation events in tissue with reduced INa.This SF formulation, however, was insufficient for the present study for two reasons. First, the effect of CI was not accounted for in the calculation of Qthr estimation using a two-step regression-based approach. The tA-dependent term Qthr(tA) in the original formulation was replaced by Qthr, defined as:thr(tA) relationships for each CI in a wide time interval  and repolarization (tr) times:d and tr are the instants when the transmembrane voltage (Vm) crossed above and below a threshold value (−85 mV), respectively, indicating transient perturbation from and return to resting Vm; Cm is the specific membrane capacitance and Iion is the ionic current per unit membrane area.To address the original formulation’s failure to correctly identify tm<0 condition never occurred, as shown in With these improvements, our new SF formulation produced values that correctly indicated AP propagation robustness, even in cases where the IQuantitative measurement of ventricular wall thickness (WT) allowed us to assess the effects of cardiac geometry on source-sink mismatch  and to identify structural characteristics common to locations from which ectopic stimuli were more likely to induce sustained reentry. We used a minimum distance algorithm to measure WT throughout the ventricles. First, surface points were manually categorized as epicardial, LV/RV endocardial, or LV/RV septal. Then, for each point in each set, the minimum distance to every other set was calculated; the smallest of these distances was selected as the local WT value. Using these values as a Dirichlet boundary condition, Laplace’s equation  of closely coupled PVCs in the rabbit ventricular model and monitored for reentry induction. Outcomes for simulations with 30% of normal Iing PVCs  illustraing PVCs . Conducting PVCs , ectopicing PVCs .Ectopic activation sequences originating from three of the sites where PVCs never induced sustained reentry are shown in To quantify our observation that sustained reentry-inducing PVCs involved conduction block in regions with steep ventricular wall expansion, we correlated ectopic stimulus locations with the corresponding WT values . E1 was m maps presented in SF calculations showed quantitatively that source-sink mismatch markedly reduced the robustness of ectopic wavefront propagation from thin to thick ventricular wall regions . LocatioNa, there were no instances of reentry induction by PVC because source-sink mismatch was not as prominent. For the same PVCs analyzed in Na condition, weak conduction due to source-sink mismatch prevented excitation of the superior septum and LV free wall , we observed no instances of sustained arrhythmia induction. This was because wavefronts from the first post-PVC sinus activation engulfed the excitable gap, eliminating conditions for reentry initiation. For the case shown in m sequences for these two simulations  occurred in areas of wavefront propagation from thin to thick ventricular wall causing conduction block, often near the ectopic stimulus site. Specifically, this behavior was observed for cases in which the LV-to-RV and septum-to-RV thickness differences were both ≥2.4 Na, no PVCs induced reentry because >95% less tissue had SF<1 compared to 30% INa cases; and,In the ventricular model with 40% of normal IPersistent post-PVC sinus activations also reduced sustained arrhythmia inducibility because wavefronts from sinus sites engulfed the excitable gap, preventing reentry initiation.These discoveries were made possible by the development of our novel methodology for calculating SF throughout the 3D ventricles, which allows the quantification of AP propagation robustness for ectopic wavefronts in tissue with impaired excitability and complex geometry. Our previous SF formulation suitably quantified the margin of safety for AP propagation in 2D tissue with homogeneous CI Na uncovers a substrate for reentry initiation due to inherently heterogeneous ventricular geometry in the absence of all other arrhythmogenic factors. In particular, we show mechanistically why PVCs originating near inherent thin-to-thick wall transitions in the structurally normal ventricles with impaired excitability are more likely to induce sustained arrhythmia compared to ectopic beats originating elsewhere. For these PVCs, INa reduction leads to a large region of critical source-sink mismatch (SF<1) along the boundary between the thin RV and the thick LV, which gives rise to conduction block. The fact that persistent post-PVC sinus activations preempted reentry initiation by consuming the excitable gap suggests that sustained arrhythmias could only be induced by this mechanism in the context of relatively slow heart rate or intermittent sinus rhythm . This is in agreement with clinical evidence, since BrS patients typically experience sustained arrhythmia and/or sudden cardiac death episodes during sleep, when the resting heart rate is lower Our analysis of SF distribution in the ventricles and its correlation with ventricular wall thickness for nearly 1000 unique ectopic stimulation scenarios provides a detailed understanding of how reduced INa magnifies the electric load imposed upon the excitatory source  during impulse propagation from thin to thick tissue Na availability compared to that in the LV Previous studies used geometrically simplified models to examine source-sink mismatch in the context of reduced excitability, yielding the observation that decreased INa loss-of-function have important implications for understanding the pathophysiological basis of BrS. Due to the fact that the genetic basis of BrS is highly heterogeneous, many plausible theories have emerged to explain the underlying cause of disease-related arrhythmias Na loss-of-function are examined in the absence of all other factors. The end result is a new explanation for the fact that ectopic beats arising in locations like the RVOT are much more likely to initiate reentry in BrS patients Insights revealed by this study regarding arrhythmogenic consequences of INa in BrS has slower recovery from inactivation In light of this finding, we speculate that a similar approach could be used to assess the organ-scale arrhythmogenic consequences of other electrophysiological abnormalities thought to be factors in BrS arrhythmogenesis. For instance, several studies have reported that IFrom a clinical standpoint, our findings suggest that cardiac imaging could be used to identify BrS patients with a high risk of experiencing arrhythmogenesis caused by source-sink mismatch in wall expansion regions. Between two individuals with the BrS genotype, we expect that the one with a particularly thin RVOT is more likely to experience a catastrophic episode of sustained arrhythmia initiated by this particular mechanism. Many studies have reported RV structural abnormalities in the hearts of BrS patients File S1Supporting figures, tables and appendix. Figure S1: Anterior (A) and left-lateral (B) views of activation sequence in response to sinus stimulation at t = 0 in the rabbit ventricular model ; see Methods section for further details. Compare this excitation pattern to Na: cardiac sodium current. Figure S2: (A) Examples of Qthr(tA) functions derived by linear interpolation for different CI values showing differences in slope and y-intercept . (B & C) Slope and y-intercept values from panel A (gold squares), along with many others (red squares), are used to derive estimator functions for Qthr, as explained in Methods section. All values shown here were generated from single-cell simulations with 30% INa. Sixth-order polynomial fits for these data sets  are given by the following two equations: thr is the threshold charge to elicit an action potential in an uncoupled cell; tA is the excitation interval (stimulus duration); and CI is coupling interval. Table S1: Convergence analysis conducted in a tissue wedge (5 cm×1 mm×1 mm) with the same electrophysiological properties as described in the Materials and Methods section. Simulations conducted with 30% of normal INa. Table S2: Additional simulation details for rabbit ventricular models. Appendix S1: Pseudo-code for calculating safety factor according to the method described in this paper.(PDF)Click here for additional data file.Movie S1Na and arrested sinus rhythm.Anterior epicardial (left) and basal (right) views of sustained arrhythmia initiation by a PVC originating from site E1 in a simulation with 30% of normal I Maps show transmembrane voltage (Vm) on the surface of the ventricles; same scale as (MOV)Click here for additional data file.Movie S2Na and arrested sinus rhythm.Posterior endocardial cutaway (left) and basal cutaway (right) views of sustained arrhythmia initiation by a PVC originating from site E3 in a simulation with 30% of normal I Same scale as (MOV)Click here for additional data file.Movie S3Anterior epicardial (left) and basal cutaway (right) views for a PVC originating from site E2 that did not induce sustained arrhythmia. Same scale as (MOV)Click here for additional data file.Movie S4Same views as  Same scale as (MOV)Click here for additional data file.Movie S5Na; right-hand panel is the same as left-hand panel from Side-by-side anterior epicardial view comparison of response to PVCs originating from E1 in simulations with 40% (left) or 30% (right) of normal I Same scale as (MOV)Click here for additional data file.Movie S6Side-by-side endocardial posterior cutaway view comparison of response to PVCs originating from E3 in simulations with persistent (left) or arrested (right) sinus activations; right-hand panel is the same as left-hand panel from  Same scale as (MOV)Click here for additional data file.


Patients with congenitally corrected transposition of the great arteries (ccTGA) and those who underwent atrial switch eventually face systemic ventricular failure due to deterioration of the morphological and structural function. Heart transplantation is at present one of the two best available options. We report our institutional experience of heart transplantation in this group, with emphasis on surgical techniques, risk factors and long-term outcome.Between 1992 and 2011, 21 patients  with TGA  underwent heart transplantation for end-stage heart failure. Previous operations were Senning procedure (n=8), Mustard operation (n=5), double switch (n=2), arterial switch (n=2), Fontan operation (n=1), mitral and tricuspid valve replacement (n=1) and palliative shunting (n=2). Six patients had pulmonary hypertension.Previous surgeries, alterations in the atrial anatomy, other anatomic abnormalities and the presence of intra-atrial conduits required technical modifications in harvesting and implantation. Postoperative morbidity was hemorrhage which was easily controlled. Cause of early mortality was severe pulmonary hypertension. Late mortality was due to graft dysfunction. At a mean follow-up of 5.9 years (1-22.8 years), overall survival rates are 78.6%, 57.1% and 42.8%, at 1, 5 and 20 years.Previous operations did not produce major technical problems in heart transplantation. Pulmonary hypertension is the only risk factor for mortality. The long-term survival rate is highly satisfactory.


Quantitative T1 imaging permits assessment of diffuse fibrosis by eliminating the use of reference tissue, but the dependence of the derived partition coefficient (lambda) on the time post-contrast injection (tpost) is not well established.Diffuse myocardial fibrosis is associated with myocardial infarction , heart f1 values as a function of tpost and the resulting dependence of the blood-tissue partition coefficient.Determine blood and myocardial T1 mapping was performed on a mid-ventricular short-axis slice using a custom saturation recovery single-shot TrueFISP sequence at baseline and one-minute intervals for 15 minutes following a bolus injection of gadopentetate dimeglumine (0.1 mmol/kg). At each time point, one "no-saturation" image and nine images with varying saturation recovery times spanning the cardiac cycle were acquired during a single breath-hold.Nine healthy subjects  were imaged using a Siemens Avanto 1.5T MRI. T1 values for each segment at every time point. Blood T1 values were computed using a region of interest within the left ventricular cavity. Lambda was computed using {lambda=[R1(myocardiumpost) - R1(myocardiumpre)]/[R1(bloodpost) - R1(bloodpre)]}, where R1=1/T1.The myocardium was divided into 18 segments and mean values were fitted to a 3 parameter saturation recovery curve to determine T1, blood T1, and lambda values averaged over all segments and subjects as a function of tpost. Average within-subject standard deviations of T1 and lambda for tpost from 3-15 min were 34.1 ms and 0.046 respectively. Linear regression for lambda and tpost (3-15 min) shows an increase in lambda of 0.001 min-1 (R2=0.75). Quantitative T1 imaging is likely to be added to a clinical protocol following LGE imaging (tpost 10-15 min), where T1 values increase by 5.9±1.6% and lambda increase by 1.1±2.7%.Figure 1 mapping can be performed in a single breath-hold with derived blood-tissue partition coefficient (lambda) values in good agreement with previous measurements3. In the post-LGE window of 10-15 min after contrast bolus, derived lambda values show less time dependence than myocardial T1.Saturation recovery SSFP T


Right ventricular ejection fraction (RV-EF) has traditionally been used to measure and compare RV function serially over time, but may be a relatively insensitive marker of change in RV myocardial contractile function. We developed a cardiovascular magnetic resonance (CMR) tagging-based technique with a view to rapid and reproducible measurement of RV long axis function and applied it in patients with congenital heart disease.We studied 84 patients: 56 with repaired Tetralogy of Fallot (rTOF); 28 with atrial septal defect (ASD): 13 with and 15 without pulmonary hypertension (RV pressure > 40 mmHG by echocardiography). For comparison, 20 healthy controls were studied. CMR acquisitions included an anatomically defined four chamber cine followed by a cine gradient echo-planar sequence in the same plane with a labelling pre-pulse giving a tag line across the basal myocardium. RV tag displacement was measured with automated registration and tracking of the tag line together with standard measurement of RV-EF.Mean RV displacement was higher in the control (26 ± 3 mm) than in rTOF (16 ± 4 mm) and ASD with pulmonary hypertension (18 ± 3 mm) groups, but lower than in the ASD group without (30 ± 4 mm), P < 0.001. The technique was reproducible with inter-study bias ± 95% limits of agreement of 0.7 ± 2.7 mm. While RV-EF was lower in rTOF than in controls , it did not differ between either ASD group and controls.Measurements of RV long axis displacement by CMR tagging showed more differences between the groups studied than did RV-EF, and was reproducible, quick and easy to apply. Further work is needed to assess its potential use for the detection of longitudinal changes in RV myocardial function. The assessment of RV function is particularly important in the setting of congenital heart disease where detecting deterioration of RV function by cardiovascular magnetic resonance (CMR) may be considered an indication for operative intervention ,2. HowevWe therefore developed a technique designed to expedite the acquisition and analysis of data on RV long axis function. A linear tag was oriented perpendicular to the basal free wall, allowing a simple automated measurement of its apically directed displacement. We hypothesized that this technique would be reproducible and could differentiate between populations with normal RVs and those with pressure and/or volume loading.Eighty four patients undergoing clinical CMR at Royal Brompton Hospital with either previously repaired tetralogy of Fallot (rTOF) with pulmonary regurgitation (PR) n = 56), or unoperated atrial septal defect (ASD) with pulmonary hypertension (PHT) (n = 13) or without PHT (n = 15) were recruited prospectively, PHT being defined as an estimated RV systolic pressure > 40 mmHg derived from the peak tricuspid regurgitant jet velocity plus right atrial pressure estimated  on echocardiography [, or unopCMR was performed on a 1.5T scanner  using an 8-element phased-array receiver coil. Subjects were positioned supine in the magnet and scout images obtained. A routine set of LV and RV short-axis cines, 7mm slice thickness, were acquired at 10mm intervals from base to apex using a breath-hold retrospective vector cardiography-gated balanced steady state free precession (SSFP) gradient echo sequence, and volumetric analysis was performed using CMRtools  [The tagged images were analysed automatically once the user had located the line joining the tagged RV free wall and septal myocardium in the first frame of the cardiac cycle . Multi-rIn a randomly selected subset of twenty four studies (2 controls and 22 patients), measurements of RV basal free wall displacements were made by 2 independent experienced observers (observers 1 and 2) both manually from the CMR 4-chamber cine acquisition Figures , and froTo assess the inter-study reproducibility of tagged myocardial image acquisition and analysis, 10 control subjects were scanned by two independent operators. Each subject underwent two completely separate scans, one by each operator. The subject was positioned in the scanner, images acquired, and subjects taken out of the scanner by the first operator for the initial scan. Then, the second operator repositioned the patient in the scanner and acquired images in the second scan. Both sets of images were analysed using the automated software by operator 1, and once more by the same operator at a later date.Statistical analysis was performed using SPSS . Data is expressed as mean ± SD and as frequencies for categorical data. Normality of all data distributions in the patient and control groups was tested using the Kolmogorov-Smirnov method. The intra- and inter-observer reproducibility of CMR tagging measurements and inter-study reproducibility were assessed using the method of Bland and Altman . RV and A total of 84 patients were studied: 56 with rTOF, 15 with unoperated ASD but no PHT, and 13 with ASD and PHT (Table There was no significant difference between the groups with respect to sex (= 0.491), however, the rTOF group tended to be younger relative to the control p = 0.002) and ASD with PHT groups (p = 0.004). The indexed LV end diastolic volume in the ASD pulmonary hypertension group was significantly lower than in the control group (p = 0.006). In addition, the indexed LV mass was significantly lower in the ASD pulmonary hypertension group relative to rTOF group (p = 0.003); however, there was no significant difference relative to the control group  . TAPSE hA previous study has attempted to quantify RV long-axis function with CMR. It relied on a manually located point on the tricuspid annulus whose motion was followed relative to the RV apex . This teWith a view to serial follow up, the automated approach markedly improved inter-study reproducibility . This greater reproducibility could serve to reduce sample size requirements if the technique were to be used in clinical trials to assess the impact of therapeutic interventions on right ventricular function. Our data provide the basis for sample size and power calculation for future studies in which RV contractile function may be an end-point.et al found that RV ejection fraction in ASD patients with pulmonary hypertension (pressure and volume overload) is similar to that in controls, but impaired in a group with pulmonary hypertension without an ASD (pressure but not volume overload), with preservation of ejection fraction in the former group [In keeping with previous studies, we found only a moderate but nonetheless statistically significant correlation between RV displacement measured by the automated CMR technique and RV ejection fraction ,19. Thiser group .et al found that while the inter-study coefficient of variation for RV ejection fraction was 4.3% for patients with normal ventricles, but rose to 10.4% for patients with congestive cardiac failure and 10.0% for patients with left ventricular hypertrophy [The incomplete correspondence of RV ejection fraction and measurements of RV displacement may also be accounted for to an extent by measurement errors. While measurements of RV ejection by CMR in healthy individuals have shown good reproducibility, the approach may be less reproducible with disease. Grothues ertrophy . With diertrophy . As EF iOur study assessed RV performance at one time point. We did not perform serial follow up of patients to prospectively assess the ability of the novel tagging technique to identify deteriorations in RV function over time. However, the technique was highly reproducible and the differences identified between the pathological groups were far greater in magnitude than the variation resulting from measurement error. Further prospective studies are required to evaluate the utility of this technique in clinical practice.It is a limitation that we did not prospectively acquire TAPSE measurements by echocardiography in the same patients. When we attempted to collect echocardiographic data retrospectively, we found it to have been sporadic, of variable quality and inadequate for meaningful for comparison with the prospectively acquired CMR data.A further limitation of the study is that the temporal and spatial resolutions are limited by the need to acquire the data within the duration of a single breath-hold. However, the multi resolution image registration has been shown  to proviMeasurements of RV long axis displacement by CMR tagging showed more significant differences between the groups studied than did RV-EF. It was reproducible, quick and easy to apply and analyse. Further work is needed to establish CMR normal ranges for RV displacement and to prospectively evaluate the utility of the technique for the serial follow up of patients at risk of RV dysfunction.GZ Yang is a director of Cardiovascular Imaging Solutions. None of the other authors have any potential competing interest.SC, PK, and JK contributed to the conception and design of the study. Data was acquired by SC and RW. Analysis and interpretation of the data, and drafting of the manuscript were performed by SC, JK, TI and PK. The design of and software analysis of the tagging sequence were done by AW and JK. All authors contributed to critical review, intellectual content and final approval of the manuscript.