Background. Ivabradine is an If ion current inhibitor that has proved to reduce mortality in patients with systolic heart failure by slowing heart rate without decreasing myocardial contractility. Photoplethysmography is a simple, low-cost optical technique that can evaluate vascular function and detect changes in blood flow, pulse, and swelling of tissular microvascular space. Objective. To evaluate the effect of ivabradine on endothelial function by photoplethysmography in diastolic and right heart failure patients. Methodology. 15 patients were included (mean age of 78.1 ± 9.2 years) with optimally treated diastolic and right heart failure. They underwent photoplethysmography before and after induced ischemia to evaluate the wave blood flow on the finger, using the maximum amplitude time/total time (MAT/TT) index. Two measurements were made before and after oral Ivabradine (mean 12.5 mg a day during 6 months of followup). Results. In the study group, the MAT/TT index was 29.1 ± 2.2 versus 24.3 ± 3.2 (P = 0.05) in basal recording and 30.4 ± 2.1 versus 23.3 ± 2.9 (P = 0.002), before versus after ischemia and before versus after Ivabradine intervention, respectively. Conclusions. Ivabradine administration improves endothelial function (shear stress) in diastolic and right heart failure patients. Diastolic dysfunction has been associated with symptoms of congestive heart failure in patients with preserved left ventricular ejection fraction . In the P = 0.05) in a mixed cohort of inpatients and outpatients with normal or mild systolic dysfunction [In outpatients with heart failure with preserved ejection fraction (HFpEF) at the baseline echocardiogram, worsening of diastolic function in a follow-up study is also an independent predictor of all-cause mortality . In addifunction , while tIn patients with atrial fibrillation, if diastolic function was assessed, it was based on deceleration time of mitral E-wave velocity and tissue Doppler imaging  .Ivabradine added to recommended treatment, improved the outcome of heart failure patients reducing cardiovascular death and hospitalizations rate . In patiIvabradine also has demonstrated a favorable effect on LV remodeling after 8 months of followup as well as and antianginal effect .  Hyperemic coronary blood flow velocity also increases after ivabradine treatment, probably because the diastolic period is prolonged (per cardiac beat and per minute). It has been speculated that the most probable explanation of the improvement of ventricular relaxation caused by ivabradine treatment could be its effect on coronary blood flow velocity during hyperemia . To evaluate the effect of ivabradine on endothelial function by photoplethysmography in patients with right heart failure and preserved ejection fraction, we performed this open-label clinical trial. This open-label clinical trial included ambulatory patients who came to the Heart Failure Clinic of the Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán.” Patients were recruited if they were men or nongravid women with more than 18 years of age with a confirmed diagnosis of stable heart failure with preserved ejection fraction in New York Heart Association functional classes II to III. Candidates were excluded if they had had myocardial infarction, unstable angina or a history of myocardial revascularization , cerebrovascular events during the previous 3 months, dysfunctional prosthetic heart valve, obstructive or nonobstructive cardiomyopathy, uncorrected congenital heart disease, active myocarditis, a history of resuscitation from sudden death, or severe arrhythmias.2, left atrial diameter > 40 mL/m2, tissue doppler E/E′ > 15 echo-blood flow Doppler E/A in >50 years <0.5, and DT in >50 years >280 ms [Heart failure was established by signs and symptoms as well as echocardiographic and radioisotopic ventriculography findings. Preserved ejection fraction was defined as a left ventricular ejection fraction ≥ 50%, LVEDVI < 97 mL/m >280 ms , 17. All patients received standard heart failure therapy and their comorbidities , at their maximum doses tolerated. Some patients that developed atrial fibrillation also received digital.This was an investigator-initiated, single center, single-arm, open-label clinical trial.After baseline measurements, in addition to conventional therapy, patients received an average of ivabradine 12.5 mg (10–15 mg) a day, according their tolerance during 6 months of follow-up , 19. Pat A baseline digital photoplethysmographic wave was recorded for 30 seconds. The forearm was then compressed with a sphygmomanometer cuff for 5 minutes using a pressure of 30 mmHg above the systolic arterial pressure recorded (ischemic phase). The compression was then released and the digital photoplethysmographic wave was recorded for 120 seconds. The wave was analyzed at 30-second intervals for comparison with the baseline values. The most representative waves were selected from the recording of each interval, and the maximum amplitude time (MAT) and total time (TT) were measured in order to calculate the MAT/TT index. A MAT/TT index of less than 30 was considered normal, as proposed in other studies .Cardiologists who performed the echocardiograms and radioventriculography did not have access to patients' information.t-test was used. A P value of <0.05 was considered statistically significant. All analyses were performed using a commercially available package . Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as percentages. To compare the changes from baseline to 6 months, a paired Fifteen patients  were studied. Arterial hypertension and hypothyroidism (under treatment and well controlled) were the most common comorbidities with patients in functional classes (NYHA) II and III . It is i Patients received an average of 12.5 (range 10–15) mg/day during the 6 months of followup. It was particularly interesting that heart rate did not decrease in any patients below the 10% recommended (88 versus 82 beats/min) in the literature in spite of the top doses received.P = 0.08). Improvement of the endothelial-dependent vasodilatation expressed by significant changes observed in the photoplethysmographic curves occurred concurrently. All patients had some degree of clinical improvement, 8/9 (88.8%) from NYHA III to II and 4/6 (66.6%) from II to I, respectively, although this did not achieve statistical significance (P = 0.05) was significantly different after the followup. There was also a reduction of 8.15% in the systolic pulmonary arterial pressure . With respect to cardiac structural changes, in the echocardiographic study, only right ventricular diastolic diameter  have normal or preserved left ventricular ejection fraction (HFPEF) , and theEndothelial dysfunction has been shown to be involved in the pathogenesis of HF, mainly HFREF. Several studies have reported that peripheral endothelial dysfunction is associated with the clinical outcome in patients with HFREF . BorlaugPeripheral endothelial function is impaired in patients with HFpEF, and when it is evaluated as a reactive hyperemia by peripheral arterial tonometry (RH-PAT), it significantly correlates with future cardiovascular events. Peripheral endothelial function is thus an independent predictor after adjusting various clinical parameters . Indeed,P < 0.0001) [ The results of the systolic heart failure treatment with the If inhibitor ivabradine trial (SHIFT) showed that treatment with ivabradine added to conventional therapy for HF was associated with an 18% reduction in the relative risk for the primary composite endpoint of cardiovascular death or hospitalization for worsening HF ( 0.0001) . It also In experimental studies, ivabradine has been demonstrated to reduces fibrosis and improve endothelial function –12, togeIn experimental postinfarction settings, both cardiac  and pulmPreserved ejection fraction is present in almost 50% of heart failure patients and is cause of half of HF hospitalizations, and traditional HF treatment is not effective. A recently published pathophysiology-based novel pharmacotherapy for these patients considers spironolactone, aliskiren, and neprilisyn as therapeutic options for HFPEF because of their anti-hypertrophic and anti-fibrotic effects . CombineThe number of patients studied was small, and the intervention period was short. It is probable that a longer followup would show changes in variables such as left ventricular diastolic diameter and other structural characteristics. In addition, the lack of direct quantification of pulmonary pressures is a drawback.  Our findings support continued investigation into the effects of ivabradine on right ventricular function, systemic arterial pressure, and systolic pulmonary arterial pressure in heart failure patients with preserved ejection fraction. More studies are required to evaluate the effects observed on a larger number of patients for a longer period.


Restoration of the mechanical and endocrine functions of the left atrium remains controversial after electrical cardioversion treatment for persistent atrial fibrillation. The objective of the prospective study was to describe the recovery of the endocrine and mechanical functions of the left atrium.Evaluation of left atrium recovery after electrical cardioversion by the new speckle-tracking echocardiography technique and proANP measurement.Twenty patients suffering from persistent atrial fibrillation with no alteration of left ventricular ejection fraction were prospectively evaluated at baseline and then one month later by echocardiography, measuring left atrial volume and left atrial deformation (MPALS), as well as the proANP and BNP concentrations. One month after cardioversion 10 patients remained in sinus rhythm and 10 showed recurrent atrial fibrillation. No significant differences between the two groups in terms of clinical, echocardiographic and endocrine parameters were observed at baseline evaluation. We observed a significant reduction of left atrial volume only in the sinus group, whereas restoration of the left atrial deformation was only partial (18%) in that group. By contrast, we registered no significant changes in ANP concentration at one month in either the sinus or the atrial fibrillation groups.These results suggest that restoration of left atrium mechanical function is only partial one month after treatment of persistent atrial fibrillation by electrical cardioversion, whereas a significant reduction of left atrial volume was noted, explaining the remaining high level of ANP in the sinus group. Atrial fibrillation (AF) is the most frequently encountered arrhythmia, affecting 2% of the population. Its freWe hypothetized that left atrium mechanical function (distensibility) was incomplete one month after the restoration of sinus rhythm, explaining a prolonged high level of ANP. We carried out a prospective study to evaluate the LA mechanical function by the new angle-independent and reproducible speckle-tracking echocardiography technique, and to gauge the endocrine function by measuring the levels of proANP and BNP at baseline and one month after cardioversion.Twenty-nine patients suffering from symptomatic non-valvular persistent AF who were admitted for direct current cardioversion were prospectively recruited. All patients referred to our center for electrical cardioversion received an adequate anticoagulant (VK antagonist with an INR between 2 and 3 during at least one month). Persistent AF was defined as AF lasting for at least 7 days but less than one year, and requiring direct current cardioversion[Patients were evaluated at baseline (one day before cardioversion) and one month later, as follows: Physical examination and standard 12-lead electrocardiogram (ECG); standard transthoracic echocardiography with a Vivid I digital ultrasound system  and digital cineloop format for off-line analysis using a dedicated software package ; clinically required blood samples were collected, in addition to a sample for the evaluation of natriuretic peptides (BNP and proANP). LA function was reevaluated one month after cardioversion because that is generally the estimated time necessary for recovery from atrial stunning or left atrial dysfunction[Direct current cardioversion was performed under general anesthesia, with one to three biphasic shocks of increasing energy, from 100 to 200 J. Patients were followed up one month later with a physical examination, ECG, echocardiography and blood samples for ANP, BNP measurement.All patients were examined in the left lateral decubitus position by M-mode, two-dimensional (2D), Doppler and TDI echocardiography, using a 3.5-MHz transducer . Standard M-mode and 2D images were obtained from 3 consecutive breath-hold cardiac cycles and were stored in cineloop format. Apical four- and two- chamber-view images were obtained using conventional two-dimensional gray scale echocardiography, during breath hold with a stable ECG recording. Particular attention was given to obtaining an adequate gray scale image, allowing reliable delineation of myocardial tissue and extracardiac structures. LA volume was calculated according to the formula 8/3π[/LA length. LA volume was indexed to body surface area. The anteroposterior diameter of the LA was also measured from the parasternal long-axis view. The lefOff-line analysis was then performed as follows. We measured the deformation of six segments located along the septum, the roof and the lateral wall of the LA cavity as seen in a 4-chamber apical view, and repeated the process with a 2-chamber view. A curve representing the average of the strain curves of the six segments was automatically plotted Figure , where tTwo independent physicians analyzed the echocardiographic measurements on ten selected subjects in order to define the intra- and inter-observer variability.Because proANP half-life is longer than that of ANP, as measured ProANP concentrations in the serum, we used the MR-proANP kit . This sandwich immunoassay uses an antibody against the mid-region of proANP (amino acids 53–90). In 325 healthy individuals, proANP concentrations ranged from 9.6 to 313 pmol/L. The median was 45 pmol/L . The 99th percentile for the control population was 197.5 pmol/L; there was no significant difference in the range or median of proANP values between males and females .BNP levels were assayed in EDTA plasma. As for proANP, we used a sandwich immunoassay: the Triage® BNP Test  for the Access 2 system . According to manufacturer claims, in 1286 subjects without chronic heart failure, the median value was 12.3 pg/mL and the 95th percentile was 73.5 pg/mL.Data were expressed as means ± standard deviations. Since normality testing of the different variables showed a non-Gaussian distribution, non-parametric statistical tests were applied. Differences in the means of the various parameters before and after cardioversion were assessed by a Wilcoxon test for paired series. Differences in the means of baseline parameters between patients with AF and patients in SR one month after cardioversion were assessed by a Wilcoxon test for unpaired series. Correlations between LA volume or MPALS and ANP or BNP concentrations were evaluated by the Spearman correlation coefficient. A p-value < 0.05 was considered to be significant. Statistical analyses were performed using JMP 9.0.1 software . For the reproducibility of the parameters, results were analyzed using Bland-Altman comparison and coefficient of variability.http://www.spc.univ-lyon1.fr/mfcalc:NSN/crit%20continu.htm).Based on our results obtained at baseline and one month after electrical cardioversion in a limited number of patients, we calculated the theoretical number of patients it should be necessary to recruit to reach a significant difference between the two groups in term of ANP level . The main characteristics of the remaining 20 patients are summarized in Table The study population initially consisted of 29 consecutive patients with persistent AF who were addressed for cardioversion. Nine patients were excluded from the study because cardioversion failed or because the patients were lost to one-month follow-up. The clinical characteristics of these nine excluded patients did not differ from other patients in terms of age 65.3 ± 10 years), sex , associated cardiac disease, ANP level (248.9 ± 108 pmol/l), BNP level (240 ± 111 pg/ml) or echocardiographic parameters , whereas the mean LA volume of patients in the AF group remained unchanged at that point . We noted a slight improvement in LVEF in the SR group one month after cardioversion , while no improvement in LVEF was seen in the AF group .Although great care was taken to ensure the quality of the data collected, we excluded one 4-chamber view and three 2-chamber views because of poor quality. Inter-observer variability coefficients of 4C-PALS, 2C-PALS and MPALS were 9%, 13% and 8%, respectively. Intra-observer variability coefficients of 4C-PALS, 2C-PALS and global MPALS were 5%, 8% and 6%, respectively. No significant difference was observed between the two independent physicians who analyzed the echocardiographic recordings. Among the standard echocardiographic parameters measured, the mean LA volume did not differ between the SR and AF groups at baseline  or LA volume . There was no correlation of BNP concentrations with MPALS or LA volume at one month .Our study shows that in patients with persistent AF treated by cardioversion, LA mechanical function recovers faster than endocrine function, but that LA distensibility is only partial one month after sinus rhythm has been restored. To our knowledge, this is the first study assessing simultaneously the relationship between LA mechanical function, as evaluated by speckle-tracking echocardiography, and variations in proANP levels one month after cardioversion. Previous studies evaluated either the mechanical LA function or the endocrine function separately,19, but Our population is quite similar in mean age, sex ratio and duration of AF to those in previous studies evaluating strain among patients with AF-21. Furtet al.[et al.[et al.[Over the last few years new echocardiographic techniques have been developed and used to analyze myocardial deformation non-invasively. Di Salvo et al. have use[et al. have rep[et al. (around [et al. (42.2 ± The particularity of our study is its focus on the link between the mechanical and endocrine functions of the LA. Indeed, our findings indicate that baseline proANP concentrations are negatively correlated with baseline MPALS, but no correlation is observed between proANP concentrations and LA volume. After one month in SR, the correlation between proANP levels and MPALS disappears, because mechanical function tends to improve, whereas proANP concentrations remain the same. Wozakowska-Kaplon has shown that mean ANP and BNP levels decrease 24 hours after electric shock and successful cardioversion. Our res2DS2-VASC score who do not need permanent anticoagulation. In absence of complete restoration of the mechanical and endocrine functions of LA one month after electrical cardioversion a prolongation of anti-coagulant agents could be proposed to the patients. Several echocardiographic studies have established in AF patients a close relationship between the risk of thrombo embolism and the LA mechanical function[These preliminary results suggest performing an evaluation of the mechanical and endocrinal functions of LA two or three months after cardioversion in selected patients. This point could be important for patients with a low CHAOur pilot study shows that one month after cardioversion for AF, neither the mechanical function of the LA, especially distensibility as quantified by speckle-tracking echocardiography, nor its endocrine function are fully restored in SR patients, demonstrating that atrial stunning can exceed one month. The incomplete recovery of LA mechanical function contributes to high ANP concentration that favors a prothrombotic state. The fact that complete recovery time of endocrinal and mechanical functions of the left atrium after electrical cardioversion is longer than one month suggests that selected patients should be reexamined two or three months later before changing therapeutic agents, especially anticoagulants. A further expanded study would be necessary to confirm these results and their potential therapeutic applications.ANP: Atrial natriuretic peptide; BNP: Brain natriuretic peptide; CNP: C-type natriuretic peptide; AF: Atrial fibrillation; TDI: Tissue doppler imaging; LA: Left atrium; MPALS: Left atrial deformation; LVEDD: Left ventricular end-diastolic diameter; LVEF: Left ventricular ejection fraction; SR: Sinus rhythm; 2C-PALS: 2-chamber peak atrial longitudinal strain; 4C-PALS: 4-chamber peak atrial longitudinal strain; MPALS: Mean peak atrial longitudinal strain.The authors declare that they have no competing interests.Study concept: ABB, EP, NZ, DB. Echocardiography: ABB, CSE, NZ. Laboratory investigations: EP, JCP. Statistics: CSE, LF, DB. Manuscript drafting: ABB, CSE, LF, DB. All authors read and approved the final manuscript.


Valvular aortic stenosis is the most common cause of left ventricular hypertrophy due to gradually increasing pressure work. As the stenosis develop the left ventricular hypertrophy may lead to congestive heart failure, increased risk of perioperative complications and also increased risk of sudden death. A functional porcine model imitating the pathophysiological nature of valvular aortic stenosis is very much sought after in order to study the geometrical and pathophysiological changes of the left ventricle, timing of surgery and also pharmacological therapy in this patient group.Earlier we developed a porcine model for aortic stenosis based on supracoronary aortic banding, this model may not completely imitate the pathophysiological changes that occurs when valvular aortic stenosis is present including the coronary blood flow. It would therefore be desirable to optimize this model according to the localization of the stenosis.In 20 kg pigs subcoronary (n = 8), supracoronary aortic banding (n = 8) or sham operation (n = 4) was preformed via a left lateral thoracotomy. The primary endpoint was left ventricular wall thickness; secondary endpoints were heart/body weight ratio and the systolic/diastolic blood flow ratio in the left anterior descending coronary. Statistical evaluation by oneway anova and unpaired t-test.Sub- and supracoronary banding induce an equal degree of left ventricular hypertrophy compared with the control group. The coronary blood flow ratio was slightly but not significantly higher in the supracoronary group (ratio = 0.45) compared with the two other groups .A human pathophysiologically compatible porcine model for valvular aortic stenosis was developed by performing subcoronary aortic banding. Sub- and supracoronary aortic banding induce an equal degree of left ventricular hypertrophy. This model may be valid for experimental investigations of aortic valve stenosis but studies of left ventricular hypertrophy can be studied equally well by graduated constriction of the ascending aorta. Valvular aortic stenosis is the most common heart valve disease and the development is often initiated by fibrosis and the subsequent development of calcification of the aortic leaflets and annulus .Severe valvular aortic stenosis eventually leads to left ventricular failure characterized by diminished stroke volume due to increased pressure work and compensatory increase in end diastolic volume and pressure. The increased pressure work causes left ventricular hypertrophy and increased left ventricular mass. Although this hypertrophy enables some compensation for the pressure induced increase in wall stress according to the law of Laplace , it is aTo evaluate the impact of different treatment options and developing new ones a human compatible animal model of valvular aortic stenosis is necessary.Earlier attempts have been made to develop animal models for left ventricular hypertrophy -15. MostSince, the pressure is elevated proximally to the stenosis the coronary vessels will be exposed to elevated systolic blood pressure and may cause increased systolic myocardial perfusion and potentially hampered diastolic perfusion of the myocardium. It may also enhance the development of left ventricular hypertrophy.Due to these model limitations in the supracoronary stenosis setting it is desirable to develop an animal model that more closely imitates the pathophysiological scenario of valvular aortic stenosis characterized by slow progression of the stenosis in an animal that shares essential anatomical features with the human heart.The aim of this study was threrfore to develop and evaluate a human compatible porcine model for valvular aortic stenosis and compare it to supracoronary aortic stenosis.The study was conducted as a prospective randomized intervention-control study with three groups of female Danish Landrace pigs.In the subcoronary group (n = 8) aortic banding was performed at the level of the aortic valve. In the supracoronary group (n = 8) aortic banding was made in the mid ascending aorta and in the control group (n = 4) a sham operation was performed in order to obtain normal values for pigs at the same stage of development with almost the same surgical trauma.Prior to surgery the pigs were randomized to one of the three study arms. Preoperative transthoracic echocardiography was conducted and the surgical banding procedure or sham operation performed subsequently. At four, six and eight weeks postoperatively the echocardiography was repeated and at the last follow-up examination at eight weeks the blood flow in the left anterior descending coronary artery was also measured intraoperatively prior to euthanasia of the animal.In order to include the scheduled number of animals 44 Danish Landrace pigs weighing approximately 20 kg (19.89 ± 1.7 kg) were included in this study.®) and 10 mg midazolam (Dormicum®).Each animal was pre-anaesthized prior to transport from the housing facility with an intra muscular injection of 40 mg azaperone (Stresnil®) and 40 mg ketamin were administered intravenously.Immediately upon arrival to the surgical facility i.v. access was obtained in an ear vein and 20 mg midazolam (Dormicum®) were administered intravenously. During the banding procedure continuous anesthesia and analgesia were maintained by isoflurane/sevoflurane aiming at a constant MAC = 1.0 and 350 μg/hour fentanyl . After the operation cefuroxim (Zinacef®) 750 mg were administered intravenously and 100 mg of the NSAID Flunixin vet. ® intra muscularly.The animal was then endotracheally intubated and then coupled to a ventilator. Before commencing surgery 4 mg pancuronium and 750 mg cefuroxim .Left ventricular free wall thickness was assessed through a right transthoracic acoustic window using the parasternal long axis scan. From the echocardiographic loops the left ventricular wall thickness was assessed using dedicated software . An anatomical M-mode assessment was applied to the loops of the parasternal long axis scan and the free wall thickness measured with the examiner being blinded for which animal was examined and also with respect to the week which the examination was performed.The coronary artery blood flow was measured using a transit time CardioMed flow probe mounted on the left anterior descending artery at the level of the second diagonal. The data was collected using LabView 8.2  and also analyzed using this software. After mounting the flow probe the measurements was obtained after approximately 30 minutes of rest when the heart rate and blood pressure were stable.syst/Qdiast.According to the blood pressure measurements the heart cycle was divided into the systolic and the diastolic part marked by the closing of the aortic valve. The coronary blood flow signal was then integrated and the ratio of the systolic and the diastolic blood flow, blood flow ratio was derived, BRF = Q3.The entire heart was excised and then fixated in formaldehyde for several weeks before further examinations. At this point the weight of the left ventricle was assessed and the apical 6 cm of the heart was cut in slices and the right ventricle removed. The heart/body weight ratio was calculated as H/BWR = (Heart weight (kg)/Body weight (kg)) × 10The primary endpoint was left ventricular free wall thickness and the secondary endpoints were post-mortem heart/body weight ratio and blood flow ratio in the left anterior descending.Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health .Qualified and experienced animal caretaker personnel monitored the health status of the animals during the study period. The experiments complied with the guidelines for animal experimental studies issued by The Danish Inspectorate for Animal Experimentation under the Danish Ministry of Justice who also approved this study and the investigation conforms to the During the development of aortic stenosis the animals were carefully evaluated for signs of heart failure and in case of failure-to-thrive they were electively euthanized.By the end of the final follow-up at eight weeks the animals were euthanized by an intra cardiac injection of saturated potassium solution during general anesthesia.The data from the three groups was compared using one way ANOVA-test. The data was normal distributed verified by Q-q plot and a scatter plot.If a p-value < 0.05 was found using the one way ANOVA, post hoc testing was performed using an unpaired t-test comparing the groups two-by-two.p-values < 0.05 were considered statistically significant. Results are displayed as mean ± standard deviation.Out of the 44 animals included in this study 10 pigs were excluded because of pre-existing disease mainly pneumonia and/or pericarditis (9) and malformation of the larynx (1). During surgery 14 died including 12 from the subcoronary group  and 2 from the supracoronary group because of postoperative ventricular fibrillation. All surviving animals  completed the follow-up period. Full data sets were acquired in 18 animals. In two animals, one from each of the supracoronary and control group, coronary blood flow measurements were not completed due to uncontrollable bleeding when mobilizing the heart and mounting the flow probe.The results are displayed in Figure The increase in wall thickness was evident after only four weeks in the two intervention groups compared with the control group but the increase was not statistically significant until after six weeks and stayed clearly hypertrophic through the eight weeks examination when comparing them to the control group. There were no statically significant differences between the two intervention groups.The coronary blood flow measurements revealed a slightly higher systolic blood flow ratio in the left anterior descending artery in the supracoronary group than the subcoronary and the control group but not statistically significant different when testing with a one way ANOVA test. The data was stratified according to the heart rate and the only interval in which all groups were represented was 50-55 BPM. We also pooled the data and calculated a flow average for all three groups including all data on surviving animals in which all flow measurements are represented meaning that the data is not stratified according to heart rate. See table This study shows that it is possible to perform subcoronary aortic banding and induce left ventricular hypertrophy based on human compatible valvular aortic stenosis. The results from the echocardiographic examinations indicate that the left ventricular hypertrophy parallels the gradually developing stenosis.The increase in wall thickness in the subcoronary group proceeds in an almost linear fashion with some degree of stagnation at six weeks. The increase in wall thickness in the supracoronary group proceeds in a linear fashion. In the control group there is almost no increase in wall thickness though showing a similar pattern with a slight decrease in wall thickness at six weeks as in the subcoronary group. This growth pattern might be within the normophysiological growth of the porcine heart since it also occurred in the control group and has been described in other studies . Since wThe post mortem examinations revealed significant variation in the weight of the left ventricle as well as the total weight of the animals. To circumvent this problem we related the heart weight to the body weight (heart/body weight ratio) and were able to perform a less biased comparison.We found that the heart/body weight ratio was significantly increased in the intervention groups compared with the control group. No significant differences were found between the two intervention groups. This was supported by the echocardiographic findings.The blood flow ratios showed a tendency towards a higher systolic flow in the left anterior descending artery in the supracoronary group compared with the subcoronary and the control group. There was, however, no statistical difference when testing both the average flow ratio and the ratio for the flow ratio interval 50-55 BPM which was the only narrow heart rate interval where all groups was represented. The low number of animals included in this study may explain the lack of significance. The results may however, still reflect a tendency towards different hemodynamic conditions according to the location of the stenosis meaning that there could be increased systolic myocardial perfusion in the supracoronary group compared with the subcoronary group. On the other hand, it did not seem to affect the development of left ventricular hypertrophy in the two intervention groups.The results indicate that it is possible to induce left ventricular hypertrophy using subcoronary banding technique. It also suggests that the blood flow in the left anterior descending artery is only slightly influenced by the localization of the aortic stenosis since the blood flow ratio only is slightly higher in the supracoronary group.Animal models producing pure valvular aortic stenosis are very scarce and only a canine model has been presented in the literature . To our The mortality levels in the subcoronary group were high. The reason for this may be that there was a learning curve for the subcoronary group since the surgery needed to perform the procedure was more complex than the surgery performed in the two other groups. The procedure in this study was performed via a left lateral mini-thoracotomy. This made the subcoronary aortic banding technically challenging. The mortality levels could possibly have been improved if the aortic banding had been performed via a median sternotomy. Using this access would inflict the animals with a more extensive surgical trauma and an increased risk of postoperative complications.Since supracoronary aortic banding is easier accessible and entails a lower mortality and almost certainly will result in left ventricular hypertrophy it may be more practical and less demanding to use this method.In future studies investigating left ventricular hypertrophy the supracoronary aortic banding method will be appropriate since subcoronary- and supracoronary aortic banding creates the same degree of hypertrophy and this method is easier accessible. In studies investigating the nature of valvular aortic stenosis the animal model should closely imitate the nature of that and therefore the subcoronary method should be used. Therefore, it may be relevant to consider the type of banding when investigating left ventricular hypertrophy or valvular aortic stenosis.Since congenital subcoronary aortic stenosis initially may be asymptomatic and may lead to the development of left ventricular hypertrophy and congestive heart failure it is important to establish an animal model that closely imitates this condition. The model for subcoronary aortic stenosis may be appropriate for studying congenital aortic stenosis and evaluating different treatments such as timing of surgery, choice of procedure and long-term outcome after treatment or without treatment.The difference between the two intervention groups and the control group might have been accentuated by doing this study in a larger scale with respect to the number of included or surviving animals.The statistics regarding the blood flow measurements are not very strong and this study must be regarded as a feasibility study in which we proved that it is possible to perform subcoronary aortic banding.The flow ratio data was difficult to compare due to different heart rates while collecting the flow measurements. This may have caused some degree of bias because a higher heart rate causes the diastolic part of the heart cycle to decrease thereby causing a higher ratio.It could have been desirable but impractical to measure the myocardial wall thickness by the transthoracic echocardiographic measurements at several locations in the left ventricle. Therefore, we can only anticipate that the growth is concentric. However, other studies have shown that left ventricular hypertrophy caused by valvular aortic stenosis is concentric  and it iAnother option that may improve this model is extending the follow-up period allowing the animals to grow even larger and also allowing the left ventricular hypertrophy to develop to a greater extent. However, an extended follow-up period may also challenge the model since congestive heart failure may arise.A human pathophysiological compatible porcine model for valvular aortic stenosis was developed by performing subcoronary aortic banding. Comparing the combined subcoronary and the supracoronary groups with the control group we found significantly increased left ventricular free wall thickness, significantly increased heart/body weight ratio and no statistically significant difference in the coronary blood flow ratio. There were no statistical differences between the sub- and supracoronary group when testing each endpoint.Unless future studies should disclose any qualitative differences between left ventricular hypertrophy induced by subcoronary and supracoronary aortic banding it may be most practical to use the supracoronary banding approach when studying left ventricular hypertrophy.This chronic porcine model of valvular aortic stenosis may very well form the basis for a wide range of experimental settings. With this human compatible pathophysiological animal model it is possible to investigate the clinical challenges entailed by this patient group and the nature of left ventricular hypertrophy due to valvular aortic stenosis. This model is suitable for evaluating new bioprosthesis and the potential impact that prosthesis-patient mismatch may have on the valve such as calcification and rupture of the valve but also the consequences of diminished regression of the left ventricular hypertrophy can be studied using this model. It also becomes possible to evaluate novel pharmacological therapies aimed at relieving valvular aortic stenosis and left ventricular hypertrophy in adult as well as pediatric patients. In addition, the model can be used to investigate how the timing of valve surgery can be optimized in this patient group.The authors declare that they have no competing interests.MS participated in the design of the study and carried out the experimental work, data analysis and drafted the manuscript. JHM participated in designing the study, coordinating the experimental surgeries and the statistical evaluation. HJ participated in the experimental surgeries. ES participated in designing the study and collected the echocardiographic follow-up examinations. All authors read and approved the manuscript.


A patient with D-TGA and surgical repair (Mustard's procedure) presented with appropriate ICD shocks due to monomorphic ventricular tachycardia, refractory to antiarrhythmic medications.The patient underwent an electrophysiological study and catheter ablation for the VT. Substrate and pace mapping techniques, with the help of an electroanatomical mapping system, was used to localize and ablate the tachycardia successfully.In patients with D-TGA and Mustard's repair, scar tissue resulting from VSD repair can act as a substrate for recurrent VT. Catheter ablation of VT is useful in management of VT that occurs despite antiarrhythmic therapy and/or when it is unstable. Dextro- transposition of the great arteries (D-TGA) with palliative intra-atrial redirection surgery (Mustard or Senning procedures) has one of the highest sudden cardiac death (SCD) risks in patients with congenital heart disease. In patients with D-TGA high rates of appropriate Implantable Cardioverter- Defibrillator (ICD) shocks for ventricular tachycarrhythmias have been noted -3. We reOur patient is a 35 years old man, with D-TGA, ventricular septal defect (VSD), and mild sub-pulmonic stenosis (PS) at birth. He underwent atrial septostomy with pulmonary artery (PA) banding  three months after birth. Following this he underwent intra-atrial baffle rerouting (Mustard's repair) with closure of the VSD at three years of age.In 2003 he survived a cardiac arrest secondary to ventricular fibrillation (VF) and was left with residual anoxic brain injury resulting in severe short-term memory impairment. He received a single chamber transvenous ICD following this event. During the ensuing years he had four appropriate ICD therapies for monomorphic VT varying in cycle length (CL) between 320 and 350 ms.The patient was started on beta-blockers and Amiodarone (300 mg maintenance dose) for prevention of VT. He continued to have ICD shocks for monomorphic VT while on antiarrhythmic therapy. After discussion with the patient and his family, an electrophysiological (EP) study and catheter ablation for VT was performed. Cardiac imaging prior to the procedure showed systemic ventricular dysfunction with a calculated ejection fraction ranging from 35-40% along with mild venous ventricular systolic dysfunction. The intra-atrial baffles were patent and the atrioventricular and ventriculo-arterial valves were normal.The EP study was performed under intravenous general anesthesia. Vascular access was obtained from the groin  using the Seldinger technique. ICD therapies were turned off and the ICD was programmed to the VOO pacing mode at a rate of 80 bpm. The EP study was performed while the patient was on 300 mg of Amiodarone and 5 mg of Bisoprolol a day.A sustained monomorphic VT with a CL of 350 ms was induced during programmed electrical stimulation . The patA substrate map of the systemic ventricle was created using a non-fluoroscopic electroanatomical mapping system  during ventricular pacing at a rate of 80 bpm (the patient had advanced AV conduction system disease and was pacing dependent). A Navistar thermocool catheter  was used for electroanatomical mapping. Intravenous unfractionated heparin was used to keep the activated clotting time (ACT) > 240 seconds for the duration of the procedure.Bipolar contact electrograms were recorded and used to create a three-dimensional map of the chamber, based on voltage amplitude. After creating an electroanatomical map of the ascending Aorta and the systemic ventricle we performed image integration . Areas wWe then performed pace mapping at a CL of 450 ms at different sites in the systemic ventricle till we obtained a 12/12 match with the induced tachycardia. The site of 12/12-pace match was at the edge of the scar in the interventricular septum, in the systemic ventricle just below the Aortic coronary cusp . Local bAfter RF ablation, attempts to reinduce VT, including programmed electrical and burst pacing from the systemic and venous ventricle were undertaken. No ventricular arrhythmias were induced. We deemed this a satisfactory endpoint, as the VT was easily inducible prior to catheter ablation. The patient withstood the procedure without any acute complications. The patient is being followed up in the ICD clinic and has not had any further ventricular arrhythmias during the past ten months. Amiodarone has been discontinued and the patient continues to be on Bisoprolol.Our patient was selected for catheter ablation of VT as he was having multiple appropriate ICD shocks while on maximally tolerated antiarrhythmic medications. The patient had a single- inducible; scar related, monomorphic VT that was not hemodynamically tolerated. The CL of the VT was identical to VTs recorded by the patient's ICD.  Activation mapping and entrainment maneuvers could not be performed because of hemodynamic instability. Therefore, substrate and pacemapping to localize the origin of the VT were performed.Unlike entrainment mapping, which is performed while the patient is in VT, one cannot be certain about whether a particular site is within a critical portion of a VT circuit. The best pacemap site provides a general idea of where the VT exits allowing the operator to deliver targeted lesions around critical areas of the VT circuit. This is a probabilistic approach to VT ablation with limitations, but it has the advantage of being performed in sinus rhythm - thereby allowing the operator to target even hemodynamically unstable VTs ,5. We haZeppenfeld and colleagues have presented insights from VT ablation in patients with tetralogy of Fallot (TOF) and intracardiac repair. They identified isthmuses around the region of patch annuloplasty and ventricular septal defect repair in the venous ventricle thought to be responsible for genesis of ventricular arrhythmias. Catheter ablation transecting anatomical isthmuses around scars along with entrainment pace mapping and substrate ablation was successful in preventing arrhythmia recurrence in these patients. In our case the clinical VT originated in the systemic ventricle and was not hemodynamically well tolerated. This prevented us from performing entrainment mapping and delineating the arrhythmia circuit. Therefore, we resorted to pace mapping to localize the exit site of the VT and used voltage based substrate ablation in and around the scar. We were not able to identify a clear anatomical isthmus at this site  and therefore did not perform transecting linear isthmus ablation as described by Zeppenfeld .Advances in imaging and mapping technologies have made ablation of arrhythmias in patients with congenital heart disease safe and effective. However, difficulties in obtaining vascular access to cardiac chambers and the potential for major complications such as cardiac perforation, intra-atrial baffle tears and damage to cardiac valves should be kept in mind while selecting patients for catheter ablation.In patients with D-TGA and Mustard's repair scar tissue resulting from VSD repair can act as a substrate for recurrent VT. Catheter ablation of VT is useful in management of VT that occurs despite antiarrhythmic therapy and/or when it is unstable.


Journal of the American Heart Association (JAHA), Lugenbiel et al1 describe a novel gene-based approach for potentially treating heart failure by targeting discrete cell populations within the sino-atrial node.Heart failure is a major public health epidemic that claims hundreds of thousands of lives annually in the United States alone. Despite important advances in the management and prevention of many cardiovascular disorders, the incidence and prevalence of heart failure are increasing with the aging of the population. Existing treatments for patients with heart failure are far from being optimal and are often associated with proarrhythmic activity and risk of sudden cardiac death. Therefore, the search for novel, effective, and safe therapeutic options for these patients represents a critical area of unmet need for this country and the rest of the world. In an elegant proof of concept study published in this issue of the 2 In fact, a strong link between average heart rate and cardiovascular morbidity in patients with heart failure has been documented. In clinical trials the ability of a given heart failure treatment to reduce overall mortality is, in some cases, predicted by its heart rate lowering efficacy. Moreover, a causative relation between elevated heart rate and heart failure is epitomized by the fact that sustained tachycardia, in the absence of other risk factors or insults, is a well-established mechanism of ventricular remodeling that culminates in the onset of heart failure.3 In the experimental laboratory, numerous groups have exploited the relation between elevated heart rate and left ventricular dysfunction by developing highly reproducible small and large animal models of heart failure using chronic tachycardia pacing of the right atrium or ventricle. These experimental models have been instrumental in advancing our fundamental understanding of the mechanisms that underlie mechanical, structural, electrical, metabolic, ionic, and molecular dysfunction in the failing heart. Of note, cessation of rapid pacing following the onset of heart failure is typically associated with reversal of pathological electrical and structural remodeling and an improved cardiac function,4 further highlighting the role of heart rate control in the management of heart failure.Several lines of evidence derived from experimental and clinical studies indicate that a controlled heart rate is an important target for heart failure therapy.6 Indeed, chronic β-adrenergic receptor stimulation, which increases the energetic cost of contractility at a time of reduced oxygen supply, can exacerbate myocardial damage and accelerate mortality in heart failure patients. In contrast, β-adrenergic receptor blockers, which are mainstays of heart failure therapy, are distinguished by their heart rate lowering efficacy and their ability to hinder and/or reverse key features of pathological remodeling in the failing heart. Because β-adrenergic receptor blockers are confounded by negative inotropic properties that can further reduce the contractile function of an already compromised failing heart, their efficacy in the acute and subacute phases is often limited. To that end, considerable interest in recent years has been directed toward the development of specific heart rate lowering agents that selectively target pacemaker channels. Ideally, such agents would mimic the beneficial effects of β-blockers in terms of heart rate reduction while avoiding their confounding side effects on contractility.Hallmark features of the failing heart include a prominent reduction in contractile efficiency and the loss of contractile reserve. These deficits, caused by altered calcium signaling, excitation-contraction coupling, and decreased myofilament sensitivity to calcium can lead to hemodynamic insufficiency, compromise, and death. To enhance cellular contractility, β-adrenergic receptor agonists, such as isoproterenol and dobutamine, have been developed. The positive inotropic property of these agents is mediated, in part, by the enhancement in activator calcium through L-type calcium channels which are phosphorylated by cAMP-dependent protein kinase A. Unfortunately the chronic use of these agents has been severely hampered by adverse effects, including heart rate acceleration and promotion of ventricular arrhythmias.fI), was developed to suppress heart rate by targeting the hyperpolarization-activated cyclic nucleotide (HCN) gene family. In experimental and clinical studies, ivabradine improved myocardial energetics and left ventricular function. Specifically, in the SHIFT trial (Systolic Heart failure treatment with fI Inhibitor ivabradine), patients with symptomatic heart failure who were treated with ivabradine had a significant benefit (by >25%) in terms of cardiovascular mortality and hospitalization when compared with the placebo treated group.7 These highly encouraging findings have cemented the concept of heart rate modulation through pacemaker channel inhibition as an important strategy for the management of heart failure.9 As with any pharmacological therapy for a chronic disease, challenges related to dosing, bioavailability, selectivity, and adverse interactions with other drugs are expected. These complicating issues warrant further optimization, as alternative nonpharmacological approaches for modulating heart rate are explored.Ivabradine, a selective inhibitor of the pacemaker current , specifically in the sino-atrial node. In effect, these authors use highly sophisticated molecular and gene therapy tools to create a “biological beta blocker” that can be locally delivered.In this issue of 10 and “bio-beta blockers” for combating tachycardia.11 This is followed by a discussion of the unique advantages and potential pitfalls of the exciting approach undertaken by Lugenbiel et al1 for suppressing heart rate.In what follows, we provide a brief overview of recent efforts to develop cell- and gene-based therapies for heart rate control, including the creation of “bio-pacemakers” for combating bradycardia14 Our growing understanding of the molecular basis of cardiac pacemaking activity, including the revelation of a complex interplay between voltage and calcium clocks within the cardiac myocyte, has been instrumental in the identification of key targets that can be exploited for the creation of viable biological pacemakers.Major milestones have been recently achieved in our collective effort to develop novel, gene-based approaches for the treatment of cardiac rhythm disorders. Indeed, several groups have made great strides toward the creation of biological pacemakers that can one day (perhaps in the near future) either fully replace or at the very least assist existing electronic devices.14 used viral gene transfer of an engineered dominant negative construct of Kir2.1 (Kir2.1AAA) to focally inhibit the inward rectifier potassium current; thereby converting normally quiescent cells into ones that exhibited spontaneous depolarization and rhythmic activity. When injected into the left ventricle, these constructs could “capture” the myocardium resulting in premature ventricular beats that likely emanated from the site of injection.14 In other seminal studies, Rosen et al systematically developed HCN based approaches for the creation of robust biological pacemakers, both in vitro and in vivo.17 These biological pacemakers provided physiologically acceptable heart rates and exhibited positive chrontropic responses to emotional arousal and stress. Indeed, the efficacy and translatability of these HCN-based approaches were elegantly documented in preclinical large animal models by the Rosen group.17In proof of concept studies, Miake et alCa-LI),18 which mediates action potential propagation in specialized conducting tissues, such as the sino-atrial and atrio-ventricular nodes.As mentioned earlier, heart rate reduction is an important target for heart failure therapy. As such, novel molecular tools that can either lower resting heart rate or dampen the excessive acceleration of heart rate upon β-adrenergic stimulation are needed. To that end, Donahue and colleagues pioneered efforts to create gene therapy tools for rhythm disorders by targeting the L-type calcium current  suppression of heart rate. This surely cannot be achieved by a short-term adenoviral mediated gene transfer strategy coupled with a highly invasive electroporation technique. The development of clinically translatable gene delivery methods and cardiotropic vectors for long-term modulation of gene expression in the sino-atrial node and/or the myocardium would be required. Indeed, the use of various adeno-associated vector serotypes or adeno-associated vector chimera may prove essential in achieving this ambitious aim. As with any good study, the intriguing findings by Lugenbiel et al


Obesity affects a third of adults in the US and results in an increased risk of cardiovascular mortality. While the mechanisms underlying this increased risk are not well understood, animal models of obesity have shown direct effects on the heart such as steatosis and fibrosis, which may affect cardiac function. However, the effect of obesity on cardiac function in animal models is not well-defined. We hypothesized that diet-induced obesity in mice reduces strain, torsion, and synchrony in the left ventricle (LV).Ten 12-week-old C57BL/6 J mice were randomized to a high-fat or low-fat diet. After 5 months on the diet, mice were imaged with a 7 T ClinScan using a cine DENSE protocol. Three short-axis and two long-axis slices were acquired for quantification of strains, torsion and synchrony in the left ventricle.Left ventricular mass was increased by 15% (p = 0.032) with no change in volumes or ejection fraction. Subepicardial strain was lower in the obese mice with a 40% reduction in circumferential strain (p = 0.008) a 53% reduction in radial strain (p = 0.032) and a trend towards a 19% reduction in longitudinal strain (p = 0.056). By contrast, subendocardial strain was modestly reduced in the obese mice in the circumferential direction by 12% (p = 0.028), and no different in the radial (p = 0.690) or longitudinal (p = 0.602) directions. Peak torsion was reduced by 34% (p = 0.028). Synchrony of contraction was also reduced (p = 0.032) with a time delay in the septal-to-lateral direction.Diet-induced obesity reduces left ventricular strains and torsion in mice. Reductions in cardiac strain are mostly limited to the subepicardium, with relative preservation of function in the subendocardium. Diet-induced obesity also leads to reduced synchrony of contraction and hypertrophy in mouse models. No sWe aimed to overcome these limitations by using a Cardiovascular Magnetic Resonance (CMR) protocol called Displacement Encoding with Stimulated Echoes (DENSE)  to quantad libitum, with 60% of calories from fat (Research Diets #D12492) or a low fat diet with 10% of calories from fat (Research Diets #D12450B). Animals were housed in ventilated cages in a temperature-controlled room with a 14:10 light:dark cycle. Body weights were quantified weekly. All animal procedures conformed to Public Health Service policies for humane care and use of animals, and all procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Kentucky.Ten 12-week-old C57BL/6 J mice were randomized to either a high fat diet Imaging was performed 5 months after starting the diet. Animals were anesthetized with 1.5-2.5% isoflurane in oxygen at 1.0 L/min. Isoflurane was adjusted to maintain respiratory rates of 100–140 breaths per minute. Three legs were shaved for placement of cutaneous ECG electrodes for cardiac gating, and the mouse was transferred to the scanning bed. A diaphragm to sense breathing was placed under the abdomen for respiratory gating. Core temperature was maintained from 36-37°C with a heated water blanket and rectal thermometer. All vital signs were continuously monitored with a fiber optic system .Displacement Encoding with Stimulated Echoes (DENSE) was utilized. Immediately after an electrocardiogram R-wave trigger detection, which marks the depolarization of the ventricles and onset of contraction, a displacement encoding module consisting of radiofrequency and gradient pulses was applied, which stores position-encoded magnetization. This was followed by successive applications of a readout module which employed a radiofrequency excitation pulse, a displacement un-encoding gradient, and an interleaved spiral k-space trajectory. Ultimately, the output of the cine DENSE sequence was 3 images: a magnitude image showing the location of the heart and two phase images showing the horizontal X-displacement and vertical Y-displacement of each pixel  with a 4-element phased array cardiac coil and a gradient system with a maximum strength of 450 mT/m and a slew rate of 4500 mT/m/s. Image acquisition has been described in detail previously ,32. Briel Figure . RelevanWe acquired 3 short-axis and 2 long-axis images for each mouse. The long-axis images consisted of a standard apical 4-chamber view and a 2-chamber view perpendicular to the 4-chamber view. The short-axis images were planned perpendicular to the 4-chamber long-axis end-systolic image at the basal, apical and mid-ventricular locations. The mid-ventricular location was prescribed 50% of the end-systolic long-axis ventricular length above the apex while the basal and apical slices were prescribed at a distance 20% of the end-systolic length above and below the mid-ventricle.The displacement-encoded phase images were used to calculate strains, torsion and synchrony offline using custom software written in MATLAB . Analysis included semi-automated motion-guided segmentation of the myocardium, phase unwrapping, tissue tracking to derive the path of each pixel throughout the cardiac cycle, and subsequent calculation of left ventricular strains ,33. The Using methodology identical to that described above for the short-axis data, the long-axis data (from the two and four-chamber images) were used to calculate longitudinal strains. The apical segments were excluded from long-axis analysis since it is difficult to define longitudinal strain where the shape of the ventricle curves at the apex. Average longitudinal strains were calculated from both the two and four-chamber images. End-diastolic and end-systolic volumes, mass and ejection fraction were derived from a smooth, 3-dimensional reconstruction of the endocardial and epicardial borders defined from the DENSE magnitude images .U-test. A value of p < 0.05 was defined as statistical significance. Values are reported as means ± SD.Analyses were performed in SPSS . Group differences were evaluated with a Mann–Whitney The mice on the high-fat diet gained weight over the course of the 5 months Figure .increased in the obese mice but was not significant (p = 0.056). The ratio of left ventricular mass to end diastolic volume was significantly increased in the obese mice (p = 0.032), consistent with a concentric hypertrophy.The obese mice had a 15% increase in left ventricular mass compared to the control mice  in the obese mice Figure .The radial uniformity of strain index (RURE) was reduced from 0.95 ± 0.02 in the control mice to 0.91 ± 0.03 in the obese mice (p = 0.032) Table . The cirWe used high-fat feeding to induce obesity in a mouse model to study the effects of obesity on the function of the heart using advanced measures of cardiac function . Our major findings are that obesity is associated with: 1) left ventricular hypertrophy; 2) no change in ventricular volumes or ejection fraction; 3) reduced cardiac strains and torsion; 4) reduced synchrony of contraction in the left ventricle; and 5) a differential effect on strains in the myocardial layers of the ventricle, with the most severe depression of function in the subepicardium and little to no effect in the subendocardium.These results are exciting as they show for the first time that mouse models of diet-induced obesity have changes in the heart that are similar to what has been reported in human studies: hypertrophy and reduced strains, torsion and synchrony in the setting of normal ejection fraction and normal ventricular volumes ,28,38. TIdentifying a precise mechanism underlying the effects of obesity on the heart is challenging. For example, mice with diet-induced obesity have mildly impaired glucose tolerance  but normTo our knowledge, this is the first study to report dyssynchrony in the setting of diet-induced obesity in mice. This is a significant finding, since dyssynchrony has been reported in human obesity  and is kOur results showed dyssynchrony according to the RURE index but not the CURE index. This could be due to the fact that the pathology underlying the dyssynchrony is not a typical conduction block but a more diffuse process such as changes in gap junctions which may affect the spread of conduction differently in the radial versus circumferential directions. However, we are confident that the observed dyssynchrony was a real phenomenon which can be clearly seen in Figure Our data show a heterogeneous effect of obesity on cardiac strains, with significant deleterious effects on the subepicardium, and relative preservation of function in the subendocardium. One potential mechanism for the heterogeneous effect may be paracrine inflammatory signaling from adjacent epicardial fat. An alternate explanation could be that myocytes in the subepicardium versus subendocardium have different mechanical function  and therThe left ventricular mass to end-diastolic volume ratio was increased in the obese mice, consistent with concentric hypertrophy. Concentric hypertrophy alters the loading conditions in the myocardium  which can affect strains. Therefore, the remodeling in the hearts of the obese mice could in part explain some of the observed dysfunction. This is consistent with the significant correlations we found between strains and the mass to volume ratio Table . Howeverimproved cardiac function [We used high-fat feeding to induce obesity in mice. The diet may have had an unanticipated acute effect on cardiac function, which our study did not consider. In fact, a recent study in humans showed that infusion of triglycerides acutely function . While tWe utilized 2-dimensional image slices to study 3-dimensional cardiac deformation. While 3-dimensional acquisition techniques for imaging deformation in the mouse heart have recently been developed , these tWe did not utilize a fat suppression technique during image acquisition. Future studies in obese mice may benefit from fat suppression to improve image quality. However, the overall quality of the images was good in both the obese and control mice Figure .Unfortunately, the quantification of torsion is not standardized in the literature. Published studies vary in both the slice selection to define the angular gradient and the normalization of the angular gradient to define torsion. We chose to normalize by the long-axis length of the ventricle, since there is evidence that this makes torsion values equivalent across mice and humans . Of the Diet-induced obesity leads to a reduction in cardiac function in mice as evidenced by reductions in left ventricular strains and torsion. Reductions in cardiac strain are mostly limited to the subepicardial layer of the left ventricle, with relative preservation of function in the subendocardium. Diet-induced obesity also leads to hypertrophy and reduced synchrony of contraction in the left ventricle of the heart. These findings help to further our understanding of the link between obesity and increased cardiovascular mortality, and also highlight important similarities between cardiac changes observed in obese mouse models and humans with obesity.CMR: Cardiovascular magnetic resonance; CURE: Circumferential uniformity ratio estimate; DENSE: Displacement encoding with stimulated echoes; RURE: Radial uniformity ratio estimate.Dr. Epstein receives research support from Siemens.SK completed the data analysis and drafted the manuscript. CH helped with data analysis and interpretation and drafting of the manuscript. CB and AM assisted with data collection and analysis and preparation of the manuscript. DP oversaw the CMR acquisition and also helped with data analysis and interpretation. LC participated in the study design and coordination, interpretation of results and drafting of the manuscript. FE developed the acquisition protocols and participated in the study design, interpretation of results and drafting of the manuscript. BF conceived the study, participated in its design and coordination, oversaw data acquisition and analysis, and helped to draft the manuscript. All authors read and approved the final manuscript.


With increasing urbanization, changes in lifestyle habits, and ageing of the population, the spectrum of causes of HF has also expanded resulting in a significant burden of both communicable and non-communicable etiologies. Heart failure in sub-Saharan Africa is notable for the range of etiologies that concurrently exist as well as the healthcare environment marked by limited resources, weak national healthcare systems and a paucity of national level data on disease trends. With the recent publication of the first and largest multinational prospective registry of acute heart failure in sub-Saharan Africa, it is timely to review the state of knowledge to date and describe the myriad forms of heart failure in the region. This review discusses several forms of heart failure that are common in sub-Saharan Africa  and presents each form with regard to epidemiology, natural history, clinical characteristics, diagnostic considerations and therapies. Areas and approaches to fill the remaining gaps in knowledge are also offered herein highlighting the need for research that is driven by regional disease burden and needs.The heart failure syndrome has been recognized as a significant contributor to cardiovascular disease burden in sub-Saharan African for many decades. Seminal knowledge regarding heart failure in the region came from case reports and case series of the early 20 Heart failure (HF) is a major public health problem worldwide. The available data suggest that while the morbidity due to HF is great in many parts of the world, the etiologies differ . The mosFactors unique to developing regions such as SSA make HF an especially challenging condition. Compared to other parts of the world, HF in SSA tends to occur at a much younger age. This finding could be due to the major contribution of rheumatic heart disease or early presentation of other degenerative causes. Misdiagnosis or under-diagnosis of HF is likely to occur where access to echocardiography or serologic markers is poor . While HThis review is designed to summarize what is known about the current forms of HF in SSA and is timely given the high prevalence of HF, growing interest and investment into cardiac disease research on the continent , 17 and Valvular heart disease in SSA is almost always due to sequelae of an infectious disease rather than degenerative changes. Recurrent pharyngeal infections with group A β-hemolytic streptococci and subsequent acute rheumatic carditis predispose to the development of rheumatic heart disease (RHD) - a chronic progressive condition with no known medical therapy. Valvular thickening eventually impairs function with subsequent valvular regurgitation. Over time, valvular stenosis may begin to predominate with further restriction in leaflet mobility and development of a transvalvular pressure gradient. Pure mitral regurgitation is the most common form of RHD in those younger than 20 years (>70% of cases) while mitral stenosis and mixed valvular disease becomes more common with advancing age . PulmonaWhile SSA is home to only 10% of the world’s population, nearly 50% of the 2.4 million children affected by RHD reside here . School-et al. [The classic natural history studies of Rowe et al. , Oleson et al.  and Granet al.  have shoet al. . The medet al. . Bacteriet al. . It is wet al.  of patieet al. .2. Arterial embolism as a presenting characteristic  is rare and its presence does not correlate with the severity of mitral valve stenosis but is related to the presence of atrial fibrillation [Rapid progression and symptomatic presentation of RHD is the rule more than the exception in SSA and both sexes are affected to a similar degree , 24. Eveillation . PatientThe most recent guidelines for diagnosing RHD recommend using echocardiography and incorporating morphologic criteria as well as Doppler-based assessment of regurgitant flow. Presumably, these expanded criteria offer the possibility of correctly identifying more subclinical disease in time to prevent progression to clinical RHD but there is no empiric evidence to support this assumption. The World Heart Federation guidelines employ two-dimensional, continuous wave and color Doppler echocardiography to categorize findings into three categories - definite RHD, borderline RHD and normal – with different criteria for those above and below 20 years of age . With suThere are no proven medical therapies to alter the natural history of RHD , 36. MedHypertensive heart disease is the cardiac damage related to chronic systemic arterial hypertension. Nowadays, among those >65 years of age, the prevalence of hypertension is roughly 30-40% in rural West Africa, 50% in semi-urban West Africa , 50-60% The causes of hypertensive heart disease in SSA seem to be similar to the rest of the world. A number of genes have been implicated in the development of cardiomyocyte hypertrophy in patients with essential hypertension which affect intracellular signaling, degradation of normal extracellular collagens and contractile dysfunction among other functions ultimately leading to left ventricular hypertrophy and HF . As oppoIn SSA, hypertensive heart disease consistently ranks in the top three causes of HF from all regions of the continent from the 1950s to the present  may be present earlier on in the course. When left ventricular hypertrophy is present the classic physical findings are an abnormally sustained apical impulse that is enlarged and displaced outside of the midclavicular line. An S4 gallop heard during auscultation is common in chronic hypertension and reflects the decreased elasticity of a hypertrophied ventricle during late diastole . The two most common tools used in SSA to define left ventricular hypertrophy are the electrocardiogram and the echocardiogram. The former provides information on voltage, cardiac rhythm, electrolyte imbalances, PR interval and QT interval while the echocardiogram will also provide determination of wall thickness, atrial size, left and right ventricular function and hemodynamics. The sensitivity and specificity of the electrocardiogram for left ventricular hypertrophy are approximately 7-74% and 41-98%, respectively, and no single criteria has the highest sensitivity, specificity, accuracy or correlation with cardiac magnetic resonance estimated left ventricular mass index -71. EchoTreatment for hypertensive HF follows the guidelines for the management of patients with HF according to clinical stage . AntihypClinically, two syndromes of pericardial diseases predominate: pericarditis and pericardial effusion. Tuberculosis is by far the commonest cause of pericardial inflammatory disease in SSA, accounting for about 10% of patients hospitalized with HF . MycobacOthers important causes of pericardial disease in SSA include metastatic neoplastic  and secondary metastatic tumors . PericarIn one South African center, tuberculosis accounted for 70% (162 of 233) of all cases referred for diagnostic pericardiocentesis . Most HIClassic symptoms of pericarditis include chest pain that typically radiates to both trapezius muscular ridges. Patients may also complain of a viral prodrome of fever, non-productive cough, myalgias and malaise. On physical examination, typical findings include a pericardial friction rub early in the course which may subsequently disappear when a pericardial effusion develops. A pericardial knock usually signifies constriction. In the presence of significant effusion, jugular venous pressure is increased, with prominent systolic x descent and blunted diastolic y descent. The precordium becomes quiet and blood pressure falls. The classic Beck’s triad of “surgical tamponade” is rarely seen in the medical patients . With reReuter et al. showed that CXR positively identified 53% (n = 90) of patients with pericardial effusion [Where resources are limited, a chest X-ray (CXR) may often be the only imaging modality available to the clinician. effusion . All of The ECG shows ST-segment elevation (in acute pericarditis) that is different from that in acute myocardial infarction: being more diffuse, involving both limb and precordial leads. After several days, the ST segment returns to baseline in a predictable manner . Other EDiagnostic pericardiocentesis yields a specific diagnosis in only 7% of cases of pericardial effusion without tamponade . The perTreatment regimens recommended for pericardial TB are the same as for pulmonary tuberculosis, consisting of 6 months of anti-tuberculous antibiotics. Corticosteroids are frequently prescribed for tuberculosis pericarditis but the evidence to support their use is limited. The effectiveness of systemic steroids is currently under investigation in a large multi-centre trial to evaluate their role  . Non-steDilated cardiomyopathy (DCM) refers to a heterogeneous group of heart muscle diseases of diverse etiologies that are characterized by dilatation and impaired contraction of the left and/or right ventricles. The histological findings are frequently nonspecific. Presentation is usually with progressive HF. Arrhythmias, thromboembolism, and sudden death are common and may occur at any stage. It is a common cause of HF in SSA . ImportaFamilial disease accounts for one third to one half of cases of DCM . More thchangaa in East Africa) to levels equivalent to those of commercial beers. Epidemics of impurities in commercially produced beers producing HF  are for the most part historical [Alcoholic cardiomyopathy is the commonest form of toxin-induced cardiomyopathy. Although the pathogenesis and factors that determine patient susceptibility are still poorly understood, alcohol is believed to be toxic to cardiac myocytes via oxygen free radical damage and defects in cardiac protein synthesis . The risstorical , howeverstorical .Myocarditis is an etiologic factor for DCM in up to 24% of cases and is associated with autoimmune disorders . Auto-imThe cardiomyopathy of iron overloading is an infiltrative disease that does not produce left ventricular hypertrophy. Hereditary hemochromatosis as well as other forms of iron deposition disease are found in SSA -109. A sPeripartum cardiomyopathy refers to an idiopathic form of cardiomyopathy presenting with HF with left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery. It is a diagnosis of exclusion. It is a rare from of cardiomyopathy in high-income countries (incidence rates 1/2500 – 4000 live births) but fairly endemic in SSA  , 113. A 3 and S4 gallops are common especially when decompensated. Fluid retention marked by elevated jugular venous pressure and peripheral edema are typical.Overall, patients with DCM present with typical symptoms and signs of HF including fatigue, dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. Palpitations and arrhythmias may result in syncope. The pulse pressure may be narrow with elevated diastolic pressure caused by systemic vasoconstriction. A displaced apical impulse, and an apical murmur of mitral regurgitation are common. On cardiac auscultation, SHIV testing is usually indicated in any patient presenting with DCM owing to its high prevalence. Consensus opinion also recommends other diagnostic laboratory studies to include complete blood count, urinalysis, serum electrolytes , blood urea nitrogen, serum creatinine, fasting blood glucose, lipid profile, liver function tests and thyroid stimulating hormone prior to labeling a patient with idiopathic cardiomyopathy . Serum vManagement of HF in patients with DCM follows similar principles as with other forms of HF with diuretics, afterload reduction and adrenergic blockade being the cornerstone. Patients receiving optimal medical therapy but who remain symptomatic should be considered for cardiac defibrillator or cardiac resynchronization therapy if they meet other selection criteria and if these options are available. Advanced therapies such as cardiac transplant or left ventricular assist devices in those with endstage disease may only be available in few countries.It is noteworthy that in patients with peripartum cardiomyopathy, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and spironolactone should be avoided in the prenatal period because of fetal toxicity. Hydralazine is particularly safe as an afterload reducing agent during this stage and digitalis can be used to increase contractility and for rate control. Bromocriptine has been shown to improve both clinical and cardiac function in pilot clinical trials but has yet to be replicated in larger studies . SubsequStandard treatment of iron overload cardiomyopathy currently includes dietary management, phlebotomy, and chelating agents. The role of calcium channel blockers in limiting iron transport into cardiac myocytes is being explored . In alcoToxoplasma gondii, coxsackievirus group B, cytomegalovirus, adenovirus or Epstein-Barr virus [Toxoplasma gondii in 3 cases, to Cryptococcus neoformans in 3, to Mycobacterium avium intracellulare in 2 and to direct HIV infection in 8 patients [HIV infection is associated with significant cardiovascular morbidity and mortality in SSA. Cardiac disease in HIV infection occurs with and without combined anti-retroviral therapy. In addition to the HIV virus itself traditional cardiovascular factors, the host response to the virus and the effects of anti-retroviral therapy are all thought to contribute to the cardiovascular disease burden . Dilatedrr virus . A studypatients .Cardiomyopathy in HIV seropositive patients is associated with low socioeconomic status, a longer duration of HIV infection, low total lymphocyte count, low CD4 count, high HIV-1 viral load and low plasma levels of selenium . A CD4 cA significant proportion of patients with HIV-associated cardiomyopathy are free of specific cardiovascular signs and symptoms . In the Treatment of cardiomyopathy associated with HIV follows guidelines for standard HF therapy . There iHypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease . AutosomHCM is characterized by left ventricular hypertrophy of various morphologies, with a wide array of clinical manifestations and hemodynamic abnormalities. Depending upon the site and extent of cardiac hypertrophy, HCM patients may develop left ventricular outflow obstruction, myocardial ischemia, mitral regurgitation or diastolic dysfunction . Most, brd most common cause of cardiomyopathy after DCM and endomyocardial fibrosis [Hypertrophic cardiomyopathy in Africa was generally regarded as rare especially in the pre-echocardiographic era. We now know that HCM is common in all parts of the continent. In Ghana, an echocardiographic study showed that HCM was the 3fibrosis . In Ethifibrosis . In Soutfibrosis . The natural history of HCM is variable and many patients never exhibit any clinical manifestations. Mitral regurgitation is common in patients with left ventricular outflow tract obstruction and is usually caused by the distortion of the mitral valve apparatus from systolic anterior motion . ProgresHCM may be newly diagnosed at any age and is usually suspected on the basis of the presence of a murmur or abnormal electrocardiogram. The physical examination in an asymptomatic patient with HCM may show a fourth heart sound or left ventricular lift. When there is significant outflow tract obstruction, a harsh crescendo-decrescendo systolic murmur develops that begins slightly after S1 and is heard best at the apex and left lower sternal border. Maneuvers that alter the degree of obstruction can cause a change in the murmur intensity.Two-dimensional Doppler echocardiography is the diagnostic modality of choice. The classical finding is septal hypertrophy out of proportion to posterior wall hypertrophy but there is heterogeneity in the morphology of the septal hypertrophy . ElectroTreatment goals for patients with HCM do not vary globally. Primary prevention of sudden cardiac death is best achieved with implantable cardiac defibrillators . Beta-adEndomyocardial fibrosis (EMF) is a form of restrictive cardiomyopathy in which deposits of dense fibrous tissue in the endocardium impair ventricular diastolic function and distort the papillary muscles of the atrioventricular valves. This results in right, left or biventricular failure and atrioventricular valve regurgitation. Isolated left ventricular involvement is the rarest form in Africa . The fibPlasmodium species [Schistosoma mansoni (in Egypt) [The majority of cases have been reported in countries which are within 15 degrees of the equator  although species  and Schin Egypt) . There in Egypt) . After on Egypt) . Prognosn Egypt) .The clinical features of EMF depend on the location and degree of cardiac involvement. A history of a febrile illness with or without urticaria is present in 30-50% of children and adolescents with EMF . When riMost cases of EMF in the literature have been diagnosed by cardiac dilatation and apical calcification on chest x-ray and low voltage, atrioventricular block and other abnormalities on electrocardiogram . ClassicDue to pathophysiology of eosinophilia, corticosteroids and immunosuppressive drugs are thought to be helpful in the early stages of the disease but there are no randomized clinical trials to support their use . DiuretiWhere capabilities and expertise exist, EMF may be successfully treated with surgical endocardectomy and valve replacement. The operative mortality by may as high as 20% , howeverth century [As a cause of HF in SSA, ischemic heart disease has always been considered a rarity until recently. As reported by Pobee and Biritwum, medical reports sent from Ghana (then the Gold Coast) to the Colonial Secretary in London showed that coronary heart disease was extremely uncommon from the 1890s to the mid 20 century , 175. In century . Further century .  et al. demonstrated a high prevalence of traditional cardiovascular risk factors in a cross-sectional study in an impoverished area of South Africa [Clinical studies corroborate findings from necropsy studies. Albertsh Africa . Tobaccoh Africa . Reportsh Africa . The Agih Africa . The INTERHEART study demonstrated that the risk factors for ischemic heart diseases are common to all regions of the world; however, there are important differences in the distribution of these risk factors according to ethnic groups . In sub-Reports from SSA hospitals suggest that African patients with coronary disease are often younger than their Western counterparts. Other clinical and laboratory characteristics appear to be the same, as are the types of complications that occur , 183. ItThe few data concerning African patients with ischemic cardiomyopathy suggest that physical signs are few and a history of angina is uncommon . Common The diagnosis of ischemic heart disease is usually based on a clinical picture and electrocardiographic findings. A high index of suspicion and broad differential, however, are necessary to perform an electrocardiogram in a patient with nonspecific signs or symptoms and this probably contributes to the low prevalence estimates . DefinitRecommendations for the treatment of ischemic cardiomyopathy apply worldwide. An approach based on stage of disease emphasizes a goal-directed stepwise approach . IncremeCor pulmonale was defined by the World Health Organization in 1963 as “hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs, except when these pulmonary alterations are the result of diseases that primarily affect the left side of the heart, as in congenital heart disease” . Since tAvailable data suggest that 20 to 25 million people in low- and middle-income countries have some form of pulmonary vascular disease, representing >97% of the global burden . Right HClinical manifestations of pulmonary hypertension and right HF are often overshadowed by the signs and symptoms of the underlying causative condition. There is no history specific for pulmonary hypertension but the history should lead to clues about the cause . The most sensitive sign of long-standing pulmonary hypertension is an accentuated component of S2 which may also be palpable in the pulmonic area. A right ventricular lift may be seen. With very high pulmonary artery pressures, diastolic and systolic murmurs of pulmonic and tricuspid regurgitation may be heard along with a systolic ejection sound and right ventricular S3 gallop. In severe right HF, cardiac enlargement, distended neck veins, hepatomegaly, ascites and peripheral edema are present. Often, the degree of ascites may be out of proportion to the degree of peripheral edema. Small series show that cyanosis is also common . The utiBecause of the diversity of diseases that cause pulmonary hypertension and right HF, no single strategy of work-up exists. Instead, historical and symptomatic clues should lead the clinician down the appropriate diagnostic pathway. When lung parenchymal or airway disease is present, pulmonary function tests will frequently reveal the nature and degree of impairment. Transbronchial biopsy, bronchoalveolar lavage and open lung biopsy are diagnostic options in patients with interstitial lung disease. Patients with cryptogenic pulmonary hypertension should undergo testing to detect pulmonary arterial emboli or other causes of obstruction with perfusion radionuclide testing or computed tomography scanning depending on availability. Serology for hepatitis B surface antigen, antinuclear antibody, rheumatoid factor and cryoglobulins may confirm a clinical suspicion for pulmonary vasculitis.Right heart catheterization is the gold standard for the diagnosis of pulmonary hypertension. However, echocardiography is frequently used to screen, diagnose and characterize pulmonary hypertension and right HF in many settings owing to the relative affordability and accessibility of echocardiography and that fact that it is non-invasive. The overall correlation between echocardiographically determined and invasively measured pulmonary systolic pressure is good (r=0.7) with 83% sensitivity and 72% specificity according to a meta-analysis of the literature . Single The underlying disease is the focus of therapy and is the best way to reduce ventricular pressure work. If right HF has not occurred, a major goal is to prevent this complication as it carries a high mortality (70% within 6 months) . Relief Diuretics should be used to diminish hepatic and peripheral edema  but cautLesser common forms of HF in SSA include high-output HF due to thiamine deficiency and arrhythmogenic right ventricular cardiomyopathy (ARVC). Thiamine (vitamin B1) plays an important role in carbohydrate metabolism . ThiaminARVC is a heart muscle disease characterized by HF, ventricular arrhythmias and sudden cardiac death. The hallmark of ARVC is fibro-fatty replacement of the myocardium (mostly the right ventricle) which predisposes to arrhythmias. ARVC has genetic determinants related to mutations in genes that encode proteins of the cardiac desmosomes . The firet al., for example, demonstrated that while the use of angiotensin converting enzyme inhibitors for patients with HF has increased from 37% in 1992 to 65% in 1994 the proportion of patients prescribed this class of medication remains strikingly low [The use of evidence-based therapies for HF has historically been low in SSA. Adewole ngly low . In Camengly low . The THESUS-HF study demonstrated that the most commonly prescribed intravenous medication for acute decompensated HF in SSA is furosemide . In addiThere have been many recent advances in knowledge of HF from around the world . While mScientific approaches to gain a better understanding of the epidemiology, treatment patterns and outcomes of HF include registries, population-based cohort studies and clinical trials. Some examples of these already exist on the continent , 18. HowThe syndrome of HF remains a major public health issue for many countries in SSA. Systolic HF appears to dominate. While ischemic heart disease is the predominate in high-income countries, the most common etiologies in SSA are distinct with hypertension, valvular heart disease and non-ischemic cardiomyopathies being the most commonly reported forms. This trend has generally been preserved over the last 4 decades; however, larger contemporary studies highlight the emergence of right-sided HF and ischemic heart disease and the waning importance of infectious causes. While atherosclerotic heart disease is still a relatively rare cause of HF, specific investigation for atherosclerotic heart disease using contemporary means has only been performed in a handful of studies. Current treatment patterns highlight the inappropriately low usage of proven therapies for HF. With the recent growth in scientific and public interest in HF, clinicians in SSA stand to gain important knowledge and a network in which to study treatment and outcomes that are relevant to the region and impactful worldwide.


Magnetic resonance imaging (MRI) within FDA guidelines for the MRI-conditional pacemaker precludes placing the heart at the center of the magnet’s bore. This in effect appears to preclude cardiovascular MR. In this manuscript, we describe a protocol for cardiovascular MR of patients with a Revo pacemaker system while operating within FDA guidelines, and the first US case of cardiovascular MR in a patient with a Revo MRI-conditional pacing system despite position constraints. Several million people are estimated to currently have cardiac implantable electronic devices (CIEDs), including pacemakers and implanted cardioverter defibrillators (ICD). This number may continue to grow with expanded indications for heart failure and primary prevention. Historically, CIEDs have been considered to be absolute contraindications for magnetic resonance imaging (MRI). However, there is an estimated 50–75% probability that MRI will be indicated for a patient over the device lifetime .There are several concerns regarding the interaction of these devices with the static and pulsed magnetic field. First, the generator or leads may be displaced, although translational forces and torque on the leads have been shown to be small at 1.5 Tesla field strength . Next, tDevice programming can mitigate some of these potential risks. However, electrical reset can occur in up to 6% of pacemaker patients undergoing MRI upon exposure to a magnetic field that overrides programming changes ,5. PacemAlthough MR conditional pacemaker, ICD, cardiac resynchronization therapy pacemaker and defibrillator systems are available in Europe and some in Asia, most are investigational in the United States . Most recently, development and Food and Drug Administration (FDA) approval of the MRI-conditional device, the Medtronic Revo pacing system , has been a notable advance. Conditions for scanning patients with the Revo system within FDA guidelines include a 6-week delay after pacemaker implantation, 1.5 T static magnetic field strength, maximum specific absorption rate (SAR) of 2 W/kg for each sequence, and maximum slew rate of 200 T/m/s. MR scanning within FDA guidelines for the device precludes placing the heart at the magnet isocenter (center of bore). However, the pacemaker system may pass through isocenter during table positioning. Isocenter must be above the superior surface of the C1 vertebra or below the inferior surface of the vertebral body of T12 . This inA 34-year-old woman had a history of an anterior myocardial infarction following spontaneous left anterior descending coronary artery dissection 11 days postpar-tum at age 28 and subsequently underwent cardiac transplantation. She was found to have chronic inflammation and episodes of acute rejection on endomyocardial biopsies. Echocardiography demonstrated abnormal diastolic function with restrictive filling and course was notable for development of clinical heart failure requiring hospitalization. Biopsies confirmed post-transplant lymphoproliferative disorder (PTLD) consistent with plasmacytoma. CMR demonstrated patchy areas of late gadolinium enhancement (LGE) in the inferior, inferoseptal and lateral walls of the left ventricle consistent with infiltrative process. The patient’s course was further complicated by development of sinus node dysfunction with sinus pauses of 4.5 seconds. Pacemaker implantation was advised. MRI-compatible dual-chamber system was implanted due to the anticipated need for future CMR studies to follow cardiac allograft involvement with chemotherapy .The patient was referred for CMR 6 months after pacer implantation. The scan was performed on 1.5 T whole body scanner , slew rate 125 T/m/s. A cardiologist, radiologist and MRI physicist were present. Isocenter was placed inferior to T12, determined by the inferior rib  scout imaging, cine SSFP sequences  in the 2 and 4-chamber long-axis and short axis cardiac planes, followed by segmented gradient-recalled phase sensitive inversion recovery (PSIR) LGE short and long axis imaging  performed after intravenous administration of 0.2 mmol/Kg gadoversetamide . These images demonstrated patchy LGE of the left ventricular inferior and lateral walls consistent with infiltrative process and known PTLD. Localized artifact from the pacemaker lead in the right ventricle was present without effect on interpretability of images : Cardiac implantable electronic devices; (ICD): Implanted cardioverter defibrillators; (MRI): Magnetic resonance imaging; (CMR): Cardiovascular magnetic resonance; (FDA): Food and Drug Administration; (SAR): Specific absorption rate; (PTLD): Post-transplant lymphoproliferative disorder; (LGE): Late gadolinium enhancement; (SSFP): Steady-state free precession; (PSIR): Phase sensitive inversion recovery.PKW- Medtronic, consultant. The other authors have no disclosures or conflicts of interest.ARB provided cardiology supervision during scanning, reviewed device interrogations, assisted in image acquisition and interpretation, and drafted the manuscript. KWC assisted with planning scan protocol. MC, a physicist, modified sequences for SAR limitations. PKW planned scan protocol, assisted in image acquisition and interpretation, and helped to draft the manuscript. All authors read and approved the final manuscript.