B.anthracis infection in 2001 and subsequent cases in the US and Europe demonstrate that anthrax is a continuing risk for the developed world. While several bacterial components contribute to the pathogenesis of B. anthracis, production of lethal toxin (LT) is strongly associated with the development of hypotension and lethality. However, the mechanisms underlying the cardiovascular instability LT produces are unclear. Some evidence suggests that LT causes shock by impairing the peripheral vasculature, effects consistent with the substantial extravasation of fluid in patients dying with B. anthracis. Other data suggests that LT directly depresses myocardial function. However a clinical correlate for this latter possibility is less evident since functional studies and post-mortem examination in patients demonstrate absent or minimal cardiac changes. The purposes of this review were to first present clinical studies of cardiac functional and histologic pathology with B. anthracis infection and to then examine in vivo, in vitro, and ex vivo preclinical studies of LT’s myocardial effects. Together, these data suggest that it is unclear whether that LT directly depresses cardiac function. This question is important for the clinical management and development of new therapies for anthrax and efforts should continue to be made to answer it.The US outbreak of  Bacillus anthracis (B. anthracis or anthrax) infection appears associated with a particularly poor prognosis. In contrast to mortality rates of 40% to 50% with shock complicating other types of bacterial infection, in recent anthrax outbreaks in the US and Europe, mortality rates in patients with shock have been greater than 75% [B. anthracis produces two toxins, lethal and edema toxins (LT and ET respectively), as well as other components  which may contribute to its pathogenesis [The development of shock in patients with than 75% ,2,3,4. BB. anthracis infection [B. anthracis are limited, there are several striking examples of patients dying with anthrax associated shock but in whom echocardiographic and even pulmonary arterial catheter measures of myocardial function close to the time of death were reported to be normal [On the other hand, some experimental data have also suggested that LT produces shock by impairing the peripheral vasculature via either disruption of endothelial barrier or vascular smooth muscle function ,7,8,9,10nfection ,11,12. Onfection ,15,16,17e normal ,19. Alsoe normal ,20. ThesB. anthracis infection, a clearer understanding of whether it does in fact directly depress myocardial function has important clinical and research implications. First, it would emphasize the need for practitioners to directly monitor myocardial function in patients with invasive anthrax infection and cardiovascular instability and to consider the early use of vasoactive agents with strong inotropic effects. Second, it would highlight the need for research directed at identifying mechanisms underlying LT induced myocardial defects and the agents best able to correct those. After a short description of LT and its intracellular actions, the purpose of the present review is to first examine whether clinical data implicates cardiac dysfunction in the pathogenesis of B. anthracis infection and to then summarize in vivo, in vitro, and ex vivo preclinical data investigating LT’s potential effects on myocardial function.Given the likely important contribution LT makes to the development of shock during 83) binds to one of at least two receptors on host cells; tumor endothelial marker-8 (TEM-8) or capillary morphogenesis gene-2 (CMG2), also termed anthrax toxin receptors 1 or 2 (ANTR-1 or ANTR-2), respectively. Both receptors are widely distributed in host tissues including the heart and blood vessels although some data suggests that CMG2 binding plays a predominant role in LT’s effects during infection [83 protomer then undergoes furin cleavage, and the remaining bound monomer (PA63) forms heptamers or octamers that up to three or four LF molecules  can bind to. This complex then undergoes endocytosis and as the endosomal pH decreases, the LF (and EF) molecules are released into the host cell’s cytosol where they can act.Lethal toxin is a binary type toxin comprised of protective antigen (PA), the component necessary for toxin uptake by host cells, and lethal factor (LF), the toxic component ,21. Durinfection . The PA8Lethal factor is a metalloprotease which has two primary actions: it cleaves mitogen activated protein kinase kinase (MAPKK) pathways 1 to 4, 6 and 7, thus disrupting key host stress kinase pathways  and; it activates the host inflammasome NLRP3, resulting in upregulation of caspase-1 and the production of IL-1 and IL-12 ,23. EvidB. anthracis are very limited. Furthermore, any abnormalities that have been reported cannot be attributed to LT alone given the multiple other bacterial components associated with this bacterium that could alter the heart [B. anthracis infection in patients as a basis for considering what LT might contribute to. In this context, clinical data are primarily comprised of histopathology findings from patients dying with anthrax infection and of functional studies available in a small number of isolated case reports.As noted above, studies investigating myocardial function in patients with he heart . Other the heart . It is sThe largest group of anthrax cases for which pathological data are available comes from the outbreak of inhalational infection in Sverdlovsk, Russia in 1979, which affected at least 94 people, 64 of whom died ,12. ThisB. anthracis cell wall and capsule fragments in mediastinal lymph nodes, soft tissue, and pleura and in the blood vessels or sinusoids of lung, liver, spleen, and intestines. Notably, findings related to the heart in patients with autopsies were not specifically recorded, other than that rare bacteria were present in coronary vessels. Individual reports from these five cases concentrated on mediastinal (lymph nodes and soft tissue), lung, intestinal and CNS tissue examination and none reported findings specifically regarding the heart or myocardium [Another group of clinical autopsies (five) or tissue samples (three lung biopsies) available for review comes from the outbreak of inhalational anthrax affecting 11 patients in the United States in 2001 . This ouocardium ,29,30,31B. anthracis among wool workers, there was no mention of abnormal myocardial changes on microscopic examination in two, while moderate sub-endocardial hemorrhage was noted in one [In three autopsy cases reported from an outbreak of d in one . In a red in one .B. anthracis infection. However, this does not exclude the possibility that electron microscopy or other histologic methods might not have shown evidence of myocardial involvement.Thus in these reports, there appeared to be limited histologic evidence of myocardial injury in patients dying with B. anthracis infection are very limited. Over the past 15 years there have been approximately 80 cases of inhalational, gastrointestinal, or injectional anthrax  reported to have occurred in the US or Europe [B. anthracis outbreak with respiratory distress with bilateral pleural effusions, peri-hilar infiltrates and a widened mediastinum on chest radiograph [B. anthracis. Echocardiography on day 2 showed an increase in the size of the pericardial effusion. The patient’s respiratory status continued to worsen and a repeat echocardiogram on day 3 showed further increase in the pericardial effusion and mild to moderate right atrial and ventricular collapse during diastole. Cardiac index was 2.6 L/min/m2 (reference range 2.4 to 4.0 L/min/m2), systemic vascular resistance was 1131 dynes·s·m2/cm5 (reference range 900–1400 dynes·s·m2/cm5) and a pulmonary capillary wedge pressure of 13 mmHg (reference range 6–12 mmHg) with no evidence of equalization of pressures. A follow-up echocardiogram 5 h later showed persistent collapse of the right atrium and ventricle concerning for tamponade. An attempted pericardiocentesis was unsuccessful and the patient expired. Autopsy showed a hemorrhagic pericardial effusion.Functional cardiac studies from patients with r Europe ,36,37,38diograph . EchocarOther clinical reports of cardiac assessment in anthrax patients provide less information. Echocardiography was performed close to the time of admission in a 44 year old male patient subsequently found to have inhalational anthrax related to infected animal hides and who presented with two to three days of fever, respiratory symptoms, and evidence of pneumonia with a loculated pleural effusion . EchocarB. anthracis infection is or is not associated with myocardial depression. It is unknown whether the limited data available regarding functional cardiac studies in clinical reports is the result of incomplete testing or because the results of such testing were unremarkable and not thought relevant for reporting.et al. in 1955 and up until the early 1970s, there were multiple studies performed by several groups employing small and large animal models examining LT’s physiologic effects, including its cardiopulmonary ones [Following the identification of LT (and ET) by Smith ary ones ,46. Whilary ones ,48. Hypoin vivo and in vitro models. One of the first studies to be published in this regard did not include hemodynamic measures but employed comprehensive histologic examination in combination with biomarker analysis in mice challenged with LT [Following the 2001 outbreak, there was renewed interest in investigating the cardiovascular effects of LT in both  with LT . This st with LT . Lethal versus were the result of the cardiac changes noted. In a subsequent study using a similar LT challenge (i.v. bolus), animals were sacrificed 2 to 5 h after LT and tissue was taken for histological analysis [in vivo study reported by this group, rats had serial blood pressure via non-invasive tail measurements and echocardiography measures at baseline before and from 12 to 48 h after intraperitoneal (i.p.) LT challenge [in vivo and in vitro studies to understand how LT might affect heart function at the cardiomyocyte level.The initial investigations reporting that LT might produce direct myocardial depression were performed by a group employing echocardiography in Sprague-Dawley rats. In one study, animals were challenged with LT as an i.v. bolus . Althouganalysis . Light ahallenge . In this90) [2+ transients within the cardiomyocytes, manifested primarily by a prolongation in Ca2+ decay. Experiments with either aponycin, an NADPH oxidase inhibitor or with catalase over-expressing mice, suggested that the inhibitory effects of LT on cardiomyocyte function was in part related to the production of superoxide and reactive oxygen species (ROS). Other experiments suggested that these or additional actions by LT produced cardiomyocyte depression via mechanisms involving; interference with the Ca2+ regulatory proteins SERCA2a and phospholamban (PLB); stimulation of autophagy and to a lesser extent endoplasmic reticulum (ER) stress; and the production of mitochondrial membrane or ubiquitin and proteasome defects. However these effects were not always consistent when the methods of cardiomyocyte exposure to LT were compared. For example, while measures 2 h after in vitro LT exposure showed up and down regulation of the Ca2+ regulatory proteins SERCA2a and phospholamban (PLB) respectively, these proteins were not altered when measured 18 h after in vivo i.p. LT exposure. Other experiments in this series of studies in knockout mice suggested that the effects of i.p. LT challenge on cardiomyocyte function were mediated in part by toll-like receptor-4 (TLR-4). Echocardiography in this experiment showed that while LT in wild type mice (WT) reduced left ventricular end diastolic dimensions (LVEDD) and left ventricular end systolic dimensions (LVESD) and calculated fractional shortening and cardiac output, these changes were smaller in TLR-4 knockout animals.In one series of studies using cardiomyocytes isolated from normal mice and treated with LT or from mice challenged 18 h previously with intraperitoneal (i.p.) LT, the investigators reported that LT inhibited cardiomyocyte peak shortening (PS) and the maximal velocity of shortening and re-lengthening (±dL/dt), and increased the time to peak shortening (TPS) and time to 90% re-lengthening (TR90) ,53,54. T2+ (Ca2+i), an effect that could result in diastolic dysfunction. Consistent with the known effect of LT on interference with MEK and activation of MAPKs, LT challenge was found to inhibit of MEK7 and JNK1 activity resulting in downstream activation of protein phosphase, dephosphorylation of PLB, and interference with SERCA2a regulated Ca2+ uptake by the sarcoplasmic reticulum. The investigators in this study suggested that the early diastolic dysfunction that was observed with LT may have a clinical correlate in the pleural and pericardial effusions and pulmonary edema sometimes noted in patients with B. anthracis infection.In another study by members of this group, serial echocardiographic measures in Sprague-Dawley rats challenged with a minimally lethal i.v. LT bolus demonstrated very early  evidence of diastolic heart failure with pulmonary artery regurgitation and left atrial dilation, when compared to baseline measurements . Left vein vivo cardiac function were described. Also, in the echocardiography data that was presented in the studies comparing TLR-4 knockout and WT mice, LT was associated with decreases in LVEDD and LVESD, and not the increases (either in both or only the latter) that would have been expected based on the original rat experiments showing increases in LVAd and LVAs [While this series of studies is informative, limited data was presented linking the mechanisms speculated to underlie LT’s depressant effects, to the echocardiographic changes  or to the hypotension and lethal effects, LT was originally reported to produce ,53,54,55and LVAs ,52. OverB. anthracis spore challenge, ones lacking it in endothelial cells alone, were not.Studies by another group have also suggested that direct myocardial depression has a role in LT associated lethality . An initAnother group studied serial electrocardiograms (ECG), cTnI and echocardiography measures up to 72 h after low or high doses of LT challenge in Dutch belted rabbits . Some anin vivo mouse and rat models, while informative, did not examine this function using methods that controlled for the potential preload and afterload effects of LT. These studies have also not typically measured pulmonary function to determine whether respiratory failure itself might have contributed to myocardial changes with LT. However, a small number of studies have attempted to address these confounding variables.These studies of LT’s effects on myocardial function in In a review of their early work, investigators that first reported the effects of LT challenge on echocardiography measures in the rat described data from six canines with indwelling left ventricular pressure-volume loop catheters that were observed for up to 96 h after a lethal dose of LT  or control  challenge ,56,57. UWe have examined the effects of LT on myocardial function while attempting to account for its possible preload, afterload, and pulmonary effects, both in canines with indwelling systemic and pulmonary arterial catheters and in isolated rat hearts perfused under constant pressure. In canine studies, sedated and mechanically ventilated animals were challenged with 24 h LT infusions and serial cardiopulmonary measures were obtained for up to 96 h . CompareCardiac index did not decrease with either toxin dose possibly because HR increased. On the one hand, decreases in LVEF in the face of unchanged PAOP and the absence of arterial hypoxemia, suggested that LT had potentially depressed myocardial function directly. However, it was also noted that daily normal saline volume loads (40 mL/kg over 40 min) were associated with increased LVEF in animals challenged with high dose LT. This latter finding in combination with the low CVP levels measured with both toxin doses raised the possibility that changes in preload with LT may have contributed in part to the reduced LVEF. In the same LT challenged canine model, compared to no hemodynamic support (fluid and vasopressor therapy titrated to PAOP and MAP respectively) or hemodynamic support alone, hemodynamic support with a PA directed monoclonal antibody increased both CVP, LVEF, MAP, and survival .in vivo rat model (50 ug/mL), did not alter any parameter measured including among others: heart rate (HR), left ventricular developed pressure (LVDP), rate pressure product (RPP), dP/dt max, and dP/dt min. Only when the concentration of LT was increased to levels 10-fold (500 ug/mL) greater than ones producing shock in vivo, were changes seen including decreases in HR, LVDP and dP/dt max and increases in dP/dt min (in vivo. Furthermore, absence of changes in cardiac function with the lower LT concentration may have been due to inadequate observation time to see changes develop.Therefore, to further examine the myocardial effects of LT in a system free of preload and afterload effects, we isolated hearts from healthy Sprague-Dawley rats and measured their function while they were perfused over four hours and under constant pressure in a Langendorff system . In thesP/dt min . The relin vivo, prior lethal LT challenge was not associated with significant differences in any parameter, including HR, LVDP, RPP, dP/dt max, or dP/dt min at any time point compared to controls (To explore this latter possibility further, we challenged Sprague-Dawley rats with a 24 h infusion of LT in doses that resulted in 30% lethality rates . At 8, 2controls . Table 2B. anthracis infection are multifactorial and complex [in vivo, in vitro and ex vivo studies provide a mixed picture as to whether B. anthracis infection is associated with myocardial depression or whether LT itself can cause this depression directly and independent of its other systemic effects. Interestingly, in the one clinical report providing both echocardiography and pulmonary arterial catheter data in a patient requiring vasopressor therapy and who ultimately died, left ventricular dysfunction other than that related to a progressive pericardial effusion appeared minimal [As recently noted, the mediators and mechanisms underlying hemodynamic instability during  complex . Likely  minimal . While d minimal ,37. In tIn conclusion, if LT does contribute to shock during anthrax infection, presently available clinical data do not provide strong evidence that this compromise is related to direct myocardial depression. However, efforts should continue to be made to further understand the impact of LT on myocardial function in anthrax sepsis both clinically and in preclinical models. This question carries important implications not only for the conventional management of patients with anthrax infection and shock but also for the development of new and targeted therapies.


Heart failure remains one of the most common causes of morbidity and mortality worldwide. The advent of mechanical circulatory support devices has allowed significant improvements in patient survival and quality of life for those with advanced or end-stage heart failure. We provide a general overview of past and current mechanical circulatory support devices encompassing options for both short- and long-term ventricular support. Heart failure is one of the most common causes of morbidity and mortality in the United States and worldwide. Although transplantation is the gold standard for end-stage heart failure, it is limited by donor supply. In the United States, about 50 000 patients die each year from heart failure but the number of heart transplants remains steady at about 2000 per year . MoreoveOur intent in this review is to provide a targeted overview of the currently available options for device therapy for heart failure. While the entire spectrum of MCS is quite broad and includes techniques such as intra-aortic balloon pump counterpulsation (IABP), and extracorporeal membrane oxygenation (ECMO), we will focus our discussion on ventricular assist devices (VAD) and total artificial heart (TAH) for the adult population.John Gibbon reported the first clinical use of MCS when he utilized cardiopulmonary bypass to repair an atrial septal defect in 1953 . This paSince then, continuous advances in device design have led to iterations of VADs that address and decrease complications such as infection, device failure, and thromboembolic events. These newer-generation devices combined with improved surgical techniques have resulted in substantial improvements in clinical outcomes. In 2005, a national registry called the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) was created to serve as a central repository for MCS clinical outcomes data. This prospective registry tracks real-time data points and has proven to be a vital component in understanding aggregate outcomes information for MCS patients.The first, and most important, steps when considering MCS therapy are to clearly elucidate the goals of treatment and to expedite early evaluation by a multidisciplinary team. This allows for selection of the appropriate device and timing of intervention for each particular patient. There are five possible goals of MCS: 1. bridge-to-transplant (BTT), 2. destination therapy (DT), 3. bridge-to-recovery, 4. bridge-to-decision, and 5. periprocedural support.MCS therapy as BTT is utilized in patients deemed to be suitable transplant candidates but needing ventricular support while on the organ waiting list. Although VAD support is widely accepted as standard therapy for these patients, there are no uniform guidelines regarding timing of device placement. Thus, the decision to initiate VAD therapy must consider each individual patient’s operative risk of VAD placement, the estimated waiting time for an available organ, and the estimated mortality while on the waiting list. VAD support in these patients achieves reduction in pulmonary arterial pressures, increase in end-organ perfusion, and improvement from cardiac cachexia, which, in turn, result in the added benefit of improved transplant candidacy. Of the disadvantages and risks of VAD therapy, two are particularly relevant for BTT patients. First, because VAD implantation generally requires a major operation, any subsequent transplantation becomes a re-operation with its attendant risks. Second, exposure to blood products during MCS device implantation can result in sensitization to HLA antibodies, which could potentially make a donor match more difficult.Patients who are not eligible for heart transplantation can be considered for MCS as DT. These patients are expected to receive MCS therapy for life, with the goals of prolongation of survival or improvement in quality of life. The benefits of MCS support as DT were substantiated in clinical trials (described below), demonstrating significant improvements in survival, functional ability, and quality of life with a DT VAD over optimal medical management.Some patients experience reverse ventricular remodeling after MCS therapy, ultimately resulting in improvement in ventricular function to such a degree that allows for MCS device explantation. MCS used in these cases is considered bridge-to-recovery. These scenarios often involve biventricular or sequential left followed by right VAD placement. Examples include viral myocarditis and giant cell myocarditis, both of which often resolve with temporary MCS support.Bridge-to-decision MCS is utilized in settings of acute hemodynamic compromise when there is insufficient time to permit a thorough evaluation of long-term MCS options. Often, the acutely ill patient may have multisystem organ failure and the benefit of long-term MCS is equivocal; in these cases, implantation of short-term MCS as bridge-to-decision can provide support until the patient’s status either improves sufficiently to justify conversion to a long-term device (as BTT or DT) or declines further, obviating the need for additional MCS therapy. Example clinical scenarios can include postcardiotomy shock, acute exacerbation of chronic HF, myocardial infarction, and cardiogenic shock after unsuccessful percutaneous coronary intervention.Short term MCS can be used as periprocedural support for patients undergoing procedures in the cardiac catheterization laboratory. One example is the use of IABP to augment coronary perfusion during high-risk percutaneous coronary intervention (PCI). More recently, percutaneous LVADs have been used to provide mechanical assistance and may offer superior support when compared to IABP, particularly during hemodynamic depression at the time of balloon inflation in PCI. Percutaneous LVADs can be placed prophylactically before high-risk PCI or as rescue therapy in setting of periprocedural emergencies such as coronary dissection or cardiogenic shock. These MCS devices can be removed after completion of the procedure or left in place as a bridge to a definitive cardiac surgical operation.It is important to note that these classifications are not fixed. A patient may receive MCS under one classification but changes in clinical status may modify that patient’s classification. For instance, a patient may receive an LVAD as BTT and then recover sufficient ventricular function such that the LVAD can be explanted, thus classifying MCS support as bridge-to-recovery. Similarly, a patient with a short-term MCS device as bridge-to-decision who undergoes heart transplantation could then be considered as having had MCS as BTT.MCS devices can be classified and categorized by four factors: duration of support (short-term vs long-term), configuration of ventricular assist (biventricular vs univentricular), pump flow pattern (pulsatile vs continuous-flow), and location of implantation .MCS is considered short-term when the duration of support is on the order of days to weeks. Currently available devices are listed in A recent addition to the armamentarium of short-term MCS options is the CentriMag . This device is an extracorporeal, continuous centrifugal-flow pump with a magnetically levitated rotor and external controller. The CentriMag is capable of uni- or bi- ventricular support with flows up to 10 L/min ,8. One oTwo percutaneous devices are currently available for short-term MCS. The TandemHeart  is a continuous-flow centrifugal pump with an external controller capable of flow rates up to 5 L/min. This device is placed in the cardiac catheterization laboratory with transseptal left atrial inflow via percutaneous femoral venous access and outflow through contralateral femoral arterial access. Though initially designed to provide temporary support for patients undergoing high-risk percutaneous cardiac interventions, the TandemHeart has also proven its utility in postcardiotomy heart failure and cardiogenic shock. Several studies have shown improvements in hemodynamic parameters and cardiac indices with TandemHeart support in bridge-to-recovery and bridge-to-decision settings ,15. The The Abiomed Impella (ABIOMED Inc) is another percutaneous short-term MCS option. This device is a continuous-flow, axial pump with an external controller. There are two models, the Impella 2.5 and the Impella 5.0, with the number designating the maximal flow rate delivered: the Impella 2.5 can deliver up to 2.5 L/min and the 5.0 up to 5.0 L/min. The device is designed to rest across the aortic valve and pump blood from the left ventricle directly into the ascending aorta. The Impella 2.5 can be inserted percutaneously via the femoral vessels in the cardiac catheterization laboratory. In a randomized clinical trial comparing the Impella to IABP counterpulsation, the Impella demonstrated superior hemodynamic support but 30-day mortality was similar in the two groups . One limThe obvious advantage of percutaneous devices is implantation performed without the need for surgery. Moreover, the insertion of percutaneous devices generally is technically less difficult and thus can be performed more expeditiously, which can prove extraordinarily beneficial in the acute setting.The early design of long-term MCS devices featured pulsatile pump technology because pulsatility was believed to be necessary for organ perfusion and recovery. These early devices contained valves to allow for unidirectional blood flow and ventricular sacs that could produce a stroke volume of 65-85 mL. Because of the complexity and number of mechanical parts, physical wear and tear of the device became a limiting factor in device durability -19. Subs2, thus excluding most children and small adults. The pump receives power from an external power source via a driveline that enters the body through the right side of the abdomen. The HeartMate XVE is constructed with textured blood-contacting surfaces that become covered by a “pseudoneointimal” layer, eliminating the need for systemic anticoagulation. The HeartMate XVE is the only pump to date with this property, thus making this device particularly attractive for patients with a contraindication to systemic anticoagulation (The Thoratec HeartMate XVE (Thoratec Corp) and Novacor LVAD system  were among the earliest implantable VADs. The HeartMate XVE quickly became the first widely utilized LVAD worldwide. It is powered by an electrically driven pulsatile pump capable of generating up to 10 L/min of flow. It contains porcine valves in the inflow and outflow conduits to maintain unidirectional flow. The inflow cannula is attached to the LV apex, the outflow cannula to the ascending aorta, and the device itself is implanted behind the rectus sheath in the subcostal region or in the peritoneal cavity. The size of the device requires that the patient’s body surface area (BSA) be greater than 1.8 mgulation .The HeartMate XVE was the first VAD to demonstrate MCS as a viable option for use as DT. In 2001, the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial randomized 129 patients with end-stage heart failure who were not candidates for cardiac transplantation to receive either optimal medical management or implantation of the HeartMate XVE . SurvivaOther examples of first generation devices include the Abiomed AB5000, the Thoratec Paracorporeal Ventricular Assist Device (PVAD) II (Thoratec Corp), and the Thoratec Implantable Ventricular Assist Device (IVAD). All are pulsatile pumps capable of bi- or uni- ventricular support. The Thoratec PVAD has been in clinical use for over 20 years and has the additional benefit of allowing patients to be discharged home with the device in place. In one series, 47% of patients supported with a PVAD survived to discharge while 68% underwent heart transplantation . The Tho2) than the XVE. As with all continuous flow devices, patients with the HMII do not have a palpable pulse. Some limitations of this type of device are hemolysis, ventricular suction events, and thrombus formation with pump stoppage (The Thoratec HeartMate II (HMII) is a second generation LVAD that received FDA approval in 2008 for BTT use. It is the most widely implanted LVAD to date with over 10 000 patients worldwide. The HMII is composed of an electrically powered rotary continuous flow pump, where the only moving part is the axial rotor. This imparts tangential velocity and kinetic energy to the blood, resulting in generation of a net pressure rise across the pump. Power is supplied by an external source that connects via a percutaneous driveline usually from the right side of the abdomen. The pump can generate flow rates of up to 10 L/min and is preload dependent and afterload sensitive. Like the HeartMate XVE, the HMII has the inflow cannula connected to the LV apex and the outflow cannula to the ascending aorta. The HMII is also implanted in a preperitoneal pocket in the left subcostal space, but its smaller size allows it to be used in smaller patients , Jarvik 2000 FlowMaker, and the HeartWare  left ventricular assist system (LVAS). The HeartAssist 5 is a small version of the Micromed DeBakey pump that can be implanted within the pericardial space. The Jarvik 2000 FlowMaker is also implanted in the pericardial space directly into the LV apex with an outflow attachment to the ascending or descending aorta. This portable device is capable of providing partial support with flow rates up to 7 L/min and allows the patient to manually adjust the pump speed depending on activity level. One key advantage of the Jarvik 2000 is its small size: it is about the size of a C battery, significantly smaller than the Thoratec HMII. The Jarvik 2000 is currently in clinical trials and awaiting FDA approval.The HeartWare LVAS has a unique design that combines magnetic levitation and hydrodynamic suspension that eliminates any contact between the impellar and pump housing. It is implanted intrapericardially with LV apical inflow and outflow to the ascending aorta. The HeartWare LVAS operates at a fixed pump speed and is capable of producing flow rates of 10 L/min. This device was studied in a BTT trial (ADVANCE) in the United States from 2008 to 2010 . 140 patThird generation of devices are centrifugal continuous-flow pumps with an impeller or rotor suspended in the blood flow path using either magnetic or hydrodynamic levitation. This eliminates component-to-component contact, thus reducing frictional wear and heat generation and theoretically increasing device durability and reliability. The magnetic levitation systems are one of three types: external motor-driven, direct-drive motor-driven, or bearingless motor. Third-generation LVADs are more widely used in Europe, where they reportedly comprise nearly 50% market share . InitialExamples of third generation devices include the Terumo DuraHeart  and Thoratec HeartMate III. The Terumo DuraHeart is commercially available in Europe and is undergoing clinical trials in the United States. The device is a centrifugal continuous flow pump that is implanted in a preperitoneal pocket and is capable of flow rates up to 8 L/min. Six and twelve month survival in a European BTT trial was 81% and 77%, respectively, with no pump failure or thrombosis during an average support duration of eight months. The most common adverse events were neurological complications (27%), right heart failure (27%), and infection (18%) . The ThoThe quest for a TAH began with the advent of MCS devices. Conceptually, the TAH is quite attractive as it offers the ability to replace the entire failing heart. The successful design and implementation of a TAH in clinical practice, however, has been much more elusive. Furthermore, the rapid expansion of VAD technology has overshadowed TAH development. As a result, the majority of patients with advanced heart failure can be successfully managed with an LVAD or BIVAD and the necessity of a TAH is debatable. The current indications for a TAH are limited and include severe bi-ventricular failure, myocardial rupture, post-transplant rejection, LV thrombus, restrictive cardiomyopathy (amyloidosis and hypertrophic cardiomyopathy), and refractory ventricular dysrhythmia.2 , a pneumatically powered pulsatile dual chamber device. Two percutaneous drivelines connect the TAH to an external power source. The patient must remain in hospital, although the recent development of a portable wearable power source, the Freedom Driver, may ultimately permit discharge to home. The Freedom Driver allows considerably greater mobility and is currently undergoing trials. The design of the CardioWest device consists of four prosthetic tilting disk valves and two 70 cc pumping chambers that can produce flow rates up to 9.5 L/min. The relatively large size of the device requires a minimal body surface area of 1.7 m2 ,38. Ther2 . SurvivaThe Abiomed TAH (ABIOMED Inc) is available in the United States under an FDA humanitarian device exemption. This TAH is a completely implantable titanium and plastic dual chamber pump utilizing an electrohydraulic mechanism to alternate ejection between the two chambers. Because the entire device is intracorporeal, there is no external driveline. Implantation of the Abiomed TAH began in 2001 under an FDA investigational device exemption. A total of 14 patients received the device with the longest duration of support being 512 days .There have been remarkable advancements in MCS options since the first days of cardiopulmonary support. Landmark trials such as REMATCH firmly established MCS as a viable, effective treatment strategy for advanced heart failure. With MCS, patients with end stage heart disease, regardless of transplant eligibility, are now living longer than ever with improved quality of life. Collaborative database registries such as INTERMACS provide contemporary, real-time data to assist in the optimization of risk stratification and patient selection. Evolution of device design will hopefully continue to decrease complications and result in smaller, portable, and more durable device options.


Patients receiving anthracyclines (A) and herceptin (H) for treatment of breast cancer require serial monitoring of LV function. Although CMR is considered the gold standard for assessment of volumes and function, most tertiary institutions rely on echocardiography or gated heart pool scans. 2D transthoracic echocardiographic (TTE) image quality relies on appropriate acoustic windows, and accuracy and reproducibility may be particularly limited in this population due to mastectomy and scar. We sought to assess the utility of TTE (LVEF and GLS) compared to CMR in the diagnosis of Stage B heart failure  in breaIn total, 44 patients (30 receiving A and 14 receiving T) underwent cardiac magnetic resonance (CMR) for LV function and advanced 2D echocardiography for LV function and global longitudinal strain (GLS) at 3 time-points . We defined stage B heart failure as LVEF < 10% from baseline, and/or LVEF below 55% and/or GLS < -19.7[CMR cine assessment of LV function was performed in all 44 patients (100%). Thirty percent (13/44) could not have accurate echocardiographic EF assessment performed at 1 or more time points. Early LV dysfunction was detected by CMR following commencement of chemotherapy (table). There was poor correlation between CMR LVEF and echocardiography EF (graph) with wide limits of agreement (-23.526 to 13.015%). At 12 months, 8 patients (18%) demonstrated stage B heart failure, however none were below the lower limits of normal (>55%). None of these showed a significant change in TTE EF, however 2 of these patients had GLS < 19.7 at 12 months.A significant number (approx. 1/3) of breast cancer patients are unable to have adequate LV function assessment by echocardiography. Subtle LV dysfunction may be a precursor to overt cardiomyopathy and is currently not adequately diagnosed by echocardiography even with inclusion of 2D global longitudinal strain. Serial monitoring of LV function using a non-radiation imaging technique is best performed by CMR.None.


Neoadjuvant therapy for cancer of the esophagus or gastroesophageal (GE)-junction is well established. The pros and cons of chemoradiotherapy and chemotherapy are debated. Chemoradiotherapy might impair cardiac function eliciting postoperative morbidity. The aim of this pilot study was to describe acute changes in left ventricular function following chemoradiotherapy or chemotherapy.Patients with esophageal and (GE)-junction cancer enrolled at our center into a multicenter trial comparing neoadjuvant chemoradiotherapy and chemotherapy were eligible. Patients were randomized to receive cisplatin and 5-fluorouracil with or without the addition of 40 Gy radiotherapy prior to surgery. Left ventricular function was evaluated using echocardiography and plasma N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) before and after neoadjuvant treatment. The primary outcome measure was left ventricular global strain (GS). Clinical effects were assessed using repeated exercise tests. Linear mixed models were used to analyze the effects of treatment group, and the interaction between groups.40 patients participated . In the chemoradiotherapy group there was no change in left ventricular global strain but mitral annular plane systolic excursion (MAPSE) of the ventricular septum, early diastolic filling velocity (E-velocity), and the ratio of early to late ventricular filling velocities (E/A ratio) decreased significantly . No changes were observed in the chemotherapy group. There was a trend towards an interaction effect for MAPSE sept and E (p = 0.09 and p = 0.09). NT-proBNP increased following chemoradiotherapy (p = 0.05) but not after chemotherapy (p > 0.99), and there was a trend towards an interaction effect (p = 0.07). Working capacity decreased following neoadjuvant treatment  and was more pronounced after chemoradiotherapy with a trend towards an interaction effect (p = 0.10).Neoadjuvant chemoradiotherapy but not chemotherapy before surgery for cancer of the esophagus or GE-junction seems to induce an acute negative effect on both systolic and diastolic left ventricular function. Future studies on neoadjuvant treatment for esophageal cancer are suggested to add measurements of cardiac function.NCT01362127.Clinical Trials.gov The online version of this article (doi:10.1186/s13014-014-0310-7) contains supplementary material, which is available to authorized users. Neoadjuvant therapy has improved long-term survival after esophagectomy for cancer of the esophagus or gastroesophageal- (GE) junction even though long-term results are still poor . CurrentRadiation therapy directed towards a tumor in the esophagus or GE-junction will inevitably irradiate the heart. Long-term side effects of modern thoracic radiotherapy include coronary artery disease and heart failure , but litThe aim of this pilot study was to describe possible acute effects of neoadjuvant therapy on left ventricular function using echocardiography and NT-proBNP in patients with cancer of the esophagus or GE-junction. The primary outcome variable was global systolic left ventricular function measured as global strain (GS). The secondary outcome variables were ejection fraction (EF), regional systolic left ventricular function, diastolic function and NT-proBNP. In addition, general physical capacity was measured using repeated exercise test.A multicenter randomized trial of neoadjuvant chemoradiotherapy versus chemotherapy for cancer in the esophagus or GE-junction was conducted between 2006 and 2013 in Sweden and Norway . The primary endpoint was the rate of complete histological response in the surgical specimen, which is a surrogate marker of improved long-term survival. The study was designed to include 180 patients based on a power calculation suggesting a sample size of 172 patients to achieve the primary endpoint assuming an increase in rate of complete histological response from 20% to 35% with a power of 80%. Inclusion criteria were age 75 years or less, histologically verified squamous cell carcinoma or adenocarcinoma of the esophagus or GE-junction, tumor stage T1-3 and N0-1 (according to AJCC TNM staging system 6th edition) [The data presented here originate from a cohort of patients within the NeoRes trial scheduled for surgery at the Karolinska University Hospital. Patients underwent an extended protocol with studies of heart function which started in 2008. Added inclusion criteria were planned thoracoabdominal surgery. The NeoRes study protocol was approved by the regional ethics committee (EPN Stockholm 2006/738-32) and was registered at the registration site of the US National Institute of Health . For the extended protocol additional ethics approval was obtained (amendment 2008/1822-32). All patients were given written and oral information and were included after a signed informed consent had been obtained.2 was given on day 1 and 5-fluorouracil 750 mg/m2/24 hrs was given on days 1–5. Cisplatin was switched to carboplatin or oxaliplatin in case of hearing impairment or renal dysfunction. Dose reduction was allowed for side effects. In the chemoradiotherapy group, concomitant radiotherapy was administered during cycles two and three with a total dose of 40 Gy; 2 Gy/day, 5 fractions per week. Radiotherapy was planned using a computer tomography-based three-dimensional treatment planning system . Treatment was administered using a multiple field technique with optimization of beam entry direction and beam weights in order to achieve a homogenous dose to planning target volume and minimize dose to organs at risk. Field shaping using a multi leaf collimator was used. For tumours located at or above the level of carina, the caudal border of the clinical target volume was 5 cm below diagnosed tumour, whereas the supraclavicular nodes defined the cranial border. For tumours located below the carina, the cranial border of the clinical target volume included 5 cm of radiographically uninvolved esophagus while the coeliac lymph nodes defined the caudal border, down to upper part of L1. In lateral, anterior and posterior directions clinical target volume encompassed gross tumour volume and the paraesophageal area with a margin of 1 cm but not including anatomical barriers as pleura, pericardium or bone. Dose–volume data of the heart including the pericardium with exclusion of the great vessels were extracted from individual dose distribution data in the treatment planning system. Planning target volume receiving >95% of planned radiation dose (PTV > 95%) all well as planning target volume receiving 95–105% of planned dose (PTV 95–105%) was measured. The percentage of the heart volume receiving 10 Gy or more (V10) and 30 Gy or more (V30) was measured. V30 was minimized as much as possible according to protocol. Surgery was scheduled 4–6 weeks after completion of neoadjuvant treatment.Chemotherapy was given in three cycles of 21 days. Cisplatin 100 mg/mStrain is a validated, relatively new, echocardiographic parameter for assessment of left ventricular function -21. StraEchocardiography was performed before start of neoadjuvant therapy and repeated 4–6 weeks after completion of neoadjuvant therapy. A Vivid 7 ultrasound scanner  and a standard 2.5 MHz transducer were used. All but three exams were performed by the same laboratory technician according to research protocol. Post processing analysis was performed by a single analyser, ML, using Echo PAC  according to the manufacturer’s instructions. Both the echocardiography examiner and interpreter were blinded to study group allocation. All exams were interpreted after inclusion was closed.A standard cardiac exam was performed on all subjects. One or more loops of three heartbeats were recorded online for each view and the best cardiac cycle selected for analysis during post processing. EF was calculated according to Simpson biplane. Mitral inflow was measured using pulsed wave Doppler. Peak velocity in the early rapid filling phase when the ventricle relaxes (E-Wave) and peak velocity of the late filling due to atrial contraction (A-Wave) were measured by pulsed Doppler across the mitral valve during diastole. Strain was measured using tissue tracing analysis in the apical four-chamber view centred on the left ventricle. For GS analysis a single cycle was used and all analyzed segments were approved by the program as well as by the analyzer. Tissue Doppler-based tissue tracing was used to measure atrio-ventricular plane movement. Mitral annular plane systolic excursion (MAPSE) was measured as the median value of three heart cycles using a region of interest (ROI) of 6×6 mm in the basal septum (sept) and basal anterolateral (lat) wall Figure . PictureVenous blood was collected in EDTA tubes before neoadjuvant treatment and on admission for surgery 4–6 weeks after neoadjuvant therapy. Electrochemiluminescence immunoassay with Modular Analytics E170  was used for the analyses, which were all performed by the Karolinska University Hospital accredited laboratory for clinical chemistry.Exercise tests of maximum work capacity measured in Watts were completed on a bicycle ergometer under the supervision of a dedicated staff member of an accredited physiology department. Maximum capacity was determined when patients were unable to maintain 60 revolutions per minute due to either, fatigue, shortness of breath or chest pain. The test could also be stopped by the staff due to the occurrence of arrhythmias, electrocardiogram changes or pathological blood pressure reactions. Testing was performed either at Karolinska University Hospital or at the patient’s referring hospital.Data were analyzed as intention to treat using a linear mixed model analysis for repeated measures data. The model was used to analyze the effects of within-group change and the interaction between groups. This was defined as the basic model. In addition to the basic model, the influence of different covariates and factors was analyzed. The group effect was the difference between radiotherapy and chemotherapy, and the trend effect was the change between the first measure and the second measure. The within-group change was the difference between the first and second measure in respective groups. The interaction effect was the difference in change between groups. The covariance structure used in the models was unstructured. Before performing analyses, tests of normal distribution were performed and log transformation was performed for non-parametric data. Due to the small data set, several mixed models analyses were performed and in each analysis one of a set of covariates was added to the basic model to test for any impact on the results. The set of covariates was gender, age, BMI, ASA classification, hypertension, ischemic heart disease, smoking, chronic obstructive pulmonary disease, anemia, diabetes, and alcohol abuse. The Bonferroni correction was used to account for multiple comparisons. Patient characteristics are presented as median (range) and data regarding heart function as mean . Subject characteristics were analyzed using 2-tailed Mann Whitney U test and 2-tailed Fisher’s exact test as appropriate.A total of 40 patients participated in the study Figure . There wEchocardiographic parameters were similar between groups before the start of neoadjuvant treatment. The neoadjuvant treatment induced no change in GS or EF in either of the groups Table . MAPSE sAfter neoadjuvant treatment we observed a significant increase of NT-proBNP in the chemoradiotherapy group , but no significant change after chemotherapy  and a trend towards an interaction effect (p = 0.07) . This decrease was more pronounced in the chemoradiotherapy group  but the interaction effect did not reach significance (p = 0.10) , coupled with an unchanged blood flow during atrial contraction (A) and accordingly a decreased E/A. These data suggest an impaired diastolic function as a consequence of impaired relaxation of the left ventricle. Hatakenaka and coworkers also reported an impairment of left ventricular relaxation after radiotherapy .Neoadjuvant chemoradiotherapy also increased NT-proBNP. This biomarker has been studied as a predictor for the risk of perioperative cardiac complications with cutoff values between 201–791 ηg/ml being suggested ,29. Pre We were unable to demonstrate a dose–response relationship between V30 and the echocardiographic changes or NT-proBNP levels. This may be due to the small number of patients enrolled but also dependent on the fact that V30 reflects the radiation dose targeting the whole heart rather than different segments. We refrained from doing a segmental analysis since this would require a larger dataset.The clinical relevance of our findings is unclear. The level of systolic impairment detected was small and probably not clinically significant in a patient with an otherwise well-functioning left ventricle. Diastolic changes were larger with mean E/A levels after neoadjuvant therapy reaching grade I diastolic dysfunction which could have clinical implications. NT-proBNP levels increased following chemoradiotherapy and might indicate an increased risk for postoperative cardiac events and atrial fibrillation. This also shows that repeated NT-proBNP measurements could be a simple method to describe impairment from neoadjuvant treatment in future studies. Preoperative working capacity, as assessed during an exercise test, trajects into perioperative risks after esophagectomy ,32. We aCisplatin and 5-fluorouracil are commonly used drugs in chemotherapy regimens for esophageal cancer. These drugs are known to be associated with cardiotoxic side effects . TherefoThe question whether neoadjuvant chemoradiotherapy is associated with an increased risk of postoperative morbidity compared with chemotherapy remains unresolved ,7. Only Impaired left ventricular systolic and diastolic function following neoadjuvant chemoradiotherapy could well have a bearing on the incidence and grade of the innately high postoperative cardiovascular and pulmonary morbidity after esophagectomy. Taken together our data emphasize the relevance of dedicated studies aimed at further clarifying the details and consequences of the cardiotoxicity of current chemoradiotherapy regimens. One pathway that needs to be explored is cardiovascular function during the perioperative period.One important limitation of our study is the small sample size, where the cases represented a cohort of patients consecutively enrolled from a larger, multicenter, randomized study. Two issues emerge as a consequence of this: the power of the observations and the possibility of selection bias. It should however, be emphasized that Karolinska University Hospital was the largest including center and the patients in our cohort represent 23% of the total study population. The randomization was not stratified to each center which may explain the small difference in the size of the treatment groups. There were no statistical differences in comorbidities between the study groups and the subsequent analysis of the effects of comorbidities in the linear mixed models did not display any significant impact on the results. Work capacity was also similar between the groups before neoadjuvant treatment suggesting comparable patients groups.The second limitation, which we tried to confront, was the missing values within our cohort. The design of the present clinical study was very complex in a logistic perspective, in that we were faced with a short timeframe during which we had to plan and complete the echocardiographic examinations, i.e. from the randomization to the start of neoadjuvant treatment. During this limited time frame several other investigations and procedures  had to be performed, usually at other hospitals. In addition, we chose to concentrate the echocardiography investigations at the tertiary referral center to increase the validity of the echocardiography. In order to partially compensate for the impact of missing data we adopted a linear mixed model statistics where the patients were analyzed as intention to treat. Linear mixed models give the opportunity to analyze all available data and not having to exclude cases where the dataset is incomplete. It also gives the option to correct for co-variables and is not restricted to a spherical or compound symmetry where we rely on the assumption that data are missing at random. By doing this we were able to mitigate some of the impact of missing data and further explore how patient comorbidity affected the results. No effect was found.Neoadjuvant chemoradiotherapy seems to induce a slight acute impairment of both systolic and diastolic left ventricle function, whereas chemotherapy does not. The systolic impairment was small and probably not clinically significant in a patient with an otherwise well-functioning left ventricle. The change in diastolic function was larger and might have clinical implications. These effects of chemoradiotherapy may enhance the risk of postoperative morbidity and should be taken into clinical consideration in patients with cardiac comorbidity. Corresponding and related effects on the heart need to be further explored in future studies of neoadjuvant chemoradiotherapy for cancer of the esophagus and GE-junction.


Idiopathic hypereosinophilic syndrome (IHES) is a rare disease that is frequently associated with cardiac thrombosis and endocardial wall thickness.This case report describes 2 patients who had IHES associated with left ventricular (LV) thrombi. The patients’ symptoms are atypical. Peripheral blood and bone marrow tests showed markedly elevated eosinophils. Electrocardiography showed ischemic changes in both patients. Negative computed tomography (CT) angiography excluded coronary artery stenosis. Transthoracic echocardiography (TTE), conventional multislice spiral CT, gemstone spectral CT, and cardiac magnetic resonance imaging were used to identify the LV intraluminal thrombus and endocardial thickening, and the diagnostic values of each imaging method were analyzed and compared.These patients were clinically diagnosed as “IHES, LV thrombosis, NYHA heart function classification I.”Both patients received oral prednisone and warfarin therapy.At 5 month follow-up, TTE rechecks showed that the size of the LV thrombotic lesion was reduced in the first case but substantially increased in the second case. There are currently several case reports on IHES that are associated with peripheral and cardiac thromboembolism.5 Here, we examine a different viewpoint from previous studies, and analyze and compare the characteristic manifestations and features of left ventricular (LV) intraluminal thrombus in patients with IHES based on transthoracic echocardiography (TTE), conventional multislice spiral computed tomography (MSCT), gemstone spectral computed tomography (CT), and cardiac magnetic resonance imaging (MRI) images.Idiopathic hypereosinophilic syndrome (IHES) is a rare clinical disease that has high morbidity and mortality due to its high tendency for hypercoagulation and associated thromboembolic complications in vital organs such as the heart, brain, lungs, and peripheral vessels.A 56-year-old man was admitted to our hospital on June 11, 2013 complaining of intermittent tightness in his chest, shortness of breath, and facial edema over the last 2 years, with acute exacerbation for 7 days. The patient had no history of smoking, drinking alcohol, or drug or food allergy. The patient did not receive any diagnosis and treatment before admission.On admission, his body temperature was 36.5°C and blood pressure was 104/60 mm Hg. The patient appeared chronically ill with slight cyanosis of the lips and facial swelling with no distention of the jugular veins, and no dry or moist lung rales were heard. The cardiac boundary was normal, and the patient’s heart rate was 72 beats/min with a regular rhythm; no murmur was noted in the auscultatory valve areas. No liver and spleen enlargement or edema was noted in the lower extremities.9/L with 70.8% eosinophils at the absolute count of 17.1 × 109/L. Bone marrow aspiration results showed 0.5% promyelocytes, 2.5% eosinophilic myelocytes, 10% eosinophilic metamyelocytes, 19% eosinophilic stab granulocytes, and 40% eosinophilic segmented granulocytes. No abnormality was found in urine, coagulation routine, liver and renal function, blood lipids, glucose, and electrolytes. The patient was negative for antibodies to hepatitis virus, Treponema pallidum, and human immunodeficiency virus (HIV). Tests for parasites, immunoglobulin, antinuclear antibody series, rheumatic factors, and complement revealed no abnormalities. Ultrasound examination of the liver, gallbladder, pancreas, spleen, and bilateral kidneys showed no abnormalities. Chest CT revealed interstitial pneumonia in bilateral lungs. Electrocardiography (ECG) showed ST-segment depression of approximately 0.1 mV in leads V3–V6 with inverted T waves in leads II, III, avF, and V3–V6  and T2-weighted imaging (T2WI) were performed using black-blood turbo spin echo (TSE) sequence. Both T1WI and T2WI images clearly showed the focal endocardial thickening at the LV apex, and the T2WI image also revealed focal heterogeneous high-density signals in the myocardium at the LV apex, highly suggestive of local active inflammatory edema  with breath-hold, retrospective ECG gating, and bright-blood true fast imaging with steady-state precession (True FISP) sequences. Tagging cine-MRI was performed using grid-tagged sequences, provided by the preinstalled “dot” program of Siemens . In addition, T1-weighted imaging . TTE showed normal chamber sizes, and a cap-shaped echo of mural thrombus that measured 37.5 × 27.1 mm was observed at the apex and middle part of the LV cavity; it was closely attached to the ventricular wall  mode of the Discovery CT750 HD CT scanner  with Iopromide  as the contrast agent. The scanning parameters were as follows: helical scanning speed of the x-ray tube, 0.6 s/r; pitch, 0.969; detector width, 4.0 cm; instantaneous voltage switch (0.5 ms) between high and low energy (140 and 80 kVp); and tube current, 600 mA. In the GSI mode, iodine and blood were chosen as the base material pair. In the images of iodine-based density, the normal LV cavity filled with the contrast agent was displayed as high-brightness signals whereas the LV thrombus was manifest as filling defects. In the images of blood-based density, the LV thrombus signal intensity was similar to that of normal LV cavity filled with blood, both displaying relatively high-brightness gray shadows  dysfunction because of the thickened endocardium.10 In case 1, a conventional nonspectral MSCT scan clearly visualized the thrombus-induced filling defects in terms of morphology, location, and size, but this approach could not either make a qualitative diagnosis based on the thrombus tissue composition, or accurately differentiate the thrombotic lesion from normal papillary muscles, which was also manifest as a low-density shadow on routine MSCT images. In case 2, the newly developed gemstone spectral CT was used with iodine and blood as the chosen base material pair.12 Single material images of iodine- and blood-based density were generated, based on the unique dual material spectral CT separation technique.14 In the isolated iodine-based density image, the LV thrombus presented as low-density shadows or filling defects, because of a lack of blood supply and thus the contrast agent (iodine) hardly reached the lesion central area of the thrombus. On the other hand, in the isolated blood-based density image, the LV thrombus and normal LV cavity presented with similar high-brightness signal intensities, probably due to the similar composition of thrombus and blood in the LV cavity (both contain blood components such as platelets and erythrocytes). Our recent study  also found that the dual material spectral CT separation technique described above is useful for differentiating between the normal LV papillary muscles and thrombotic lesions. Our study showed that the normal papillary muscles presented as a similar low-density shadow or filling defect as the thrombotic lesion in the iodine-based density images, due to a lack of blood supply. However, because its composition is different from blood and the thrombus, papillary muscle presents as a low-density shadow in blood-based density images, whereas both the LV cavity and thrombotic lesion showed similar high-brightness gray shadows. Our limited case report presented in this article may not be sufficient for discussing spectral CT utility; of course, these findings need further validation through clinical practice.In this article, both patients have symptoms such as shortness of breath or chest pain. ECG showed characteristic ischemic changes, and myocardial injury markers elevated in the second patient. Both patients were initially suspected of having “acute coronary syndrome,” but the negative CT angiogram excluded coronary artery stenosis. Although clearly showing the 3D coronary arteries, cardiac CT imaging is also capable of showing the low-density shadows or filling defects caused by thrombotic lesions.To further define the nature, location, extent, and severity of the heart involvement and obtain information such as cardiac function and myocardial motion, both patients underwent cardiac cine-MRI scans using the bright-blood True FISP sequence. In both cases, single-slice cine images demonstrated extremely high tissue resolution, evidenced by the different MRI signals obtained from the LV thrombus, normal LV cavity, and thrombus-attached endocardium, thereby facilitating the correct measurement of thrombus size and assessment of attached endocardial thickness.15 However, a distinct plane between the thrombus and its adjacent endocardium should exist for the thrombus to be removed. Due to MRI’s high tissue resolution, it is of great value for preoperative therapeutic decision-making and selection of operative strategies.16 Cardiac MRI examination has another distinct advantage because it uses bright-blood sequences for cine imaging that do not require injected contrast agent. Additionally, we found that TSE T2WI imaging is sensitive for the detection of inflammatory edema, and the grid-tagged cine-MRI is beneficial for the assessment of myocardial motion dysfunctions.In clinical practice, an intracardiac thrombus can be removed by surgical resection.4 Although images using edema-specific TSE T2WI sequences provide information on active myocardial edema, the existing imaging results in this article did not reveal sufficient information for myocardial necrosis and fibrosis. Iodine-enhanced delayed myocardial perfusion spectral CT imaging may be helpful.10 However, both our patients required 3D CT angiography; this scan was obtained in a few seconds after the concentration of the contrast agent (iodine) reached a peak level at the aortic root, and double cardiac CT scans exposed the patients to excessive radiation. Thus, this approach was not used for patients. In addition, delayed gadolinium-enhanced myocardial perfusion MRI is of great value for identifying and evaluating thrombi, necrosis, and fibrotic scars.18 Although these procedures were not performed for these patients, they are worthy of further study in the future.For IHES patients who have heart involvement, correct evaluation of the scope and extent of myocardial necrosis and fibrosis is of great importance for disease staging, guiding patient treatment and estimating prognosis.19 At 5 month follow-up, the size of LV thrombus was reduced in the first case, but substantially increased in the second case. Cytotoxic agents such as hydroxyurea and α-interferon may be needed for these patients, and surgical thrombectomy and endocardial resection may be the options.19Glucocorticoids and warfarin are the first-line drugs for IHES associated with cardiac thrombosis.10 our study demonstrated that timely, accurate, and valuable diagnosis of cardiac thrombosis associated with IHES can be made based on imaging tools such as TTE, gemstone spectral CT, and MRI, in combination with clinical manifestations and laboratory test results. TTE is not capable of detecting coronary artery stenosis, and because of its low tissue resolution, it cannot provide sufficient and comprehensive information for associated cardiac lesions with IHES. Cardiac MSCT has a unique advantage for 3D coronary angiography, and the newly developed gemstone spectral CT may play a critical role in qualitative and differential diagnosis of cardiac thrombus components. Compared with other methods, cardiac MRI with its high tissue resolution is valuable for lesion assessment and therapeutic guidance. Finally, we conclude that for IHES patients with suspected cardiac involvement, a combination of imaging methods such as TTE, spectral CT, and MRI provides accurate, comprehensive, and valuable information for disease diagnosis, treatment guidance, and prognostic evaluation, which requires further clinical research, application, and promotion.In summary, although endomyocardial biopsy is the gold standard for diagnosis of cardiac attacks associated with IHES,Ethical approval was obtained from the ethics committee of the China-Japan Union Hospital of Jilin University. Written informed consent was obtained from both the patients for publication of this case report and any accompanying images.


In both ischemic (ICM) and non-ischemic (NICM) cardiomyopathy late gadolinium enhancement (LGE) is an important cardiovascular magnetic resonance (CMR) technique. LGE CMR, traditionally performed in 2D during multiple breath-holds (MB), is challenging for vulnerable patients and subject to slice misregistration. Therefore, LGE CMR during free-breathing (FB) is more robust and enables to perform 3D acquisition, increase resolution and apply phase-sensitive inversion recovery (PSIR). We developed and clinically tested a high spatial resolution PSIR LGE sequence using a respiratory navigator in both ICM and NICM patients. Reliability and image quality were compared to a multiple breath-hold 3D approach (MB-3D).Approval was waived by the institutional ethical committee. Between May 2012 and November 2013 FB-3D and MB-3D sequences were acquired in patients suspected of ICM and NICM. Data of 48 patients  were retrospectively collected. LGE sequences were acquired using a 3.0 Tesla MR system. For both FB-3D (1.68 x 1.68 x 3.4 mm) and MB-3D (1.86 x 2.8 x 10 mm) a PSIR sequence was used. Multiplanar reformats with high resolution  and low resolution  were constructed. LGE mass and image quality  were compared using the Friedman test, Wilcoxon signed rank test, spearman correlation and Bland-Altman analysis.34 ICM patients  and 14 NICM were included . In figures Free-breathing 3D phase-sensitive inversion recovery LGE CMR enables reliable myocardial scar tissue assessment with significantly improved image quality as compared with multiple breath-hold 3D imaging in ischemic and non-ischemic cardiomyopathy.No funding.


To report initial experience with TE-averaged susceptibility weighted imaging (SWI) in normal subjects and acute myocardial infarction (AMI) patients for the detection of intramyocardial hemorrhage (IMH).15 healthy control and 11 AMI subjects were studied at 1.5T before contrast agent administration with a dark blood double inversion recovery multiple spoiled gradient-echo sequence. Magnitude, susceptibility weighted and TE-averaged images were reconstructed from raw data. Contrast and signal-difference-to-noise were measured and compared between methods for IMH detection.There were six patients with microvascular obstruction (MVO) and four patients with IMH detected by TE-averaged SWI imaging. All patients with IMH on SWI scans had MVO on late gadolinium-enhanced (LGE) imaging. There was a three-fold increase in IMH contrast with SWI compared to magnitude images. IMH contrast decreased and signal-to-noise increased with increased TE averages.TE-averaged SWI imaging is a promising method for myocardial tissue characterization in the setting of AMI for the detection of IMH. Along with gray-scale colormap inversion, it combines not only magnitude and phase information, but also images across TEs to provide a single image sensitive to IMH with characteristics similar to LGE imaging. Magnetic resonance (MR) offers a noninvasive imaging modality with ongoing technical developments for the assessment of myocardial function, perfusion and tissue characterization –4. In thSusceptibility weighted imaging (SWI) ,45 uses In a recent publication , we showStudy data from a previous published report  which st2, slice thickness = 8 mm, velocity compensation in read and slice) was used for SWI imaging. Imaging was performed in mid-diastole using a prospectively gated segmented acquisition of k-space over 13 heartbeats with ECG gating using a signal from leads placed on the subject's chest. Raw k-space data were saved to the scanners hard disk and transferred to a personal computer for offline image reconstruction. A phase sensitive inversion recovery gradient-echo pulse sequence  was used for late gadolinium enhanced (LGE) infarct imaging , left circumflex coronary artery [n = 3] and right coronary artery [n = 5]. Peak cardiac serum biomarkers were Creatine Phosphokinase (CPK) (n = 10) = 1612.9 ± 813.5 (u/l), Creatine Kinase-MB (CK-MB) (n = 10) = 123.0 ± 95.7 (ng/ml), MB Relative Index (n = 10) = 7.3 ± 3.4 (%) and Troponin I (n = 8) = 25.4± 29.5 (ng/ml).Results from a representative AMI subject are given in Figs Quantitative results from ROI measurements displayed in There were six patients with microvascular obstruction and four patients with intramyocardial hemorrhage detected by TE-averaged SWI imaging. All patients with IMH on SWI scans had MVO on LGE scans. Results of IMH and MVO volume measurements are displayed in There was a no significant difference in segmental T2* between LGE absent (34.1 ± 0.7 ms) and LGE positive segments without IMH (T2* = 35.3 ± 1.2 ms). But both were significantly different with segments with IMH (T2* = 16.2 ± 3.3 ms) detected by TE-averaged SWI imaging (p<0.001), showing that TE-averaged SWI imaging is consistent with T2* calculations.This study has demonstrated the utility of SWI imaging for myocardial tissue characterization in the acute phase of myocardial infarction. SWI depicted myocardium in areas of MVO indicative of IMH. When compared to magnitude imaging, SWI provided incremental improvements in IMH contrast and TE-averaging provided incremental improvements in image SNR. Combined with grayscale colormap inversion, TE-averaged SWI imaging provided a high image contrast and SNR method for the depiction of IMH with characteristics similar to LGE infarct imaging.There are a number of MR methods for the detection of IMH with encouraging reports in the literature. T1 weighted imaging is sensitive not only to IMH  but alsoHigher main magnetic field strengths (3T or 7T) have the advantage of better susceptibility weighting, but may have more artifacts. Optimal field strength for IMH detection would have to be determined, but preliminary results obtained in this paper support the use of 1.5T SWI imaging for the detection of IMH. Gray scale inversion of SWI images yields positive contrast with bright injured myocardium and dark or nulled viable myocardium. Image contrast could improve adoption with bright IMH similar to infarcted myocardium in LGE imaging, but could also cause confusion between the two imaging techniques. Another advantage of this technique and motivation of this work is the combination of multiple (in this case 24) magnitude and phase images into a single image. Similar to T2* mapping. TE-averaged SWI imaging yields fewer images through image information combination to improve physician evaluation speed.The results of this study should be considered in light of some limitations. Limitations of this study include the small study size, predominantly male study population. Patients in this study were physiologically stable and without contraindication to MR imaging. The patient population must be considered when interpreting the data and may not be representative of a larger population. IMH was not seen in normal volunteers or in segments without LGE. This study has demonstrated the feasibility of IMH detection with TE-averaged SWI imaging, but future larger studies are needed to determine its widespread performance and accuracy across a wide range of infarct ages and types. Optimal imaging parameters for routine clinical imaging have not been determined in this study. The optimal longest TE, number of echo times as well as the necessity of velocity compensation in imaging myocardium should be further investigated. We did not investigate lower bandwidth acquisitions which would increase signal-to-noise at the expense of a longer sampling intervals during the cardiac cycle and hence did not determine the optimal bandwidth for cardiac SWI imaging. Semi-automated image analysis was used and manual drawing of endo- and epi-cardial borders as well as intensity threshold may be operator dependent.In conclusion, TE-averaged SWI imaging is a promising method for myocardial tissue characterization in the setting of AMI for the detection of IMH. Along with gray-scale inversion, it combines not only magnitude and phase information, but also images across several TEs to provide native images sensitive to IMH with characteristics similar to LGE imaging.


To assess the prognostic value of myocardial pre-contrast T1 and extracellular volume (ECV) in systemic amyloid light-chain (AL) amyloidosis using cardiovascular magnetic resonance (CMR) T1 mapping.i) and 15 min post-bolus (ECVb). Fifty-four healthy volunteers served as controls. Patients were followed up for a median duration of 23 months and survival analyses were performed. Mean ECVi was raised in amyloid (0.44 ± 0.12) as was ECVb (mean 0.44 ± 0.12) compared with healthy volunteers (0.25 ± 0.02), P < 0.001. Native pre-contrast T1 was raised in amyloid . All three correlated with pre-test probability of cardiac involvement, cardiac biomarkers, and systolic and diastolic dysfunction. During follow-up, 25 deaths occurred. An ECVi of >0.45 carried a hazard ratio (HR) for death of 3.84 [95% confidence interval (CI): 1.53–9.61], P = 0.004 and pre-contrast T1 of >1044 ms = HR 5.39 (95% CI: 1.24–23.4), P = 0.02. Extracellular volume after primed infusion and ECVb performed similarly. Isolated post-contrast T1 was non-predictive. In Cox regression models, ECVi was independently predictive of mortality  after adjusting for E:E′, ejection fraction, diastolic dysfunction grade, and NT-proBNP.One hundred patients underwent CMR and T1 mapping pre- and post-contrast. Myocardial ECV was calculated at contrast equilibrium  and pre-contrast T1 are biomarkers for cardiac AL amyloid and they predict mortality in systemic amyloidosis. See page 203 for the editorial comment on this article (doi:10.1093/eurheartj/ehu442)1Systemic amyloid light-chain (AL) amyloidosis is a multiorgan, infiltrative disorder caused by an underlying plasma cell dyscrasia and is characterized by tissue and organ amyloid deposition with interstitial expansion. Cardiac involvement is present in ∼50% of patients at presentation and is the principal driver of prognosis. Treatment comprises chemotherapy or autologous stem cell transplantation to suppress clonal light-chain production, which may retard disease progression or facilitate regression.2 but are influenced by renal impairment which is present in a quarter of patients at presentation. ECG criteria, low limb lead voltages,3 or fragmented QRS complexes4 are also predictive, but are confounded by pericardial effusions and conduction abnormalities. Echocardiographic parameters also predict outcome,7 but coexisting causes of left ventricular hypertrophy or diastolic impairment may affect interpretation.Current predictors of survival rely on measuring surrogate rather than direct markers of interstitial expansion. Concentration of the serum biomarkers NT-proBNP and Troponin T form the basis of the Mayo Staging classification8 Recently we have shown that pre-contrast, native myocardial T1 mapping correlates with cardiac disease burden and detects early disease.9 T1 mapping pre- and post-contrast can be used to derive the partition coefficient and, with the haematocrit, the myocardial extracellular volume (ECV)12 which is a direct measurement of myocardial interstitium and therefore likely a surrogate marker of amyloid burden.14 The ECV can also assess amyloid burden in other organs.15 Furthermore, in other cardiac diseases, myocardial ECV predicts outcome.16Cardiovascular magnetic resonance (CMR) using the late-gadolinium enhancement (LGE) technique adds value in the diagnosis of cardiac involvement in AL amyloidosis. Altered gadolinium kinetics also shows some correlation with survival.10 or sufficiently through delayed study following administration of a bolus of gadolinium. Both techniques measure ECV the same where the ECVs are typically 0.4 or less, but one paper has shown a bias towards over-estimation of the true ECV in high ECV conditions (including n = 20 amyloid patients).17Technically, measurement of the ECV requires equilibration of contrast concentrations between blood and myocardium, which can be achieved precisely using a somewhat cumbersome primed contrast infusion,i); pre-contrast T1; bolus-only ECV (ECVb); and post-contrast T1.We hypothesized firstly that the myocardial ECV and pre-contrast T1 would correlate with disease burden in cardiac AL amyloidosis as assessed by current measures. Additionally, we tested the ability of both biomarkers as predictors of survival in AL amyloidosis by comparing the predictive power of: ECV after primed infusion  and in whom there were no contraindications to CMR (presence of non-MR compatible devices) or contrast administration (GFR < 30 mLs/min) or potential confounders to T1 measurement  were recruited. These 100 patients include all 60 patients studied previously in the baseline study.All patients had histological proof of systemic AL amyloidosis except 2 (2%), who died before biopsy could be undertaken, but in whom monoclonal gammopathies were present and the organ distribution of amyloid on SAP scintigraphy was characteristic of AL type. Histology was performed with Congo red followed by immunohistochemical staining; tissues examined were: kidney (26%), endomyocardium (7%), bone marrow (13%), upper gastrointestinal tract (7%), liver (3%), fat (15%), spleen (1%), lung (1%), rectum (9%), soft tissues , lymph node (3%), and peritoneum (1%).18 Echocardiographic assessment of diastolic function was performed using the E:E′ ratio. Where transmitral E-wave deceleration time and isovolumetric relaxation time were available, a diastolic dysfunction grade of 0–3 was assigned according to established British Society of Echocardiography (BSE) criteria.All patients underwent 12 lead ECG, assays of the cardiac biomarkers NT-proBNP and Troponin T, and echocardiography at baseline. Mean ECG QRS voltage in limb and praecordial leads were calculated.19 pre- and post-contrast (0.1 mmol/kg bolus and 0.0011 mmol/kg/min infusion of Dotarem™) as part of the Equilibrium CMR (EQ-CMR) technique, the post-contrast T1 map being performed at 15 min and after equilibration (mean time from bolus 45 min), as previously described.10All additionally underwent conventional CMR on a 1.5 T magnet . T1 mapping was performed using the Shortened Modified Look Lockers Inversion (ShMOLLI) recovery sequenceFigure 1); ROIs were mid-myocardial  and were drawn without reference to the LGE images .13 We quantified interstitial expansion with the ECV as described previously: ECV = λ(1 − haematocrit), where λ = [ΔR1myocardium]/[ΔR1blood pool] pre- and post-Gd (where R1 = 1/T1).Standard CMR parameters of structure (left ventricle (LV) mass, left atrial area with/without indexing for body surface area, maximal septal thickness) and systolic function  were assessed. A region of interest (ROI) was drawn in the basal septum in a four-chamber view in all patients and in the left atrium for blood T1 measurement as papillary muscle hypertrophy made drawing an ROI in the LV cavity challenging (see n = 19 of the 100) pre-dated availability of ShMOLLI T1 mapping and had utilized multibreath-hold T1 measurement.10 We have demonstrated equivalence of ECV values derived from this technique with ShMOLLI ECV and so these data were not excluded from the analyses.20Some ECV data . The number of patients dead and alive was assessed after a median duration of 23 (interquartile range: 6–25) months. Some analysis involved sub-grouping patients into pre-test probability of cardiac involvement. This was done as previously described and as stated below.Left ventricle (LV) wall thickness of ≥12 mm by echocardiography in the absence of any other known causeRight ventricle (RV) free wall thickening co-existing with LV thickening by echocardiography in the absence of systemic or pulmonary hypertensionPossible cardiac involvement—any of:LV wall thickening by echocardiography in the presence of hypertensionRV thickening by echocardiography in the presence of pulmonary hypertension2Normal wall thickness by echocardiography with diastolic dysfunction and raised serum biomarkersNo suspected involvement:Normal wall thickness by echocardiography with normal serum biomarkersDefinite cardiac involvement—any of:21 Analysis was performed using SPSS , R programming language for statistical computing  and in Stata . All continuous variables were normally distributed except NT-proBNP and Troponin T which were log (ln) transformed (base e) to achieve normality for further analysis. Linear regression models measured the association between quantitative ECV and other variables; variance inflation factors <2 excluded collinearity.Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at University College London.R values. Means are presented ±SD. The χ2 test was used to compare categorical variables between patients and controls whilst the unpaired t-test was used to compare continuous variables between the patients and controls. A one-way ANOVA with Bonferroni correction was used to test ECV with pre-test clinical probability of cardiac involvement.13Pearson's correlation coefficients are presented in terms of 22 were used to assess the capacity of ECVi compared with ECVb and pre-contrast myocardial T1 for discriminating between surviving and dying patients with AL amyloidosis. For fixed times  and specificity level, we have compared the sensitivity of ECVi, ECVb, and pre-contrast myocardial T1 measurements for detecting patients who will die by time t. For the ROC curves constructed using the nearest neighbour estimator (NNE) we used a narrow span of λ (0.25 × nobs−0.20) to yield only moderate smoothing. To permit comparison of ROCs by the NNE estimator, a set of simple KM estimator ROC curves for this data at t = 24 months are also provided .To test the prognostic value of ECV and pre-contrast T1, survival was evaluated using Cox proportional hazards regression analysis, providing estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and Kaplan–Meier curves. Conventional ROC analysis could not be performed because the follow-up period was not the same for each patient. Therefore, time-dependent ROC curvesOptimal myocardial T1 and ECV values were explored by Cox regression, using the median and the 1st or 2nd tertiles as cut-off values. The two groups resulting from each cut-off were compared using the Harrell's C statistic (a measure of discrimination between groups) to determine the better model and thus biomarker for predicting survival. All variables were first explored with univariate Cox regression. Multivariable models evaluated the independent predictive value of ECV above other clinically and statistically significant covariates.Table 1 summarizes baseline characteristics for patients and healthy volunteers. Within the patient cohort, 14 (14%) patients were on treatment for hypertension; 10 (10%) had confirmed coronary artery disease by angiography, 1 (1%) had had a stroke, and 2 (2%) had diabetes. Fifty patients were treated with chemotherapy for the first time which comprised triple therapy with either cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, bortezomib and dexamethasone (CVD), depending on local guidelines of regional NHS Trusts within the UK. Seventeen patients were treated for a 2nd or 3rd time having relapsed—treatment was either with CVD or a lenalidomide-containing regimen in these instances. Nine patients had not received any chemotherapy as there was no clinical indication  and 24 patients were under a stable follow-up with no indication for further chemotherapy at the time of scan.Twenty-one patients had a pre-test probability of no cardiac involvement, 26 had possible cardiac involvement, and 53 had definite cardiac involvement.i from infusion measurement unless otherwise stated. Healthy controls were younger on average, but our work and others suggests any ECV changes with age are small compared with amyloid changes.24 There were proportionately more females in the control vs. the patient group. This slightly increases the control group ECV and pre-contrast T1 compared with that of a gender-matched group .All ECV values are the ECVP < 0.001) and correlated with pre-test probability of cardiac involvement by conventional parameters (P < 0.001)13 . Mean pre-contrast myocardial T1 values were raised in patients compared with healthy volunteers  and also correlated with pre-test probability of cardiac involvement (P < 0.001).9Table 2 provides the Pearson correlation coefficients of ECV, pre-contrast and post-contrast myocardial T1 to other cardiac parameters, many of which typically change in cardiac amyloid. Extracellular volume correlated significantly with 17 of 19; pre-contrast T1 with 12, and post-contrast T1 with 10.As in previous work, mean cardiac ECV was greater in patients compared with healthy volunteers with a wider range  as shown in Figure 2.With regards LGE, 25 patients had no LGE, 50 had global subendocardial enhancement, and 10 had extensive enhancement. Eight had patchy enhancement and seven had evidence of only altered gadolinium kinetics, i.e. reversed nulling of myocardium and blood after gadolinium administration. Extracellular volume correlated significantly with increasing degrees of LGE (Table 3).At follow-up (median 23 months), 25 of 100 patients had died. For each potential predictor, median and tertile cut-points were assessed for predictive power and the best result presented , P = 0.004 . The survival curve indicates that there is an ∼40% chance of death at 23 months in patients with an ECV ≥ 0.45 compared with 15% for patients with an ECV < 0.45. For pre-contrast myocardial T1, the 1st tertile (cut-point 1044 ms) was the best predictor: HR 5.39 (1.24–23.4), P = 0.02 . ECVb with median of 0.44 also predicted survival with an HR of 5.09 (1.09–23.7), P = 0.04 . Post-contrast T1 did not predict survival .For ECVi, ECVb, and pre-contrast T1 were compared to determine the stronger discriminator using the Harrell's C statistic , all three performed similarly (see Table 3). The time-dependent ROC analysis revealed that overall (considering both earlier [t = 12] and later [t = 24] follow-up times), the three ROC curves for ECVi, ECVb, and pre-contrast T1 show quite similar discrimination for cumulative mortality .When the three predictive models ECVi > 0.45 remained significantly associated with mortality  in multivariable Cox models that included measures of systolic and diastolic function and serum biomarkers: E:E′, diastolic dysfunction grade (≥2), ejection fraction, and LnNT-proBNP . E:E′ and NT-ProBNP also remained independently predictive.The value ECV13 We have also demonstrated that both these biomarkers have ‘real-world’ clinical significance in that both are predictors of mortality in AL amyloidosis.Extracellular volume is the first, non-invasive quantifier of the cardiac interstitium, while pre-contrast T1 is a composite measure of interstitium and myocardial cells. This study demonstrated that ECV and native myocardial T1 as measured by the newer T1 mapping techniques, both correlate with current markers of disease severity in cardiac AL amyloidosis, supporting previous work.13 Here, these early results are strengthened by increased numbers and, additionally, prognostic significance of the biomarkers is demonstrated, even with therapy. The half of AL amyloid patients with an ECV > 0.45 had a three- to four-fold increased likelihood of death—roughly a 35–40% chance of death at 23 months compared with lower ECV patients despite therapy, lending support to ECV as a key amyloid biomarker.Amyloidosis is the exemplary interstitial disease of the myocardium. Cardiac involvement portends a poor prognosis which has driven the need for better methods of detecting early cardiac disease. We previously described both pre-contrast T1 mapping and ECV measurement as potential, non-invasive techniques for directly measuring the cardiac AL disease burden in amyloid.16 Here, we have demonstrated that ECV adds incremental value over and above existing clinical markers when risk-stratifying patients. Unfortunately, it was not possible to include NYHA class in the multivariable model because this information was not available in all patients due to other factors limiting exertion such as peripheral and autonomic neuropathy due to systemic amyloidosis. Additionally, the limited number of deaths limits very extensive multivariable analysis so this may not represent the optimal multivariable model.Recent work published in this journal in non-amyloid patients, where ECV likely measures diffuse fibrosis, has also showed predictive power—in 1176 consecutive CMR referral patients over a median of 1.3 years follow-up, 24 deaths occurred with ECV carrying a hazard ratio of 1.52 (1.21–1.89) for admissions with heart failure and all-cause mortality.2 In new presentations, median survival was reduced from 26 to 10 months when either NT-proBNP or Troponin T was raised and reduced further still to only 3 months if both biomarkers were raised, although the authors are in the process of further refining this model with inclusion of values for serum-free light-chain concentration.25 Our survival data in the 49 patients scanned at presentation is currently underpowered to determine any incremental benefit of ECV in this specific patient group; this remains work in progress.We used an arbitrary categorization for the presence or otherwise of cardiac amyloid. The Mayo staging system is the most recognized predictor of survival in systemic AL amyloidosis.13Extracellular volume is predictive, regardless of treatment status and indeed irrespective of whether patients are presenting at diagnosis or years into the disease process. Some patients in the cohort had modest ECV increases (ECV 0.30–0.40) without any other evidence of cardiac involvement , reinforcing our original findings that even patients classified as having no cardiac amyloid do in fact have raised ECVs, suggestive of low-grade cardiac disease. A plausible role for aggressive therapy in such patients to prevent progression to overt cardiac disease can be entertained.13Although T1 mapping is now more mature with sequences available on all platforms, it is difficult to compare ECV and T1 to LGE because, as previously stated, the absence of LGE likely does not equate to the absolute absence of cardiac amyloid and PSIR imaging which can be helpful with LGE imaging in amyloid, is not available on all platforms. We have previously demonstrated that when ROIs are drawn in LGE-positive and LGE-negative areas in the same patient, the ECV, whilst lower in LGE-negative areas, is still not normal.9 particularly as 20–30% of patients with systemic AL amyloidosis have an eGFR of <30 mL/min at presentation and in these patients, the Mayo staging system is in part confounded by elevation of serum biomarkers due to renal dysfunction. Here, pre-contrast myocardial T1 by ShMOLLI is an alternative to ECV. It is an equally strong predictor but as mentioned earlier, it represents a composite signal from cells and interstitium, not just the interstitium alone like ECV. Some work may be needed to derive normal pre-contrast T1 values in patients with renal impairment due to non-amyloid-related pathologies. An additional issue is that pre-contrast T1 presents greater standardization challenges.The simpler pre-contrast myocardial T1 technique does not require a contrast agent and shows promise,b) was as good as ECVi. Our previous work showed that, in most disease states, ECVb carried excellent agreement with ECVi when the tissue ECV was <0.4, but generated higher results in high ECV scenarios—such as areas of scar and amyloid.17 Nonetheless, this study suggests that the ECVb passes a key clinical utility test of being prognostic. Post-contrast T1, however, was not useful either at baseline or to predict outcome.From a practical perspective, the bolus only approach to ECV  in areas of thinner myocardium towards the apex but as technology advances with motion correction T1 mapping sequences, this will become possible. As stated earlier, the number of events limits extensive analysis. That said, these are nevertheless hard endpoints and multivariable analysis can still be performed in these situations.The myocardialextracellular volume, ECV, is a recently developed, non-invasive quantifier of cardiac amyloidosis. We confirm earlier results that ECV increases with established disease and detects early cardiac involvement. Extracellular volume after primed infusion is a promising clinical biomarker which passes a key test as a predictor of mortality. The pre-contrast T1 mapping method and the faster bolus-only ECV measurement techniques are equally prognostic, providing options for patients in renal failure or, in combination add robustness and diagnostic confidence.European Heart Journal onlineSupplementary material is available at .GlaxoSmithKline for some of our research studies in amyloid and are supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Funding to pay the Open Access publication charges for this article was provided by the British Heart Foundation.This work was supported by Conflict of interest: S.M.B. reports the following disclosure: Project part funded by GSK. A.D.W. reports the following disclosure: received money in relation to consultancy with GSK. J.C.M. reports the following disclosure: consultancy agreement with GSK subsequent to this manuscript being submitted. S.K.P. reports the following disclosure: NIHR BRC Research grant. All other authors do not have anything to disclose.