Diastolic dysfunction evaluation may be relevant for early diagnosis of hypertrophic cardiomyopathy (HCM) and subsequent risk assessment. The aim of our study was to assess phase contrast cardiac magnetic resonance (PC-CMR) diastolic parameters obtained with a semi-automated method in relation to left ventricular (LV) remodeling and late gadolinium enhancement (LGE) in patients with HCM.We studied 48 patients with HCM and 23 healthy volunteers matched for age, sex and body surface area (BSA). Mitral inflow and myocardial velocities were assessed using through plane 2D PC-CMR (VENC=150cm/s and 20cm/s respectively). Transmitral peak flow-rates (Ef and Af) and early E' peak myocardial longitudinal velocity were obtained semi-automatically using CardFlow (INSERM U678). LV volumes, segmental thickness and mass were obtained from SSFP images. LGE volume was quantified semi-automatically using a 6 SD threshold.Peak myocardial longitudinal velocity E' was significantly lower and E/E' was significantly higher in patients with HCM compared with controls (Table). We found a linear relationship between decreased E' and increased LV mass index (p<0.0001), decreased mass/end-diastolic volume (M/EDV) ratio (p<0.0001), increased LGE mass (p=0.04) and LGE extension (p=0.04). The relationships between E' and LV mass index and M/EDV were independent of age, gender, BSA and systolic blood pressure (p<0.001).Comparison of patients with HCM and healthy volunteers by CMR showed significantly altered LV diastolic function related to LV hypertrophy and LGE. Assessment of diastolic function may be considered for a comprehensive cardiac evaluation in HCM.None


Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy.P<0.0001). MSC‐treated animals had unchanged end‐diastolic volume  and end‐systolic volume  from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC‐treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV  and ESV . Ejection fraction increased from 29.69±1.68% to 35.85±2.74% at 3 months post‐MSC injection and progressed to 39.02±2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow‐up (P=0.33).Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post‐MI animals received either intramyocardial allogeneic MSC injection  or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3‐dimensional cardiac magnetic resonance imaging angiography–derived anatomy to accurately target infarct border zone injections. MSC‐treated animals had a 19.62±2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09±2.31% from 3 to 6 months postinjection (Intramyocardial injection of allogeneic MSCs leads to a sustained and progressive reduction in infarct size, which in turn drives reverse remodeling and increases in ejection fraction. These findings support ongoing biological activity of cell therapy for substantial periods and suggest optimal end points for future clinical trials. MSCs are easily isolated from a bone marrow biopsy, have profound effects on other cells, such as immunomodulation and regulation of cardiac stem cell niches, and can even induce differentiation of other stem cells.10 Large animal and early clinical data in subjects with ischemic cardiomyopathy support the ability of MSCs to attenuate and even induce reverse remodeling.12 Although enthusiasm for cell‐based therapy is increasingly supported, very few studies have addressed long‐term effects and sustainability of cell therapy. Importantly, some studies, albeit in patients treated at the time of MI, have suggested that cell‐based therapy may not produce durable effects, with regression of favorable effects over time. With regard to ischemic cardiomyopathy, follow‐up periods for preclinical models are typically in months, whereas in clinical investigations patient follow‐up has not exceeded 1 year. To address this issue, we assessed longer‐term follow‐up in a well‐established porcine model of ischemic cardiomyopathy and sought predictors of long‐term benefit. Here we show that reverse remodeling is not only sustained but actually progressive.Cell‐based therapy is emerging as a potentially transformative treatment for advanced heart failure. Many cell types isolated from either a bone marrow or cardiac biopsy are currently under investigation in clinical trials.4 CMR allows for highly accurate and detailed cardiac phenotyping in large animal translational studies, but short follow‐up in these studies has limited our understanding of long‐term LV structural changes after MSC therapy. Using merged CMR and electroanatomical 3‐dimensional imaging to guide intramyocadial injection catheters, we tested the hypothesis that allogeneic MSC therapy produces reverse remodeling through durable scar size reduction in ischemic cardiomyopathy.Advances in cardiac magnetic resonance imaging (CMR) have provided unprecedented imaging capabilities to investigate structural changes in the left ventricle (LV) and is considered the “gold standard” for measuring chamber volumes.13 At 3 months post‐MI animals were randomized to injection of 200 million allogeneic MSCs or no injection control (LV catheterization without injection). Serial CMR was performed to assess structural changes in the LV over a 9‐month period. All animal protocols were reviewed and approved by the University of Miami Institutional Animal Care and Use Committee.Female Gottingen minipigs  underwent closed‐chest ischemia–reperfusion to generate a model of ischemic cardiomyopathy as previously described.Each pig was placed under general anesthesia using ketamine (33 mg/kg intramuscularly) for induction and isoflurane  via face mask. Endotracheal intubation was done, and the pig continued on isoflurane . Cut‐down of a carotid or femoral artery and vein was done for placement of vascular introducers. Heparin (100 IU/kg) and lidocaine (3 mg/kg) were given intravenously followed by infusion of lidocaine (0.01 mg/kg per minute) for the duration of the infarction.Using angioplasty techniques, the LAD coronary artery was occluded immediately beyond the first diagonal branch for 150 minutes. After 150 minutes, the angioplasty balloon was deflated and coronary angiography performed to confirm reperfusion. The animal was recovered from anesthesia, and a chronic ischemic cardiomyopathy model developed over the 3 months following infarction.CMR studies were conducted on a Siemens Symphony 1.5T  scanner with Syngo MR A30 software using a 4‐channel body coil with ECG gating and short breath‐hold acquisitions. Postprocess image analysis was performed with custom QMass  and Segment Software . All animals underwent CMR at baseline , 3 months post‐MI (stem cell injection time), 6 months post‐MI, and 9 months post‐MI (before euthanizing). Pigs were placed under general endotracheal anesthesia as described above during all CMR procedures.3×π/6]), providing a diastolic and systolic SI value.15 Three‐dimensional reconstruction sequences were acquired during the first‐pass perfusion phase following intravenous infusion of gadolinium 0.3 mmol/kg . A series of axial images  were acquired to create a 3‐D stack of images.Steady‐state free precession (SSFP) cine images in 2‐chamber short ‐axis planes  were obtained. At end‐diastole and end‐systole, semiautomated epicardial and endocardial borders were drawn in contiguous short‐axis cine images covering the apex to mitral valve plane to calculate end‐diastolic volume (EDV) and end‐systolic volume (ESV), stroke volume (SV), and ejection fraction (EF). Sphericity index (SI) was calculated as the ratio of the LV diastolic volume and systolic volume to the volume of a sphere with the diameter of the long axis of the LV in diastole and systole obtained from a 4‐chamber SSFP image  unipolar voltages values in each of 17 segments was correlated with the CMR DE findings, allowing the description of unipolar voltage values in normal myocardium, subendocardial scar, and transmural scar.Short‐axis and 2‐chamber long‐axis delayed enhancement (DE) images  were acquired 8 minutes following intravenous infusion of gadolinium 0.3 mmol/kg. Infarct scar size was calculated from the short‐axis delayed myocardial enhancement images covering the apex to the mitral valve plane.17 MSCs were amplified, harvested, and cryopreserved. On the morning of stem cell injection, cells were thawed, washed, and resuspended in 5 mL of phosphate buffered saline.A bone marrow (BM) aspirate was obtained from the iliac crest of a male swine. MSCs were isolated from other BM cells by Ficoll density centrifugation and plastic adherence as previously described.x, y, and z planes, thus capable of creating a 3‐dimensional reconstruction of the heart.18 In addition, a local electrocardiogram can be obtained to provide real‐time myocardial voltage data to guide catheters to damaged areas of the LV. EAM was done in an angiography suite using a NOGA XP Cardiac Navigation System  using custom merge software. A NOGASTAR mapping catheter acquired local electrocardiograms, and a MYOSTAR catheter was used for intramyocardial injection of stem cells.EAM uses a magnetic field that guides an intramyocardial catheter that measures magnetic field strength in the Animals were placed under general anesthesia as previously described. Cut‐down of the carotid or femoral vasculature was done for placement of 8 French and 9 French vascular introducers into the artery and vein, respectively. EAM was acquired via a catheter inserted retrograde into the LV under fluoroscopic guidance. The mapping catheter tip was directed to acquire a series of endocardial contact points, and a 3‐dimensional map of the LV was constructed showing corresponding unipolar electrocardiographic voltage. Points  encompassing the anterior, septal, inferior, and lateral walls were acquired to create the map.The gadolinium‐enhanced axial CMR angiography images were transferred to a EAM workstation. The heart and great vessels were reconstructed and LV segmented for image integration with the EAM to exclude other structures. Manual landmark and automated surface registration were used to integrate the CMR and EAM images; Automated surface registration was done using endocardial surface contour alignment. Image integration created a merged image of EAM unipolar voltage data projected onto a CMR 3‐dimensional reconstruction of the LV.Once the CMR‐EAM merged image was created, the injection catheter was guided by fluoroscopy into the LV. The target area of the injections was the infarct border zone (rim of tissue immediately adjacent to the infarct territory), where 200 million allogeneic bone marrow–derived MSCs were injected into 15 sites. Each injection consisted of a 0.5‐mL aliquot of cells.Criteria used to confirm engagement of the needle tip within the myocardium were: (1) loop stability <2.5 mm; (2) EAM confirmation of perpendicular placement of catheter tip; and (3) cine fluoroscopy confirmation of catheter stability and perpendicular placement of catheter tip.P<0.05 was considered statistically significant.All data are presented as mean (±standard error of mean). Repeated‐measures (RM) ANOVA was used to test differences between means with time postinjection used as the repeated factor, and a Bonferroni correction was used for multiple testing. A 1‐way RM ANOVA was used for within‐group analyses and a 2‐way RM ANOVA for between‐group analyses. GraphPad Prism  was used to analyze all data points and plot graphs. P<0.0001). A compensatory parallel increase in EDV with ESV  occurred to preserve SV , but resulted in significantly depressed EF . DE‐CMR showed anterior wall scar encompassing 18.27±1.0% of LV mass 3 months post‐MI. Correlation of CMR DE imaging with EAM showed lower unipolar voltage in scarred myocardium  compared with normal myocardium   .P=0.02; All animals that underwent stem cell injection (n=6) and the no‐injection controls (n=6) were alive at 9 months. One swine developed bradycardia and hypotension requiring atropine during MSC injection, and 1 animal had sustained ventricular tachycardia requiring cardioversion. Both pigs completed the stem cell injection procedure and the study protocol without further arrhythmias or adverse events. Integration of CMR with EAM resulted in an average reconstruction difference of 3.8±2.8 mm, with larger EAM‐derived chamber volume compared with CMR angiography P=0.02; H. EAM obP<0.0001; P<0.0001; P=0.24), whereas scar size as a percentage of LV mass decreased 9.68±2.65% (P=0.02) (MSC therapy reduced scar size as measured by absolute volume 3 months postinjection and persisted 6 months postinjection (P=0.02) C and 2D. C and 2D3 MSC‐treated animals showed no increase in EDV (P=0.08) or ESV (P=0.28) from preinjection (3 months post‐MI) to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002) (P=0.003) and a trend toward improved diastolic SI (P=0.11), whereas no‐injection controls' systolic SI (P=0.15) and diastolic SI (P=0.56) were unchanged. Furthermore, correlation in percentage change in infarct size with EDV  and ESV  suggests that scar size reduction with MSC therapy regulates ventricular remodeling (Ventricular remodeling after MI manifests by increased ventricular volumes (EDV and ESV) and geometrical alteration of the LV cavity from an elliptical to a spherical shape. Both placebo and MSC‐treated animals showed significant increases in ESV and EDV during the first 3 months after MI C and 3D,=0.0002) C and 3D.=0.0002) . MSC‐tremodeling .P=0.0001), whereas controls had persistently depressed EF during follow‐up from 3 to 6 months post‐MI (P=0.33).Accompanying these favorable effects on LV structure were substantial improvements in EF . EjectioHere, we report the long‐term results of allogeneic MSC therapy in a swine model of ischemic cardiomyopathy. The effects of MSCs on scar size reduction are durable and progressive, support reverse remodeling, and are associated with improvements in LV function. In addition, we present an imaging platform that integrates 3‐dimensional CMR reconstruction of the LV with real‐time EAM viability data to guide transendocardial injection of MSCs to scarred areas of myocardium.10 Taking advantage of the unique immunomodulatory properties of MSCs, allogeneic transplantation is well tolerated.19 Previous large animal studies have shown scar size reduction can manifest as early as 3 days after MSC injection, with the longest follow‐up being 90 days.20 Here, we studied swine for 6 months after MSC therapy in a large animal model of chronic ischemic cardiomyopathy and showed a durable 25% reduction in infarct size with MSC therapy  or due to cell sources . Indeed, further work is required to determine optimal MSC dosage.The dosage of MSC therapy for this large animal study was chosen based on previous work by our group in a similar large animal model that showed that 200 000 autologous MSCs had greater effects on scar size than lower doses.In conclusion, MSCs reverse ventricular remodeling through durable infarct size reduction in swine with ischemic cardiomyopathy. These favorable changes in LV structure with MSC therapy are accompanied by long‐term improvements in cardiac function. Together these findings support the ongoing biological activity of cell therapy to create reverse remodeling in a process driven by infarct size reduction that occurs progressively. As such, infarct size and measures of remodeling are optimal end points for clinical trials.


A transient and reversible reduction in cardiac output–low cardiac output state (LCOS) often occurs following surgery for congenital heart disease. Inappropriately managed LCOS is a risk factor for increased morbidity and death. LCOS may occasionally be progressive and refractory needing a period of “myocardial rest” with extracorporeal life support (ECLS). ECLS is currently considered a routine tool available for rapid deployment in most industrialized countries. Accumulated experience and refinements in technology have led to improving survivals – discharge survivals of 35%–50%, with almost 100% survival in select groups on elective left ventricular assist device. Thus, there is an increasing trend to initiate ECLS “early or electively in the operating room” in high-risk patients. India has a huge potential need for ECLS given the large number of infants presenting late with preexisting ventricular dysfunction or in circulatory collapse. ECLS is an expensive and resource consuming treatment modality and is not a viable therapeutic option in our country. The purpose of this paper is to reiterate an anticipatory, proactive approach to LCOS: (1) methods for early detection of evolving LCOS and (2) timely initiation of individualized therapy. This paper also explores what is feasible with the refinement of “simple, conventional, inexpensive strategies” for the management of LCOS. Therapy for LCOS should be multimodal based on the type of circulation and physiology. Our approach to LCOS includes: (1) intraoperative strategies, (2) aggressive afterload reduction, (3) lusitropy, (4) exclusion of structural defects, (5) harnessing cardiopulmonary interactions, and (6) addressing metabolic and endocrine abnormalities. We have achieved a discharge survival rate of greater than 97% with these simple methods. A transient and often reversible reduction in cardiac output–low cardiac output state (LCOS) with an associated decrease in systemic oxygen delivery often occurs following surgery for congenital heart disease.2 The LCOThe reduction in cardiac output is due to a transient “myocardial dysfunction” following cardiopulmonary bypass (CPB). Factors The risk is greatest for neonates and young infants undergoing complex surgical repairs, those needing prolonged aortic cross clamp times, those presenting in circulatory collapse and those infants and children with preexisting right ventricular, left ventricular or biventricular dysfunction.Extracorporeal life support (ECLS) is currently considered a routine and useful tool in the pediatric cardiac intensive care unit and is available for rapid deployment whenever needed in most industrialized countries. Current indications for ECLS include: (1) failure of separation from cardiopulmonary bypass, (2) postoperative severe low cardiac output state or failed hemodynamics, (3) postoperative cardiac arrest, 4) severe pulmonary vascular hypertension and 5) acute respiratory distress syndrome.[ severe p acute reet al. reported an impressive overall hospital survival of 67% for ECLS after surgery for congenital heart disease and a 100% survival in select subgroups with elective or early use of ventricular assist device (VAD) for single ventricle and biventricular disease.[Refinements in ECLS have led to steadily improving outcomes with discharge survivals of 38% in neonates and 43% in older children.7 Factors disease. Further  disease.Thus, with accumulated experience and refinements in technology the trend in the industrialized world is to initiate ECLS “early or even electively in the operating room” rather than as a “desperate late rescue modality.”8 CurrentThe potential need for ECLS in India is “huge” given the large numbers of infants with transposition of great arteries, obstructed total anomalous pulmonary veins, truncus arteriosus presenting late, i.e., with unstable hemodynamics or with severe reactive pulmonary hypertension. Infants with “preexisting ventricular dysfunction” undergoing definite surgery –  are on the increase–constituting a potential and undisputed substrate of infants who are likely to benefit from elective or early institution of ECLS.In reality, ECLS is not freely available in most parts of the non-industrialized world where according to current western recommendations it is possibly most needed. Why is this so? The reasons are primarily the prohibitive costs, lack of infrastructural resources as well as the highly skilled and well trained manpower that an ECLS program entails. In our country, despite the rapid industrialization over the last decade, pediatric cardiac care is mainly provided by “nongovernmental institutions.” Thus, the costs of ECLS have to be largely borne by the family. Most cases of refractory LCOS, where ECLS may be most useful often occur in infants and children whose families are least able to afford such expenses. Despite favorable cost–utility analysis in the West, many hosThe second practical consideration is the complex circuitry with a “very narrow margin for error” which has the potential to increase dangerous complications in the hands of staff of widely varying capability. Western Thus, in our country, alternative, reproducible, less expensive modalities which are “not resource consuming” assume increasing importance and often need to be speedily employed. The various strategies used for “perioperative manipulation of the circulation” in children with congenital heart disease have been elegantly summarized in a recent article by Shekerdemian.The purpose of this paper is to reiterate some simple, conventional, evidence based, low cost strategies for the management of perioperative LCOS that are practiced in our unit.Even though progressive LCOS occurs after cardiac surgery, appropriate anticipation, early identification and aggressive management has been shown to minimize the need for ECLS to <2% of all children who undergo CPB. Thus, ouWe have been successful with this approach. Our annual 30 day survival for the last 7 years has been in the range of 98%–98.5% in patients with mean Basic Aristotle risk stratification score ranging from 6.9–7.0. The annual 30 day survival for the last 7 years for neonates ranges from 91% to 94% and annual 31 day to 1-year old survival  is 97%–98.5%.We follow a “systematic approach” to LCOS based on refinement of a range of diverse conventional strategies illustrated in Our focus is on efficient surgery with (1) shorter aortic cross clamp times and (2) avoiding long ventriculotomies to minimize postoperative LCOS. We practice well-described preemptive surgical strategies like creation of a “right to left shunt or a decompressive patent foramen ovale” as a “pop off” mechanism for the hypertensive right ventricle . Likewise, there has been a lower threshold for “deferred sternal closure” in the operating room to avoid emergency sternotomies in the ICU. Our indications for deferred sternal closure include: ventricular dysfunction, myocardial edema, high left atrial pressures, and late presenting total anomalous pulmonary venous connections.An important preemptive surgical strategy in our unit is the use of routine intraoperative echocardiography to refine surgical repairs and to avoid significant residual defects. In a review of children on postoperative ECMO, 60 cardiac catheterizations resulted in a total of 50 transcatheter, surgical or combined interventions. This papWe have also evolved a useful preemptive surgical strategy of leaving a “residual dynamic right ventricular outflow tract gradient” after repair of late presenting tetralogy of Fallot to minimize postoperative right ventricular dysfunction and secondary LCOS.We use various well-described modalities to minimize CPB mediated injury in an attempt to reduce perioperative LCOS and ensure better hemodynamics.–19et al. showed that combined preoperative and intraoperative corticosteroid administration was more effective in diminishing inflammatory mediator expression and was associated with better systemic oxygen delivery.[This includes the use of prophylactic intraoperative corticosteroid administration to attenuate the CPB related intense inflammation.–18 Shroedelivery. A “best delivery. on the sUltrafiltration  has been shown to be effective in the (1) removal of inflammatory mediators – (interleukin 6 and tumor necrosis α) as well as in the (2) reduction of extracellular total body water secondary to CPB with improvement in cardiac and pulmonary function.20 We useIntraoperative phenoxybenzamine–a potent vasodilator had fallen into disrepute over the last many years due to the prolonged vasodilation, associated hypotension and absence of an effective antidote. There has been a resurgence of interest in phenoxybenzamine in recent times. Apart fr12Cardiac ECMO for biventricular repairs is instituted in about 60% of instances for “failure to wean” satisfactorily from CPB. Our straet al. with the nadir in cardiac output occurring 9–12 h afte surgery–the cardiac output approaching “normal” within 24 h.[A typical time course for “CPB related LCOS” has been shown by Wernovsky hin 24 h. An evolvA combination of clinical, hemodynamic and biochemical parameters is used to diagnose “evolving LCOS.”2425 Clin242) has been shown to be more useful in predicting evolving LCOS.[2 to below 55% has been associated with increased early morbidity and mortality.[Biochemical markers of impaired systemic oxygen delivery include increased metabolic acidosis, elevated blood lactate levels and reduced mixed venous oxygen saturation. Worsening metabolic acidosis is a relatively late sign of reduced cardiac output, therefore, an attempt has to be made to diagnose LCOS before frank metabolic acidosis develops. Elevated blood lactate level during the first 8 hours of surgery has been shown to be a useful predictor of adverse hemodynamic events in infants and children operated for heart disease and has been used for adjustment of hemodynamic support. Evolvinging LCOS. A fall iortality.2 is less than 70% or if the arterio venous oxygen saturation difference (SaO2–SvO2) is greater than 30% in systemic to pulmonary artery shunts and cavo pulmonary connections .[Blood lactate level and mixed venous oxygen saturation are performed routinely on arrival in the ICU. It is our practice to upgrade the inotropic support if the SvO rations). More imprations).25Apart from intraoperative echos, serial echos are also done in the unit to detect subclinical systolic or diastolic ventricular dysfunction, patch dehiscence, residual defects and pericardial collection.Successful management involves more than “inotropy.”2425 The 241224Our practice of inotrope and vasoactive medication use is neither empirical nor arbitrary. It is based on an alogorithm, which is periodically modified and refined with emerging evidence. The following are the broad principles, which will provide a template for our current practices.Preload optimization with fluid augmentation before inotropy is of paramount importance in improving stroke volume. ResidentOur preferred first line inotrope has been dobutamine for the last many years. We do not use dopamine. Our practice is backed by recent data demonstrating the adverse effect of dopamine on systemic hemodynamic status and oxygen transport in infants following the Norwood operation.If additional inotropy is needed, we upgrade to milrinone after weighing “cost benefit” considerations. The Primacorp study (a well-designed prospective randomized controlled study) demonstrated that the use of high dose milrinone reduced the risk of LCOS in a heterogenous group of infants undergoing biventricular repairs. MilrinonHowever, the use of milrinone is strictly individualized and not entirely based on the recommendations of the Primacorp study due to cost constraints. By and large, the neonate, infant or child has to “earn the need for milrinone use.”Separation from CPB is usually achieved with dobutamine in most instances-neonates, small infants, arterial switches, TAPVC re-routing, tetralogy of Fallot, large L-R shunts with borderline operability. Milrinone is commenced electively in the operating room only occasionally. Our indications for institution of Milrinone are shown in We continue dobutamine when milrinone is added. This practice is based on the observation that appropriate “lusitropy and inotropy are additive” in improving cardiac output.μg/kg/min and gradually graded up in sick hypotensive, very high-risk neonates and infants.[Milrinone is commenced in a very low dose of 0.2  infants.32Inotropes are upgraded (number of drugs and dosage increase) according to various parameters which are closely titrated.25 These Clinical: Significant tachycardia, peripheral vasoconstriction.2, SaO2–SvO2 difference, lactates, anion gap.Biochemical: Deranged SvOHemodynamic: Persistent LaP surges, increased CVP.Echo: Worsening systemic ventricular function, significant pulmonary hypertension with or without RV systolic dysfunction, significant RV diastolic dysfunctionOther inotropes: Epinephrine is used only occasionally in our unit. It is used only for resuscitation and occasionally, in low dose, for severe systolic dysfunction. Doses of epinephrine greater than 0.2 mc/kg/min are associated with significantly increased afterload and are generally avoided.Vasopressors: Norepinephrine is used for right ventricular dysfunction especially when associated with significant peripheral vasodilatation, in vasodilatory shock and in pAggressive afterload reduction is our mainstay of management in severe systolic ventricular dysfunction. This practice is based on the observation that afterload reduction is associated with a proportionally greater increase in cardiac output in severe ventricular dysfunction as compared to mild or moderate ventricular dysfunction. Figure . AfterloAfterload reduction in the postoperative period is achieved with:Phenoxybenzamine—commenced intraoperatively and continued postoperatively—the main problem being its long half-life (>24 h) occasionally causing protracted and severe systemic hypotension.Sodium nitroprusside is easier to titrate and is a gentler vasodilator due to its short half-life and rapidity of action.Sodium nitroprusside is used for afterload reduction due to its favorable qualities and low cost. It is particularly useful in infants and children with postoperative systemic hypertension associated with normal systemic ventricular function or mild systemic ventricular dysfunction. The dose is titrated to systemic blood pressures and peripheral temperatures.Thus, indications in our unit for the use of sodium nitroprusside are: coarctation repair, duct ligation, Fontan operation (it is our drug of choice), valvuloplasty/valve replacements, and occasionally large L-R shunts .2–SvO2 gradient, increasing peripheral vasoconstriction (exclude occult hypovolemia) or other features of LCOS— or significant systemic ventricular dysfunction then the policy is to upgrade to milrinone [Milrinone: In any of the above situations if there is worsening lactic acidosis, increasing SaOilrinone .We manage primary left ventricular dysfunction after an arterial switch for late presenting dTGA with aggressive afterload reduction than with increasing inotropy.Nitroglycerine is used primarily for its venodilator properties following valvuloplasty or valve replacement and as a pulmonary and coronary vasodilator (coronary spasm). Nitroglycerine is also used for preload optimization whenever the central venous pressures are elevated.A “nonsinus rhythm” is associated with a lower cardiac output than a sinus rhythm. Similarly very slow or very rapid heart rates are associated with suboptimal cardiac output. Arrhythmias occur frequently in the postoperative cardiac surgical pediatric patient-the most common being nonsustained ventricular arrhythmias with an incidence of 22%. Every at12425Junctional ectopic tachycardia (JET) is a common and potentially dangerous tachyarrhythmia that tends to occur in the first 48 hours especially after surgeries involving closure of a large ventricular septal defect including tetralogy of Fallot. Younger Nonsustained ventricular arrhythmias and JET are both worrying arrhythmias and need further evaluation i.e. to look for occult ventricular dysfunction and residual structural defects.Myocardial contraction and relaxation are mediated by cyclic fluctuations in cytoplasmic calcium concentration. The neonatal and infant myocardium depends much more on “extracellular calcium” for its systolic and diastolic function, since the sarcoplasmic reticulum is sparse and immature. Thus, it is important to maintain adequate extracellular calcium levels in neonates and small infants. Hypocalc25Thyroid hormone levels (triiodothyronine and thyroxine) have been shown to be reduced for prolonged periods after cardiopulmonary bypass contributing to postoperative myocardial dysfunction. Two stud40Hyperglycemia in the postoperative cardiac infant has been shown to adversely impact outcomes.43 Our prResidual structural defects should be diligently looked for if the post operative recovery is not “as expected.” Our approach to persistent postoperative LCOS is aggressive – meticulous echo cardiographic evaluation followed by cardiac catheterization if needed.242524Prolonged acidosis and high dose catecholamines are known to induce adrenergic receptor down regulation reducing catecholamine effectiveness leading to a vicious cycle of increased catecholamine requirement, increased myocardial oxygen consumption, tachycardia, tachyarrhythmias, increased afterload, myocardial ischemia, apoptosis and aggravation of systolic and diastolic dysfunction giving rise to a scenario of catecholamine resistant hypotension. Figure 2/day to sick neonates and infants with LCOS. We do not wait for refractory LCOS to develop and have a low threshold to use low dose corticosteroid in high risk scenarios.Thus, despite issues of late presentation and pre-existing ventricular dysfunction the policy in our unit is to avoid high dose catecholamines. Published data suggest that seriously ill patients have relative adrenal insufficiency. In a retPositive pressure ventilation is an important hemodynamic tool in the management of postoperative systolic ventricular dysfunction.254725et al. demonstrated that the institution of nasal continuous positive airway pressure (CPAP) in adults with cardiogenic shock and increased left ventricular end diastolic pressures significantly improved cardiac output.[25In a landmark study, Bradley c output. Positivec output. Positivec output.2547The group of patients who specifically benefit from the hemodynamic effect of positive pressure ventilation include those with post operative systolic systemic ventricular dysfunction: (1) small infants and older children following repair of large left to right shunts , (2) primary left ventricular dysfunction following arterial switch for transposition of great arteries, (3) repair of total anomalous pulmonary veins, 4) repair of anomalous origin of the coronary artery, (5) primary left ventricular dysfunction following aortic or mitral valvuloplasty or replacement. Our policy is to ventilate these patients till hemodynamically stable and routinely support them with “elective continuous positive airway pressure ” for a period of time after tracheal extubation.47 We havet al. characterized the right ventricular diastolic performance after complete repair of tetralogy of Fallot.[Surgery for tetralogy of Fallot comprises 20%–25% of all surgeries performed for congenital heart disease in India. In the current era, surgery for tetralogy of Fallot is associated with excellent discharge survivals of greater than 98%–99%. Early po12f Fallot. This stuf Fallot..et al. showed the benefits of negative pressure ventilation in improving cardiac output in postoperative tetralogy of Fallot.[51Thus, measures to optimize cardiac out in post operative tetralogy of Fallot include those which improve diastolic pulmonary flow. These are a combination of ventilatory and hemodynamic strategies.51 Ventil50f Fallot. NegativeFallot.51 HemodynaIn summary, our management of tetralogy of Fallot is based on a combination of well described modalities. They are surgical strategies , ventilatory and hemodynamic measures to augment pulmonary diastolic flow and optimize cardiac output. An intraoperative peritoneal dialysis catheter is sited routinely in infants to decompress the abdomen and prevent ascites secondary to right heart failure to facilitate early extubation. Our outcomes with these measures have been gratifying—discharge mortality of 0.8% in a consecutive series of 900 surgeries which include complex tetralogy of Fallot.The Fontan operation is characterized by a passive forward pulmonary blood flow which depends on an adequate preload and a low resistance unobstructed pulmonary circulation. The pulmonary blood flow in Fontan patients depends on a low intrathoracic pressure. Thus, forward pulmonary blood flow and cardiac output is optimal during spontaneous respiration and significantly compromised by positive pressure ventilation.4753–55 T47The circulation in the bidirectional cavo-pulmonary shunt (BCPS) is similar to the Fontan in that the pulmonary blood flow is preload dependent and depends on a low resistance pulmonary circuit. Since the pulmonary blood flow is entirely derived from the upper body venous return any elevation in superior vena caval pressures, increase in pulmonary artery pressures or increase in airway resistance adversely affect pulmonary flow, cardiac output and cause systemic desaturation.2 in ~high 40s) to enhance cerebral vasodilatation and reduce superior vena caval pressures. Any reactive airways is aggressively managed and the infant is extubated as soon as possible.[Our practice is to nurse infants coming to the ICU after a BCPS in the sitting position to assist systemic venous drainage and augment forward pulmonary blood flow.25 We venpossible. These prpossible.–58In summary, a multimodal “highly individualized” approach based on simple, inexpensive evidence-based methods is recommended for management of perioperative LCOS. We have had satisfying outcomes with this approach without rescue ECLS in two very difficult situations-primary arterial switch for the late presenting dTGA with IVS and ALCAPA with left ventricular dysfunction.Primary outcomes  and secondary outcomes  were comparable in a group of 22 consecutive infants who underwent late primary arterial switch (median age 55 days) to the early switch group.Similarly, excellent results were obtained in 16 consecutive infants who underwent repair for ALCAPA with left ventricular dysfunction. In-hospital mortality was 0, with a median ventilation of 5 days and hospital stay of 15.5 days using conventional methods without rescue ECLS.Over the years, we have learnt to refine standard therapies and individualize LCOS treatment to specific circulations without resorting to rescue ECLS. Deaths do occur due to refractory LCOS in our unit, but they are occasional and usually related to lack of recognition of (1) evolving LCOS, (2) acute pulmonary hypertension, (3) dangerous arrhythmias, and (4) failure to detect a residual defect.Thus, our current focus is more on “fast track training” of new recruits and “better error control” than the pursuit of ECLS.Many western units have moved to a “routine ECLS policy” in select sub groups. We need


Pantherophis guttatus), but also in the genotyped anole (Anolis carolinenis and A. sagrei) and the Philippine sailfin lizard (Hydrosaurus pustulatus). Structures and chambers of the formed heart were traced back in development and annotated in interactive 3D pdfs. In the corn snake, we found that the ventricle and atria grow exponentially, whereas the myocardial volumes of the atrioventricular canal and the muscular outflow tract are stable. Ventricular development occurs, as in other amniotes, by an early growth at the outer curvature and later, and in parallel, by incorporation of the muscular outflow tract. With the exception of the late completion of the atrial septum, the adult design of the squamate heart is essentially reached halfway through development. This design strongly resembles the developing hearts of human, mouse and chicken around the time of initial ventricular septation. Subsequent to this stage, and in contrast to the squamates, hearts of endothermic vertebrates completely septate their ventricles, develop an insulating atrioventricular plane, shift and expand their atrioventricular canal toward the right and incorporate the systemic and pulmonary venous myocardium into the atria.Birds and mammals both developed high performance hearts from a heart that must have been reptile-like and the hearts of extant reptiles have an unmatched variability in design. Yet, studies on cardiac development in reptiles are largely old and further studies are much needed as reptiles are starting to become used in molecular studies. We studied the growth of cardiac compartments and changes in morphology principally in the model organism corn snake ( Mammals and the common lineage of birds and crocodilians (the archosaurs) are the only vertebrates where the cardiac ventricle has complete anatomical division of the systemic and pulmonary sides. Both mammals and birds stem from a lizard-like ancestor  and whili.e. squamates and chelonians) receives inflow from three systemic veins to the right atrium as well as one or two pulmonary veins that feeds into a single orifice to the left atrium, while the outflow occurs through three arteries, the left and right aortae and a single pulmonary artery The fully formed heart of non-crocodilian reptiles  and in the green and brown anoles (Anolis carolinensis and A. sagrei). Genome sequencing was recently completed in the green anole The few embryological studies on reptile hearts are in stark contrast to the vast number of studies of cardiac development in fish, amphibians, birds and mammals This study provides a developmental series from the onset of chamber formation of some of the most commonly used squamate models, the corn snake and the anole. The reptile heart and the ventricle in particular have a very complex anatomy and we have therefore provided comprehensively annotated 3D models in pdf format of all investigated stages of the corn snake from 2 to 42 days after egg laying. Secondly, we discuss separately the findings in the context of cardiac evolution. It is the ventricular anatomy that varies the most between reptiles, mammals and birds. This study emphasizes the ventricle.P. guttatus guttatus) and two fertilized eggs of the Philippine sailfin lizard (Hydrosaurus pustulatus) were incubated on gravel to prevent contact with water in an incubator at 29°C and 85% humidity. Fertilized eggs of the green and brown anoles (Anolis carolinensis and A. sagrei) were bought commercially and fixed immediately in a 4% paraformaldehyde phosphate-buffered saline solution overnight and then 70% ethanol followed by embedding in paraplast. Corn snake embryos were fixed similarly at 2, 10, 12, 14, 16, 20, 26, 35 and 42 days post egg laying (referred to as days) out of ca. 60 days, sailfin lizard embryos at 4 and 7 days out of ca. 60 days and anoles at stages 5, 7, 9, 12 and 17 out of 19  do not require approval from the Institutional Animal Care and Use Committee. The fertilized corn snake and sailfin lizard eggs were donated to us (R-JO) from the Diergaarde Blijdorp  whereas fertilized anole lizard eggs were obtained commercially. All embryos were sacrificed by immersion in 4% paraformaldehyde except in the late developmental stages, corn snake 42 days and anole lizard stages 17 and 19, where the embryo was first decapitated and the head split saggittally to stop all brain activity. Adult reptiles were commercially obtained and sacrificed in Denmark in accordance with Danish Federal Regulation, where the harvest of tissue of sacrificed animals by anesthesia does not require approval from Institutional Animal Care and Use Committee; the animals were anaesthetized with 100 mg pentobarbital  per kilo body mass and then had their hearts excised. The carcass of a euthanized ostrich was given to us (BJ and TW) by Givskud Zoo, Denmark.Most specimens were cut in 10 µm sections, except corn snakes of 26, 35 and 42 days and 3 months that were cut in 14 µm sections and the adult green anole which was cut in 12 µm sections. Myocardial staining was performed as previously described in-situ hybridizations for Tnnt2 (anole cardiac troponin T) for myocardial stain and Tbx5 on anole stages 7, 9 and 17 We used Python molurus; field-of-view: 60×80×80 mm3; repetition time: 75 ms; echo time: 5.4 ms and excitation flip angle: 45°. Images were isotropically acquired with a spatial resolution of 0.9×0.9×0.9 mm3/voxel. Ostrich; field-of-view: 230×230×140 mm3, voxel size: 0.48×0.48×0.48 mm3, repetition time: 15.1 ms, echo time: 6.9 ms, excitation flip angle: 30°. Reconstructed images were exported in DICOM format and loaded to Amira and treated as above.In our discussion of the evolutionary fates of the bulbuslamelle we compare to python and bird hearts on the basis of 3D models made from MRI scans. The MRI scans were performed with clinically available Philips Achieva 1.5 T system . The hearts were imbedded in agar and positioned in the centre of the magnet. Data were acquired with a dedicated radiofrequency surface coil using high-resolution 3D gradient–echo sequence with the following parameters: Amira models were converted to interactive 3D pdfs using Adobe Acrobat Pro Extended® version 9.3 as previously described The cardiac lumen and the following structures of the corn snake heart are annotated in the supplementary 3D pdfs based on morphology; sinus venosus, sinuatrial valves (10 days onwards), septum spurium, atria , atrioventricular canal, ventricle, bulboauricularlamella (10 days onwards), bulbuslamelle (10 days onwards), bulbo-ventricular fold (2 days)/muscular ridge (10 days onwards), vertical septum (20 days onwards) and myocardial outflow tract. The Amira® files, which the 3D pdfs –7 are baWe recorded the beating hearts of the corn snake from days 10 and 20 with emphasis on the systemic inflow to the heart and the sequence of chamber contractions and these videos are included in the online material -S6.i.e. 2 days in the corn snake, chamber formation, i.e. the ballooning of ventricular and atrial compartments, was already initiated (i.e. juvenile snake), this volume has less than doubled to 7.2 µl . In the corn snake, the atrioventricular and ventricular mesenchyme, which in later stages remodel into the atrioventricular (ca. 35 days) and arterial valves (ca. 35 days), constituted 0.1–0.15 µl throughout development and 0.17 µl at three months after hatching. By 20 days in the corn snake, one-third through development, the ventricle and atria constituted ca. 80% and ca. 15% respectively of the total myocardial volume which is essentially the proportions of the 3 months heart , the sinus venosus and mesenchymal tissue throughout development in both the corn snake and the anoles. Only the sinus venosus myocardium was often damaged and thus incompletely reconstructed. As described for mammals and birds, there are clear compartmental differences in growth hs heart . Halfwayhs heart .The hearts mature towards the adult shape throughout development. This is particularly evident in corn snakes, where the heart becomes more elongate than the anole heart . At 2 daThe appearance of structures is listed chronologically for the corn snake, the sailfin lizard and the anoles in There is initially a very short distance from the entry of the systemic veins through the pericardial wall to the (right) atrium, but it increases many fold during development. Accordingly, vessels form and elongate in between and they are referred to as the sinus venosus when they acquire cardiac musculature. The sinus venosus initially (2 days) consists of the left and right (anterior) sinus horns. Later, ca. 12–16 days, a third vessel appears which stems from the liver and is confluent with the sinus horns immediately upstream of the right atrium. Video recordings show sequential contractions in the sinus venosus, the atria and the ventricle -S6 and sThe future pulmonary vein is indicated by 7 days by a mesenchymal cushion associated with the dorsal wall of the atrium and from 10 days onward a lumen can be seen within the cushion. Unlike mammals, no myocardium develops around the pulmonary vein. By 7 days, sinuatrial valves have started to form, protruding into the atrial lumen.musculi pectinati) appear by 10 days, the most prominent of which is the septum spurium of the right atrium which is continuous with the sinuatrial valves. The atrial septum has also started to form at 10 days but is not completed by 42 days. The atrial septum develops slightly to the left of the body midline such that a small cul-de-sac is formed to the right atrium to the left of the deepest part of the sulcus of the atrial roof. Eventually, by 42 days, the atrial walls are entirely trabeculated except immediately above the atrioventricular canal, i.e. the atrial floor, or vestibule.Initially, the atrium is a smooth-walled chamber encompassing a single lumen. The lateral walls of the atrium seemingly outgrow the roof and a deep sulcus is eventually created between the left and right atrium . InternaThe atrioventricular canal initially is a free standing tube, but becomes progressively enclosed by ventricular myocardium , 2E. AlrThe ventricle develops in between a left-sided atrioventricular canal and a right-sided conus orifice. Trabeculations develop in the entire ventricle, except towards the atria and in between the atrioventricular canal and the conus orifice and this smooth-walled part is referred to as the inner curvature. The early trabeculations (2 days) are congregated into multiple trabecular sheets that are parallel to the saggital plane . AlreadyFormation of the cavum pulmonale probably occurs as a consequence of the ventricularization of the conus and by 14 days a shallow cavum pulmonale appears that will become deeper as the ventricle continues to elongate. The early ventricle therefore appears to consist of the cavum arteriosum and cavum venosum and later, from ca. 14 days onward, the cavum pulmonale develops . ConcomiFrom about 10 days onward smooth-walled myocardium associated with the atrioventricular cushions appears to project into the ventricle from the atrioventricular canal ventrally and dorsally and these are called the bulboauricularlamella  [15]. InAt 2 days the myocardial outflow tract is thin-walled but nevertheless has little lumen because it is almost entirely filled with cushion material . Its luminal length is more than 1000 µm as it curves from the extreme right of the ventricle to the left and then cranially . By 10 dChelydra serpentina, where a straight heart tube is formed on the embryonic midline ca. 9 days post egg laying Lacerta agilisNatrix natrixHeart tube formation and looping has not been treated here and takes place prior to egg laying in the corn snake, the anole lizard and the Philippine sailfin lizard. These processes were described and visualized in the turtle In using nomenclature of the fully formed heart on embryonic structures, it is important to appreciate that the formation of the heart is a highly dynamic process where many cells are added from extra-cardial precursor pools The association of specific ventricular cava with an atrial inflow or an arterial outflow relates to distinct phases in formation of the ventricle; the early trabeculated ventricle, from ca. 2 days onward, is associated with the atrioventricular canal and gives rise to the cavum arteriosum and most of the cavum venosum. Only about 14 days later does the cavum pulmonale start to form by ventricularization of the myocardial outflow tract. Also, it is only by the ventricularization of the myocardial outflow tract that the aortic base becomes associated with the cavum venosum. A small bit of heart tube, the inner curvature of the ventricle, always remains between the right aortic base and the atrioventricular canal  of the sinus venosus into the right atrium, which renders the dorsal wall smooth and the early atrium remains as the appendage characterized by pectinate/trabeculated musculature e.g.. The lefThe atrium, or atria, of ectothermic vertebrates is very voluminous compared to those of endotherms and contributes more to ventricular filling than in endotherms The formed heart of all amniotes contains two atria separated by a complete septum, but only in mammals is the atrial septum formed by two septa. The two septa are the septum primum and, associated with the atrialization of the sinus venosus, the septum secundum. The septum primum is formed first and has a free edge towards the atrioventricular canal that expresses the transcription repressor Tbx3 In embryogenesis, all vertebrates have a myocardial atrioventricular canal. Only in mammals and birds does the so-called insulating plane of fibro-fatty tissue ingress into the myocardium of the atrioventricular canal so that a single communication remains, the atrioventricular bundle The mesenchyme of the atrioventricular canal is strikingly similar in amniotes with a large cushion dorsally and ventrally Once the squamate atrioventricular canal has settled on the left of the body midline, it remains there throughout development . It doesBmp2 and Tbx3 and a similar crest has not been found in lizards Tbx5 and the left-right gradient is thus established over the muscular ridge, rather than the vertical septum . In reptiles, the atrioventricular canal myocardium is contiguous with smooth-surfaced ventricular myocardium referred to as bulboauricularlamella In contrast to amniotes, the myocardial outflow tract of fishes and amphibians is retained in the adult formed heart. It is prominent in cartilaginous fish, where it constitutes ca. 10–20% of the entire cardiac mass, in sarcopterygii fish like lungfishes, and basal actinopterygii fish, such as sturgeons as well as most amphibians In reptiles, the myocardial outflow tract is partially divided by a muscular protrusion, which is continuous with the muscular ridge caudally and the arterial aorticopulmonary septum cranially. Therefore, as the muscular outflow tract becomes ventricularized this protrusion blends seamlessly into the muscular ridge and is considered a part of it. It has been suggested that the protrusion is homologous to the spiral valve of the amphibian heart and the so-called conal septum of the mammalian heart that separates the lumen of the right ventricular outflow tract from the aorta It is perplexing that birds and monotreme mammals have a mural muscular flap valve at the right atrioventricular junction, because they evolved independently from reptilian ancestors where a similar structure is not easily recognized  [46], [7The developing reptile heart is characterized by fast growth of the chambers and slow growth of the flanking segments, exactly like in mammals and birds. In reptiles, a myocardial sinus venosus is retained in the formed heart, whereas the sinus venosus of mammals atrializes to the right atrium to form a vestibule in the dorsal right atrial wall. Associated herewith, is the absence (reptiles) and presence  of an atrial septum secundum. A myocardial sleeve is absent from the reptilian pulmonary vein and there is no vestibule in the left atrium. The atrioventricular canal of reptiles is not interrupted by an insulating plane, as in mammals and birds. Also, the atrioventricular canal remains on the cardiac left, whereas it expands and migrates to the right in mammals and birds (and crocodilians) associated with the formation of the ventricular septum.aortico-pulmonary septum: the arterial septum of the truncus arteriosus that separates the pulmonary arterial lumen from the aortic lumina.bulboauricularlamelle, dorsal: smooth-surfaced ventricular myocardium, situated in the inner-most dorsal base of the ventricle in between the atrioventricular canal and the arteries.bulboauricularlamelle, ventral: smooth-surfaced ventricular myocardium, situated in the inner-most ventral base of the ventricle in between the atrioventricular canal and the arteries.bulboauricularsporn: thickened myocardium in between the atrioventricular canal and the right aorta. Derived from the inner curvature of the embryonic heart tube. Synonyms; bolvo ventricular spur bulbo-ventricular fold: the inner curvature of the transition from ventricle to myocardial outflow tract. Synonyms; bolvo ventricular spur, conoventicular flange bulbuslamelle: smooth-surfaced ventricular myocardium juxtaposed to the muscular ridge. In pythons and varanid lizards, it separates the cavum pulmonale and the cavum venosum during ventricular systole. Defined here as the smooth-surfaced structure to the right of the bulboauricularsporn, and therefore the atrioventricular canal, that holds the dorsal valves of the aortae. Derived from the ventricularization of the myocardial outflow tract. Synonyms; bulbar flange.cardiac shunt, left-to-right: the circulation of pulmonary venous blood (oxygen-rich) to the pulmonary circulation.cardiac shunt, right-to-left: the circulation of systemic venous blood (oxygen-poor) to the systemic circulation.i.e. the ‘systemic side’ of the ventricle.cavum arteriosum: the left-sided chamber of the ventricle that receives blood (oxygen-rich) from the left atrium; i.e. the cavities to the left of the muscular ridge and the bulbuslamelle.cavum dorsale: the combined cavum arteriosum and cavum venosum, i.e. part of the ‘pulmonary side’ of the ventricle. Synonyms; cavum ventrale.cavum pulmonale: the right-sided chamber of the ventricle that receives blood (oxygen-poor) from the right atrium in diastole; i.e. part of the ‘pulmonary side’ of the ventricle.cavum venosum: the central chamber of the ventricle siyuated to the right of the vertical septum and to the left of the muscular ridge and the bulbuslamelle. It receives (oxygen-poor) blood from the right atrium in diastole and is traversed by blood (oxygen-rich) from cavum arteriosum in systole; cavum ventrale: synonym for the cavum pulmonale.et al., 1974).muscular ridge: the smooth-surfaced myocardial ridge-like structure of the ventricle to the right of the atrioventricular canal that is continuous with the aortico-pulmonary septum and holds the ventral valves of the aortae and the dorsal valve of the pulmonary artery. Synonyms; horizontal septum, Muskelleiste, cloison helïcoidale, ventricular septum, septum interventriculare  of spongy myocardium in the ventricle situated immediately under the atrioventricular canal. The atrioventricular valves ‘plunge’ unto it during diastole.Figure S13D models of the heart of the corn snake (Pantherophis guttatus), 2 to 16days post laying.(PDF)Click here for additional data file.Figure S23D models of the heart of the corn snake (Pantherophis guttatus), 20days post laying to 3months.(PDF)Click here for additional data file.Figure S33D models of the heart of the anole lizard.(PDF)Click here for additional data file.Figure S43D models of the heart of the embryonic chicken (4 and 6days post laying).(PDF)Click here for additional data file.Figure S53D models of the heart of embryonic man (Carnegie stages 14 and 18).(PDF)Click here for additional data file.Figure S63D model of the heart of the adult Burmese python (Python molurus).(PDF)Click here for additional data file.Figure S73D model of the heart of the adult ostrich (Struthio camelus).(PDF)Click here for additional data file.Figure S8Growth of cardiac compartments. The atrial and ventricular compartments showed exponential growth, whereas there was little change in the myocardial volume of the atrioventricular canal and the myocardial outflow tract.(TIF)Click here for additional data file.Figure S9Proliferation of the hearts in two specimens of anole lizard, as assessed by BrdU incorporation.A. A 7 µm section of the st5 specimen, close to the transverse plane, showing myocardium (blue), nuclei (green) and BrdU positive nuclei (orange). B. A 7 µm section of the st12 specimen, close to the horizontal plane, showing myocardium (blue), nuclei (green) and BrdU positive nuclei (orange). C–D. Reconstructions of the myocardium upon which is projected the fraction of BrdU positive nuclei as described in E. Internal view of the ventral halve of the st5 specimen showing relatively high proliferation in the ballooning atria  and ventricle (ven). F. Internal view of the ventral halve of the st12 specimen. At this stage the cardiac compartments almost have the proportions of the fully formed heart and proliferation is lower than in the st5 specimen, albeit the outer curvature of the ventricle still shows some proliferation.(TIF)Click here for additional data file.Movie S1Seen from the right, the beating heart of a corn snake embryo 10days after egg laying. mot, myocardial outflow tract.(AVI)Click here for additional data file.Movie S2Seen ventrally, the beating heart of a corn snake embryo 10days after egg laying. mot, myocardial outflow tract.(AVI)Click here for additional data file.Movie S3Seen from the left, the beating heart of a corn snake embryo 10days after egg laying. mot, myocardial outflow tract.(AVI)Click here for additional data file.Movie S4Seen from the right, the beating heart of a corn snake embryo 20days after egg laying. mot, myocardial outflow tract.(AVI)Click here for additional data file.Movie S5Seen ventrally, the beating heart of a corn snake embryo 20days after egg laying. mot, myocardial outflow tract.(AVI)Click here for additional data file.Movie S6Seen from the left, the beating heart of a corn snake embryo 20days after egg laying. mot, myocardial outflow tract.(AVI)Click here for additional data file.


Myocardial infarction (MI) documented by late gadolinium enhancement (LGE) has clinical and prognostic importance, but its detection is sometimes compromised by poor contrast between blood and MI. MultiContrast Delayed Enhancement (MCODE) is a technique that helps discriminate subendocardial MI from blood pool by simultaneously providing a T2-weighted image with a PSIR (phase sensitive inversion recovery) LGE image. In this clinical validation study, our goal was to prospectively compare standard LGE imaging to MCODE in the detection of MI.Imaging was performed on a 1.5 T scanner on patients referred for CMR including a LGE study. Prospective comparisons between MCODE and standard PSIR LGE imaging were done by targeted, repeat imaging of slice locations. Clinical data were used to determine MI status. Images at each of multiple time points were read on separate days and categorized as to whether or not MI was present and whether an infarction was transmural or subendocardial. The extent of infarction was scored on a sector-by-sector basis.Seventy-three patients were imaged with the specified protocol. The majority were referred for vasodilator perfusion exams and viability assessment . Forty-six patients had a final diagnosis of MI . MCODE had similar specificity compared to LGE at all time points but demonstrated better sensitivity compared to LGE performed early and immediately before and after the MCODE (p = 0.008 and 0.02 respectively). Conventional LGE only missed cases of subendocardial MI. Both LGE and MCODE identified all transmural MI. Based on clinical determination of MI, MCODE had three false positive MI’s; LGE had two false positive MI’s including two of the three MCODE false positives. On a per sector basis, MCODE identified more infarcted sectors compared to LGE performed immediately prior to MCODE (p < 0.001).While both PSIR LGE and MCODE were good in identifying MI, MCODE demonstrated more subendocardial MI’s than LGE and identified a larger number of infarcted sectors. The simultaneous acquisition of T1 and T2-weighted images improved differentiation of blood pool from enhanced subendocardial MI. The introduction of late gadolinium enhancement (LGE) as a means to identify myocardial infarction (MI) and predict recovery of left ventricular systolic function was a key factor in pushing cardiovascular magnetic resonance (CMR) into mainstream clinical use. The abiMI as documented by LGE has prognostic significance,3. AtypiTo improve clinical workflow efficiency, many imaging sites perform LGE imaging,7 approxMultiContrast Delayed Enhancement (MCODE) is a CMRIn this clinical validation study, our goal was to prospectively assess whether the T2- weighted image acquired during an MCODE acquisition adds diagnostic value to the LGE images. We hypothesized that MCODE should significantly decrease false negative LGE images for diagnosing MI in both acute and chronic MI when contrast between blood and infarct is poor and the transmural extent of infarction is subendocardial.The study was approved by the Institutional Review Board, and all subjects provided informed consent. Imaging was performed on either a 1.5 Tesla Siemens Espree or Avanto MRI scanner . Seventy-three patients with a variety of diagnoses referred for CMR that included LGE were imaged . Patients with hypertrophic cardiomyopathy were excluded from analysis (n=2). Clinical data were obtained through patient history and medical records. Patients were categorized as having an MI if they had: 1) a history of an acute chest pain syndrome with associated abnormal cardiac enzyme elevation 2) evidence of MI by Q waves on EKG with angiographically significant coronary artery disease or an abnormal nuclear perfusion study, or 3) fixed perfusion defect on a nuclear study. Other patients were categorized as not having an MI.All patients underwent cine imaging of the heart, using steady-state free precession techniques in a volumetric short-axis stack with standard three-, two-, and four-chamber long axis views. Typical parameters for the cine imaging included a matrix size of 256 × 144, slice thickness of 6mm, TE 1.65, bandwidth of 977 Hz/Px, and a flip angle of 50°. After administration of 0.15-0.2 mmol/kg gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) , a stack of short-axis and three standard long axis LGE images were acquired using a phase sensitive inversion recovery (PSIR) spoiled 2 for a nominal 360 × 270 mm2 field of view, slice thickness 6 mm, TI optimized on an individual basis (but commonly 300 ms), TE 2.47 ms, TR 6.4 ms, BW 201 Hz/pixel, spoiled GRE read-out, excitation flip angle 25° for the T1-weighted PSIR LGE image and 15° for the T2-weighted image. MCODE was a breath-held, ECG triggered, segmented acquisition with inversions every 3 R-R intervals, acquiring an IR, PD, and T2-weighted image on alternate heartbeats. Typical segmentation was 30 phase encode lines per heartbeat at a nominal 60 beats per minute heart rate, corresponding to a breath-hold duration of 15 heartbeats including 3 discarded beats. The effective TE for the T2-weighted images was 40 ms. Using the segmented FLASH read-out leads to a minor T1-weighted contrast which has been found to be negligible for this application of discriminating blood pool from myocardium[Prospective comparisons between MCODE and standard PSIR LGE imaging were done by targeted, repeat imaging of select slice locations. A standard PSIR LGE image was obtained, followed by an MCODE acquisition and another standard PSIR LGE image on three sequential breath holds. The rationale behind repeating the standard PSIR LGE imaging was to minimize differences in image contrast attributable to renal clearance and therefore primarily compare the MCODE LGE T1 and T2 images with conventional PSIR LGE. The MCODE acquisition resulted in PSIR LGE and T2-weighted images within the same breath-held acquisition. Typical imaging parameters of the MCODE sequence included a matrix of 256 × 119, corresponding to a spatial resolution of 1.3 × 2.3 mmEach image, within the standardized image set - the initial late gadolinium enhancement images (LGE1), the repeated late gadolinium enhancement images (LGE2), the MCODE (containing a PSIR LGE image and a T2-weighted image), and the third late gadolinium enhancement images (LGE3) - were read on different days from other images of the same patient by a single Level III cardiovascular magnetic resonance imaging cardiologist with over 10 years’ experience. All PSIR LGE images were categorized as to whether or not MI was present and whether a MI was transmural  or subendocardial . The MCODE images were reviewed independently from the standardly acquired LGE images. During the MCODE analysis, the LGE and T2 images were reviewed both side by side, as well as in a superimposed “flicker”-mode.For images demonstrating MI, additional analysis was performed. The number of sectors with MI on LGE2 and the MCODE LGE/T2 image pair were individually tallied to determine the extent of the infarction. In all patients with MI, on the MCODE LGE T1 image, regions of interest were drawn within normal myocardium, around myocardial infarction, and within the blood pool. From the T1 image, the same regions of interest for the normal myocardium and MI were copied and applied to the MCODE T2 image. Signal intensities were reported as mean ± standard deviation.t-test was used to compare mean values of normally distributed data. A Wilcoxon test was used to compare paired categorical data or data that were not normally distributed. A McNemar test was used to compare pairs of correlated proportions. A Friedman test was used to detect differences in repeated measures for data that were not normally distributed. A Mann–Whitney test was performed on unpaired categorical data or continuous data that were not normally distributed. A weighted statistic score and corresponding p values described by Kosinski[Statistical significance was analyzed using MedCalc Version 12.0.1 statistical software . Descriptive data are reported as mean ± standard deviation (SD) if data were normally distributed or median with interquartile range if not normally distributed. A D’Agostino Pearson test was used to determine if continuous data were normally distributed. A Kosinski were useThe final data set consisted of 71 patients who were imaged using the multi-technique MCODE/LGE protocol. The enrolled patients represented a mixture of patients with known coronary artery disease (CAD) (54%) or intermediate to high likelihood of coronary disease with 30% (21 patients) having greater than three TIMI risk factors. Fifty-two of the 71 patients were male, and the mean age was 57.9 ± 11.1 years. Thirty-one percent of the patients were specifically referred for assessment of viability (including 12 acute and 10 chronic MI’s), while another 52% were referred for assessment of ischemia. The remaining patients were referred for indications such as assessment for nonischemic cardiomyopathy , aortic assessment , and congenital assessment .Within the group, 46 patients were categorized with MI  and 25 patients without infarction. The 46 MI’s included 35 patients who had outside confirmation of a clinical event with a chest pain syndrome and cardiac enzyme abnormality and nine patients who had evidence of Q waves on EKG with angiographic evidence of CAD or an abnormal nuclear stress test. Two patients did not have a prior history of MI but had fixed nuclear defects consistent with MI.Among the non-MI group, no one had a clinical history of an acute coronary syndrome nor evidence of Q waves by EKG.Compared to the patients without MI, the MI subgroup of patients were more likely to have a prior history of CAD, hypertension, hyperlipidemia, and diabetes and had lower ejection fractions. Baseline characteristics are summarized in TableThe mean time between contrast administration and the LGE1 image was 11±5 min. The mean time between contrast administration and the LGE2 image was 19±5 min. The mean time between the contrast and the MCODE image was 20±5 min. On average, the MCODE acquisition was performed 50 s after the LGE2 and 46 s before the LGE3. The mean time between contrast administration and the LGE3 image was 20±6 min. FigureTablesLGE1, LGE2, LGE3, and MCODE identified all transmural MI’s. All MI’s missed by LGE were in subendocardial MI’s. When analyzing subendocardial MI, LGE1 images identified 22 of the 30 subendocardial MI’s, while LGE2 and LGE3 images identified the presence of infarction in 23 of the 30 subendocardial MI’s. MCODE identified 30 subendocardial infarctions.Two patients had MI incorrectly identified by both MCODE and LGE. One of the two patients had Q waves in leads V1-V2 corresponding to a subendocardial anteroseptal region of LGE identified by both LGE and MCODE but no other confirmation of a clinically defined MI or significant coronary artery disease in a left anterior descending artery territory, and one patient had no corroborating evidence of MI, by clinical history, EKG, or other testing.One MCODE false positive study did have angiographic evidence of significant coronary artery disease in the circumflex distribution and is displayed in FigureIn sector-wise comparison of the two techniques, MCODE detected 99 sectors of infarction compared to 83 sectors detected by LGE2 (p < 0.001). FigureFigureOn MCODE T1 imaging, the signal intensity differences between MI and the blood pool were not statistically different (mean difference 16 arbitrary units (AU) ± 114, p = 0.4). On the T2 imaging, the signal intensity differences between MI and the blood pool were significant . In comparing acute MI T2 signal intensity differences of infarcted myocardium to blood pool against those of chronic MI’s, there was no significant difference (p = 0.09). FigureMCODE, a method that acquires both a LGE image and a T2-weighted image, improves detection of subendocardial MI and assessment of the extent of infarction compared with a conventional LGE image. While LGE and MCODE were equivalent in transmural MI, MCODE detected more subendocardial infarctions and found a greater extent of infarctions than conventional LGE. The main reason why MCODE improves the characterization of MI relates to the simultaneous acquisition of T1-weighted and T2-weighted images. Even in cases where there is poor contrast between the MI and the blood pool, the T2 image has excellent contrast between blood and myocardium. Thus, the simultaneous acquisition of LGE and T2-weighted images improves the ability to differentiate subendocardial contrast-enhanced infarcts because the T2-weighted image helps differentiate blood from myocardium.Good blood pool to infarct/scar contrast depends upon multiple factors related to gadolinium kinetics: gadolinium dose, elimination rate of contrast, time between contrast agent administration and imaging. Additional factors that contribute to the ability to identify regions of LGE include its size, the image spatial resolution, and partial volume effects. If the issue were solely one of allowing enough time to pass to allow more clearance of gadolinium from the blood pool, then imaging at a later time frame after administration of contrast would solve the problem. Our study suggests that the issue is not dominated by timing between contrast injection and imaging. The bracketed LGE-MCODE-LGE experiment demonstrates that contrast timing washout does not explain why MCODE performs better than standard LGE. However, whether LGE works better at other time periods needs to be defined by future studies.Particularly in the assessment of viability, answering the question of whether LGE is or is not present may not be enough. Clearly delineating the extent of an infarction may aid in targeting what vessels to revascularize. The patient displayed in FigureWhile the present study is limited to evaluating patients with LGE in a MI pattern, there is prognostic significance affiliated with abnormal LGE patterns of either MI or atypical LGE. In a group of 857 patients with complete CMR cine and LGE exams, Cheong et al. demonstrated that abnormal LGE in both coronary artery disease and non-coronary artery disease patients was shown to predict all-cause mortality or cardiac transplantation. ApproprWhile the study design was carried out in a rigorous fashion, there were some limitations to the overall study.One might argue that the SSFP cine image that is usually acquired in a complete CMR study could perform a function similar to the T2-weighted image in the MCODE image pair. This specific comparison was not performed in the current study, and therefore, it is difficult to know if the MCODE approach is superior to using the SSFP cine image without the direct comparison. However, multiple factors limit this comparison - the SSFP image and the T1 LGE image are acquired on separate breath-holds and at different time points, and there are often significant differences in slice positions or patient position, in temporal resolution and in trigger times, to mention a few.While the study design did directly compare the standard LGE technique to the MCODE technique at similar times, the timing of the comparison was substantially later than the initial LGE acquisition. Therefore, the performance of MCODE, if applied at the same earlier time point as the initial LGE imaging, is unknown. In theory, at the earlier time point when the LGE blood-MI contrast is less, MCODE may have performed better.A concern raised from this study’s findings might be that the standard LGE technique did not perform as well as expected compared to larger scale trials reporting the sensitivity and specificity of LGE in the diagnosis of MI. HoweverAnother recognized limitation is the fact that both standard LGE techniques and MCODE perform well in the diagnosis of MI. Therefore, large differences between the two techniques are difficult to detect in a study of this relatively smaller size.Our study demonstrates that in cases of subendocardial MI, the T2 data acquired by the MCODE sequence adds additional information to the final interpretation above that of the data obtained in a PSIR LGE T1 image alone. As more studies demonstrate the prognostic and clinical decision-making impact that LGE has on patients, CMR techniques need to also be able to more precisely identify LGE.AU: Arbitrary units; CMR: Cardiovascular Magnetic Resonance; FLASH: Fast Low Angle Shot; Gd-DTPA: Gadolinium-diethylenetriamine pentaacetic acid; LGE: Late gadolinium enhancement; LGE1: Initial late gadolinium enhancement image; LGE2: Repeated late gadolinium enhancement image; LGE3: Third late gadolinium enhancement image; MCODE: MultiContrast Delayed Enhancement; MI: Myocardial infarction; NPV: Negative predictive value; PSIR: Phase sensitive inversion recovery; PPV: Positive predictive value; SD: Standard deviation.Dr. Arai is principal investigator on a US Government Cooperative Research and Development Agreement (CRADA) with Siemens.AEA, WPB, and PK conceived of the study design and actively worked to coordinate details of the study, analysis of data, and drafting of the manuscript. CM, MYC, OJB, SV, and JRW were involved in the acquisition of data. SMS and SWL were involved in the acquisition of data and aided in statistical analysis. All authors were involved in the final editing of the manuscript and approve its content.


Anabolic-androgenic steroids (AAS), a synthetic derivate of testosterone, have become a popular drug among athletes and bodybuilders to enhance muscle mass and improve the athletic performance. Many pathological effects such as hepatic and endocrine dysfunction, behavioural changes and cardiovascular complications have been reported.Within these ast ones, we find an increase in left ventricular muscle mass, concentric myocardial hypertrophy, left ventricular diastolic dysfunction, arterial hypertension, prothrombotic effects, changes in the concentration of cholesterol levels, particularly a reduction in HDL cholesterol concentration, myocardial infarctions in relation to endothelial dysfunction, vasospasms or thrombosis and sudden cardiac death.We report the case of a 32-year-old patient with a history of arterial hypertension, depressive syndrome and consumption of cocaine, amphetamines and AAS who developed severe left ventricular systolic dysfunction and myocardial hypertrophy with signs of heart failure and peripheral arterial embolism. Anabolic-androgenic steroids (AAS) are synthetic derivates of testosterone used primarily for hormone replacement in male hypogonadism. However, in many countries, this medication is sold over-the-counter to enhance muscle mass and improve the athletic performance. Physiologically, elevations in testosterone concentrations stimulate protein synthesis resulting in improvements in muscle size, body mass and strength. AAS is by far the most detected doping substance banned by all major sporting bodies. AAS can cause many adverse effects such hepatic failure, endocrine dysfunction, behavioural changes or cardiovascular complications depending on the length and dose-dependent of drug abuse.A 32-year-old patient with episodes of arterial hypertension self-treated with beta blockers, depressive syndrome and frequent consumption, in adolescence and youth, of cocaine, amphetamines and AAS  attended to the emergency department due to headache and abdominal pain in association with a hypertensive crisis (220/100 mmHg). The patient had an athletic constitution, with a weight of 109 kg and a body mass index of 33.3 kg/m2, and referred in the last months exercise intolerance attributing his current clinical symptomatology to the intake of undercooked meat . Three days after requesting voluntary hospital discharge, the patient returned to the emergency department with intense weakness, deep sweating and severe arterial hypotension after beta blocker intake, requiring fluid and catecholamines perfusion for a few hours. Analytically, there was leukocytosis (19.5 10 3/µL) with an impairment of the renal function (creatinine of 1.7 mg/dL), an alteration of the lipid metabolism  of 206 mg/dL, high-density lipoprotein (HDL) of 21 mg/dL and triglyderides of 259 mg/dL) and an elevation of the liver enzymes  of 766 u/L and glutamic-pyruvic transaminase (GPT) of 205 U/L. Basic coagulation study was normal and urine test showed positivity for methamphetamines and barbiturates. Electrocardiogram was in sinus rhythm and the echocardiogram showed severe left ventricular dysfunction, dilation, hypertrophy and increase in the ventricular mass , mild right ventricular dysfunction (tricuspid annular plane systolic excursion ]TAPSE) having the external genitalia with a normal appearance.However 2 weeks later the patient was readmitted to the hospital due to critical ischemia of the lower limbs. Systemic heparinization associated with intravenous prostaglandin was started, presenting the patient an improvement of his symptoms with recovery of the mobility and the sensitivity. Control echocardiography showed severe global left ventricular dysfunction with a pedunculated mobile thrombus adhered to the ventricular septum . ArterioAnabolic steroids have become a popular drug among athletes and are known to have a multitude of pathological effects when administered in suprapharmacological doses. Serious adverse effects include hepatic and endocrine dysfunction, behavioral changes and cardiovascular complications such as arterial hypertension, especially in those with pre-existing hypertension , myocardMeanwhile, left ventricular hypertrophy (LVH) differential diagnosis may be considered in arterial hypertension, hypertrophic cardiomyopathy, accumulation myocardial diseases, non-compact myocardium, valvular and combined cardiac pathology, compensatory LVH in athletes and the consumption of anabolic steroids. In this context, Nieminen et al.  reportedAlso, unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals . CocaineIt is also important to draw attention to the fact that drug abuse addictions and psychiatric disorders often occur at the same time having certain mental conditions such as depression, bipolar disorders, psychosis, aggression and violence, mania, suicide and symptoms of dependence and withdrawal on discontinuation associated with AAS consumption , 12. Because the over-the-counter availability and unrestrained self-medication with products containing AAS create a heightened potential for serious side effects, we should be aware of those bodybuilder patients, especially if they have a psychiatric disorder background with the consumption of other types of drugs.


The perforator-based flaps in the sacral and ischial region is designed according to the localization of perforators that penetrate the gluteus maximus muscle, reach the intra-fascial and supra-fascial planes with the overlying skin forming a rich vascular plexus. The perforator-based flaps described in this article are highly vascularized, have minimal donor site morbidity, and do not require the sacrifice of the gluteus maximus muscle. In a period between April 2008 and March 2009, six patients with sacral pressure sore were reconstructed with propeller flap method based on superior gluteal and parasacral artery perforators. One flap loss was noted. Three cases of ischial pressure sore were reconstructed with longitudinal propeller flap cover, based on inferior gluteal artery perforator. One flap suffered wound infection and dehiscence. Two cases of pilonidal sinus were reconstructed with propeller flap based on parasacral perforators. Both the flaps survived without any complications. Donor sites were closed primarily. In the light of this, they can be considered among the first surgical choices to re-surface soft tissue defects of the sacral and ischial regions. In the series of 11 patients, two patients (18%) suffered complications. Sacral and ischial soft tissue defects have always been a challenge to the plastic surgeon. Numerous surgical techniques are employed in their repair and each has its own advantages and disadvantages. Pressure sore and pilonidal sinus are common conditions resulting in sacral and ischial soft tissue defects. We present 11 patients operated on for sacral, ischial pressure sores and pilonidal sinus using perforator-based flaps.The study was conducted in the Department of Plastic Surgery, Government General Hospital, and Madras Medical College. Eleven patients, eight males and three females, were operated upon over a period of 12 months (April 2008 to March 2009). The mean age of the group was 37 (age range: 22–50 years). Dimensions of the skin defects and operative details for all patients are shown in 2–14 × 11 cm2 were designed. Flaps were mostly raised based on one or two perforators at least  experienced only one recurrence during the 13.6-month follow-up period with 35 gluteal perforator flaps for the coverage of 22 sacral, seven ischial and six trochanteric pressure sores in 32 patients. Soft-tissue integrity depends not only on carefully designed reconstructions but also the patient’s ability to restore blood flow following ischaemia and the avoidance of prolonged pressure.In our present series, the superior and inferior gluteal artery perforators were found in the same site as mentioned above. Design of the propeller flap chosen, considering the possibility of recurrence is represented in the following schematic diagrams Figures  and 10. et al. describel.[et al. harvesteIn conclusion, relatively large defects were reconstructed with single flaps with favourable results. The pedicled perforator propeller flaps of the refined design can be used efficiently in various reconstructions of sacral and ischial defects.


The clinical presentation of pheochromocytoma is variable and many biochemical and imaging methods have been suggested to improve the diagnostic accuracy of what has been termed "the great masquerader". This case-report is of a middle-aged woman with a non-specific clinical presentation suggesting acute coronary syndrome or subacute myocarditis. Cardiovascular magnetic resonance (CMR) at presentation showed myocardial edema and intramyocardial late gadolinium enhancement (LGE). An adrenal mass was seen, which was confirmed as pheochromocytoma and surgically removed. Our case shows evidence for acute adrenergic myocarditis, with resolution of both the edema and the LGE after surgical excision. Pheochromocytomas are cathecolamine-producing tumors derived from the sympathetic or parasympathetic nervous system. The clinical presentation is variable, ranging from adrenal incidentalomas to patients with hypertensive crisis or, rarely, with congestive heart failure. The high circulating levels of catecholamines resulting from a pheochromocytoma may cause direct myocardial injury. Focal myocardial necrosis and inflammatory cell are present in 50% of patients who die with pheochromocytoma and may contribute to clinically significant left ventricular failure. The diagnosis is based on documentation of catecholamine excess by biochemical testing and localization of the tumor by imaging.A 64-year-old woman was referred to our hospital with symptoms of breathlessness, dizziness and palpitations. Her past medical history was relevant for hypertensive episodes and for a recent episode of gastroenteritis. Clinical examination of the heart, lungs and abdomen was unremarkable. The ECG showed left ventricular (LV) hypertrophy with ST-segment depression and her blood pressure was 180/110 mmHg. Chest X-ray was normal. Troponin I values was in the normal range, Creatine-kinase (CK-MB) was slightly increased  as the leukocyte count and C-reactive protein values . Echocardiogram showed mild left ventricular (LV) increased wall thickness and hypokinesia of postero-lateral segments, but normal overall systolic function (LVEF 56%). Based on the echocardiographic findings and clinical presentation, the final diagnosis was unclear but sub-acute myocarditis and acute coronary syndrome with subendocardial ischemia were considered the two most likely differential diagnosis. The patient was subsequently referred for a cardiovascular magnetic resonance (CMR) study to further evaluate LV function and myocardial tissue characterization. The LV cine images confirmed the abnormalities observed with echocardiography  from the adrenal medulla or from extra-adrenal abdominal paraganglion tissue . The preA diagnosis of pheochromocytoma should be considered in patients with hypertension and unexplained symptoms. The classic presentation with severe headache, palpitations, chest pain, sweating, tremor is the most common but epinephrine and dopamine-secreting tumors also occur and patients with these tumors present with hypotension or cardiogenic shock when beta adrenergic stimulation overrides alpha-adrenergic stimulation. High catecholamine level can cause direct myocardial damage with focal degeneration and contraction band necrosis of the myocytes, monocytic infiltration, medial thickening of small and medium size coronary arteries and interstitial fibrosis. The clinical picture of catecholamine myocarditis is common in autopsies studies of patients died from pheochromocytoma as well as those died from the stress of physical assault -4.CMR is a non-invasive imaging technique that can diagnose acute and chronic myocarditis with combined T2- and T1-weighted after contrast (LGE) that highlight the presence of acute myocardial damage with myocardial inflammation and edema . In our For our patient, comprehensive CMR showed reversible acute adrenergic toxicity in addition to identifying the pheochromocytoma.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.AR conceived the study and drafted the manuscript, PP carried out the CMR examinations, AM participated to the collection and presentation of clinical and images data, EB carried out the histological examination and the histology images, CBD participated to the revision of the manuscript. All authors read and approved the final manuscript.Four chambers cine at admission. CMR four-chamber cine showing increased LV wall thickness with normal functionClick here for fileFour chambers cine at post-surgical follow-up. CMR four-chamber cine showing normalization of LV wall thicknessClick here for file