Time-varying elastance models can simulate only the pressure and volume signals in the heart chambers while the diagnosis of clinical cases and evaluation of different treatment techniques require more information. In this study, an extended model utilizing the geometric dimensions of the heart chambers was developed to describe the cardiac function. The new cardiac model was evaluated by simulating a healthy and dilated cardiomyopathy (DCM) condition for adults and children. The left ventricular ejection fraction, end-diastolic volume, end-diastolic diameter and diastolic sphericity index were 53.60%, 125 mL, 5.08 cm and 1.82 in the healthy adult cardiovascular system model and 23.70%, 173 mL, 6.60 cm and 1.40 in the DCM adult cardiovascular system model. In the healthy child cardiovascular system model, the left ventricular ejection fraction, end-diastolic volume, end-diastolic diameter and diastolic sphericity index were 59.70%, 92 mL, 4.10 cm and 2.26 respectively and 30.70%, 125 mL, 4.94 cm and 1.87 in the DCM child cardiovascular system model. The developed cardiovascular system model simulates the hemodynamic variables and clinical diagnostic indicators within the physiological range for healthy and DCM conditions proving the feasibility of this new model to evaluate clinical cases in adults and children. Numerical modeling of cardiac physiology plays an important role to evaluate clinical scenarios and outcomes of different treatment techniques before experimental or clinical applications. Nonetheless, the information obtained from a numerical simulation depends on the modeled relations in the utilized model. For instance, time-varying elastance models describe the pressure-volume relations in the heart chambers using an elastance function which changes with respect to time over a cardiac cycle . The timMore detailed numerical models such as single fiber contraction models describe the cardiac function by simulating the contraction of a sarcomere over a cardiac cycle . The sinMulti-scale models of the cardiac dynamics simulating the physiological processes at the cellular, protein and organ levels also were developed and used to understand the pathophysiology of heart failure . HoweverThe similarities and differences between children and adult physiologies have been subject to developmental theories . HemodynThe aim of this study is to develop a lumped parameter model describing the cardiac function and circulatory system and simulating the diagnostic criteria for the clinical cases, therefore, can be used to evaluate physiological scenarios and treatment techniques for cardiovascular system diseases in adults and children at different ages.Vlv) was expressed using the left ventricular radius (rlv), long axis length (llv) and an additional coefficient (Klv) which allows to include effects of the contraction in the long axis and scales the proportion between the left ventricular radius and volume over a cardiac cycle.llv) assumed to be constant over a cardiac cycle, so, the left ventricular radius (rlv) and the change of the left ventricular radius with respect to time (drlv/dt) can be described as given below.The mathematical model proposed in this study describes the relationship between the pressure and radius in the heart chambers. Left ventricular geometry resembles a truncated ellipsoid , therefodVlv/dt) can also be described as the difference between the mitral and aortic valve flow rates .Change of the left ventricular volume with respect to time (drlv/dt) becomes as given below.Change of the left ventricular radius with respect to time  is described using an activation function , end-systolic elastance , the left ventricular radius (rlv) and left ventricular radius at zero pressure volume .Vlv) as described in the Vlv,0). The activation function  driving the left ventricular contraction is adapted from [t is the time over a cardiac cycle, T1, T2, and T are the times at the end of systole, end of the ventricular relaxation and duration of the cardiac cycle.The left ventricular pressure during the active contraction and the relaxation phases (ted from  and giveplv) signal over a cardiac cycle is obtained using active and passive components of the left ventricular pressure .The relationship between the left ventricular pressure and the radius for the passive left ventricular contraction is adapted from  using thVrv).Krv, lrv and rrv are the scaling coefficient, the right ventricular length from base-to-apex and right ventricular radius. The right ventricular radius (rrv) and the change of the right ventricular radius with respect to time (drrv/dt) are described as given below.Right ventricle has a more complex shape with respect to left ventricle and resembles a crescentic cross-section and a triangle from the side view . The creQtv and Qpv are the flow rates through the tricuspid and pulmonary valves. The right ventricular active and passive pressure components  are modeled as given below. The right ventricular pressure is obtained using active and passive pressure components.In the equations above, pla is the left atrial pressure, Kla, lla, rla and rla,0 are the left atrial scaling coefficient, length, radius and radius at zero pressure. Ela is the left atrial elastance function and is described using the left atrial activation function  as given below.The left and right atrial geometries were modeled using a similar model to the left ventricular geometry. Therefore, the same relations for the left and right atrial volumes and radiuses are used as in the left ventricle model with different parameter values. The atrial pressure-radius relationship is modeled adopting a time-varying elastance pressure-volume and expressing the atrial volume as a truncated ellipsoidal shape.The right atrial pressure-radius relations are described in the same way as the left atrial pressure-radius relations. The parameter values used in the adult atria and ventricle models are given in K values were adjusted to simulate the end-systolic and end-diastolic heart chamber radiuses (r) within the reference range for the physiological heart chamber pressures and volumes. The zero pressure volume values of the heart chambers (V0) reported in the literature [Ees) were selected as 2.5 mmHg/mL and 1 mmHg/mL similar to the reported values in [A, B) were 1 and 0.02 [T1, T2, Ta, T, D) were selected considering the duration of the cardiac cycle phases [The longitudinal lengths of the left and right ventricles and atria were selected considering the anatomical ranges given in –23 for tterature ,24 used alues in ,26. The and 0.02 . The pare phases .The circulation loop was described using a lumped parameter model which includes electrical analogues for the blood vessel resistance, compliance and inertance. The heart valves were modeled as ideal diodes allowing one-way blood flow. The time-varying geometric models of the heart chambers and electric-analogue of the circulatory loop are given in 2 body surface area and 8–12 age interval [V0) were decreased in the child cardiovascular system model [C) were reduced in the children as the vessel compliance increases with the increasing body surface area and age [R) are kept the same in the child cardiovascular system model as in the adult cardiovascular system model because the difference between the adult vascular resistances and children vascular resistances for the considered ages is not very high and the vascular resistances vary in a very high variation range in children [T) was decreased to 0.75 bpm in the child cardiovascular system model as the heart rate increases with the decreasing age [Vtot) is significantly less in children with relatively small body surface area with respect to the adult cardiovascular system [2 body surface area is around 2000 mL [The healthy child cardiovascular system model was simulated by modifying the parameters used in the healthy adult cardiovascular system model. The model parameters were adjusted to simulate children with 1 minterval . The sysinterval . The veninterval  for the em model . The com and age . The reschildren . Duratiosing age . The totr system . The tot 2000 mL . The parEes,lv) in both adult and child cardiovascular system models. The diastolic dysfunction in the left ventricle was simulated by decreasing the coefficient (A) used in the Klv) was also increased to simulate the remodeling in the left ventricular wall and the enlargement of the left ventricular cavity. The modified parameters in the left ventricle and circulatory system for both adult and child cardiovascular system models are given in the Tables DCM is a condition which left ventricle is dilated and weakened due to contractile dysfunction . Diastolfs) and sphericity index (si) were used to evaluate healthy and DCM conditions in the adult and child cardiovascular system models along with the ejection fraction, volumes and dimensions of the heart chambers.Fractional shortening  which include the effects of the longitudinal contraction and irregularities in the heart chamber geometries and allow simulation of the physiological heart chamber diameter signals was used in the proposed cardiovascular system models. The scaling coefficients (K) also relate the diameter and volume signals in the heart chambers. Modifying these parameters for a heart chamber does not influence the volume and pressure signals while the diameter changes. A higher value of the scaling coefficients (K) shows a stronger longitudinal contraction and a more complex geometry for the heart chambers. Right ventricle has the most complex geometry among all the heart chambers, and right ventricular longitudinal contraction contributes to the ejection of the blood through the pulmonary valve significantly [Krv) with respect to the scaling constants in other heart chambers were used in the adult and child cardiovascular system models. Also, higher scaling constant values for the heart chambers in the child cardiovascular system model with respect to the adult cardiovascular system show stronger longitudinal contractions in children. In the adult and child DCM models, the scaling coefficients (Klv) were modified as well as the systolic elastances  and zero pressure-volume values  for the left ventricle because of the remodeling in the myocardial tissue causing in an increase in the left ventricular volume and diameter. The modifications in the systolic elastance  and zero pressure-volume  were done to simulate the impaired contractile behavior and enlarged cavity volume in the DCM left ventricles. The scaling constant (Klv) was modified to simulate the changes in the contractile strength of the longitudinal contractions.Scaling coefficient  as in 2D echocardiographic cardiac imaging describes the right ventricular volume signals for the healthy and DCM models accurately.Accuracy of the right ventricular volume estimation from 2D echocardiography requires assumptions on the geometry of right ventricle . TrimmedThe pressure and volume signals simulated in the adult cardiovascular system model for the healthy condition remain within the physiological range ,48–51. T2 corresponding to 8–12 years children’s body surface area [2 with slightly higher right ventricular volume and may reach to values around 100 mL/m2 while the end-systolic volume in the ventricles is around 30 mL/m2 and with 45 mL/m2 upper reference limit [2 body surface area corresponds well with the reported volume indexes in literature. The left atrial volume signal over a cardiac cycle in the healthy child cardiovascular system corresponds to a reported average left atrial volume signal over a cardiac cycle quite well [2 body surface area. Typically, the left ventricular end-diastolic and end-systolic diameters are around 4.1 cm and 2.6 cm, the right ventricular basal diameter at the end of the diastole is around 2 cm and the left atrial maximal diameter 2.9 cm and changing again within a physiologic variation range for the studied age interval [In pediatric patients, fractional shortening and ejection fraction are the most commonly used parameters to evaluate the left ventricular function . Measureace area  and the ace area . The sysace area . Reporteace area . The simce limit . The volite well . Moreoveite well  matches interval –71. The The DCM cardiovascular system model simulating the child circulation responded to the changes in parameters in a similar way as the adult DCM cardiovascular system model. Cardiac output and ejection fraction reduced from healthy values to the values characterized as impaired ,73. The Mitral regurgitation may occur in DCM because increased left ventricular size cause improper leaflet coaptation . SimulatThe developed cardiovascular system model is driven by an activation function which utilizes time signal to simulate the hemodynamic variables. Clinically, wall stress and strain are also commonly used physiologic parameters. Simulation of these parameters requires performing finite element analyses since wall stress and strain have orientations in space and also depend on the geometry of myocardium. Additionally, the interaction between the ventricles through the intraventricular septum can be simulated using finite element analyses. The ventricles interact in the developed cardiovascular system model due to change in the parameters such as contractility as afterload and preload of the heart chambers are influenced because of variation of this parameter. However, it should be noted that the developed cardiovascular system model simulated the hemodynamic parameters for normal and DCM conditions in adults and children within the physiological range. Moreover, lumped parameter models have the advantage of performing simulations in shorter computational times, and they are powerful clinical decision-making tools .The DCM in adult and child cardiovascular system models was simulated by adjusting the parameters in the cardiovascular system models manually. Progression of heart failure depends on complex and interacting mechanisms which are not entirely understood . ModelinThe cardiovascular system model presented in this study can be used to simulate different clinical cases for different ages and conditions as it allows to simulate clinical indicators extracted from the geometry of heat chambers. In the future, it is aimed to use this cardiovascular system model to simulate heart failure for pediatric patients in patient-specific studies to evaluate mechanical circulatory support. An important portion of the pediatric patients implanted with a heart pump exhibit complications associated with mechanical circulatory support . ContinuIn this study, a mathematical model simulating hemodynamic parameters and clinical indicators in the cardiovascular system was developed to evaluate clinical cases in adults and children. The developed numerical model demonstrated its feasibility to simulate clinical cases and can be used to evaluate clinical cases and treatment techniques in adults and children at different ages.S1 File(ZIP)Click here for additional data file.


Mechanical circulatory support (MCS) for failing single ventricle (SV) physiology is a complex and challenging problem, which has not yet been satisfactorily addressed. Advancements in surgical strategies and techniques along with intensive care management have substantially improved the outcomes of neonatal palliation for SV physiology, particularly for hypoplastic left heart syndrome (HLHS). This is associated with a steady increase in the number of SV patients who are susceptible to develop heart failure (HF) and would potentially require MCS at a certain stage in their palliation. We have reviewed the literature regarding the reported modalities of MCS use in the management of SV patients. This includes analysis of various devices and strategies used for failing circulation at distinct stages of the SV pathway: after neonatal palliation, after the superior cavo-pulmonary connection (SCPC), and after total cavo-pulmonary connection (TCPC). Fontan and Baudet introduced the concept of single ventricle (SV) palliation in 1968, in a patient diagnosed with tricuspid atresia, by total right heart bypass achieved with atrio-pulmonary connection –4. The FAs reported in previous studies –11, patiVA-ECMO is the most common type of MCS used in children, not only because it can provide biventricular cardiac and respiratory support, but also due to lack of alternative technology suitable for the pediatric population. In the setting of acute cardiac failure, VA-ECMO support remains an important option because it can be established immediately and maintained for a period of duration until correctable factors are identified. It may be used as bridge to decision or bridge to a more long-term device or to transplantation. In essence, VA-ECMO is a closed cardiopulmonary bypass system with the venous drainage cannula in jugular or femoral vein or right atrium. The blood is pumped through a membrane oxygenator with heat exchanger for temperature regulation and returns to the patient via an aortic cannula in the carotid or femoral artery or ascending aorta.Recently, technological advancements and experience have improved the durability and decreased the complication profile of VADs, with a consequent 10-fold increase in the number of VAD implantations as reported by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 2006 to 2010 . In caseA short-term MCS employed in many centers are centrifugal VADs, which have gained popularity as bridge to decision or toward long-term VADs or to transplantation. They are relatively easy to implant and can be adapted to all age groups. The Levitronix CentriMag  and the RotaFlow from Maquet  are most frequently used in the United States. They can be supplemented with an oxygenator to simulate a VA-ECMO and provide renal support with a dialysis machine .However, the most common VAD used amongst the pediatric population is the Berlin Heart Excor (BHE) . The BHE consists of a para-corporeal, pneumatically driven, polyurethane blood pump   with a mThe last category of VADs used are intracorporeal devices. These continuous flow pumps can be differentiated into axial flow  or centrifugal pumps , with different flow rates and shut off pressure thresholds. There has been considerable discussion pertaining to their individual unloading characteristics as well as comparison with pulsatile flow pumps, when accounting for the mechanism and timing of SV failure. Horne et al. have described a useful algorithm for the treatment of SV failure in various age groups, with respect to the aforementioned devices' specifications, size of patient, and underlying mechanism .The remaining MCS device available is the Total Artificial Heart (TAH) by SynCardia . It is a pulsatile biventricular support device implanted after cardiectomy, and is available as 70cc pumps or as the newly manufactured 50cc pumps for smaller patients. Its use has been advocated by Horne et al. especially in Fontan failure with increased pulmonary vascular resistance (PVR) ± ventricular dysfunction . RossanoSV patients present a difficult challenge with regards to optimal configuration of anatomy, unilateral vs. bilateral support, device selection, and cannulation strategies. It is therefore reasonable to suggest that the optimal mechanism for support will vary depending on the etiology of failure. Because of the extreme variability of patients, cardiac anatomy, comorbidities, and mechanism of failure, it is necessary to define ideal management strategies following the three different SV stages: neonatal palliation including Stage I Norwood, superior cavo-pulmonary shunt, and following completion of Fontan circulation.During the neonatal period, it is impossible to create a Fontan circulation because of an elevated PVR as well as sizes of the superior vena cava (SVC), inferior vena cava (IVC), and pulmonary arteries. Therefore, a staged approach is utilized which allows the body to adapt progressively to the hemodynamic conditions of each SV stage. Different surgical procedures are used in the neonatal period based on the primary type of CHD. This includes pulmonary artery banding or modified Blalock-Taussig shunt (mBTs) ± Damus-Kaye-Stansel (DKS) anastomosis otherwise known as stage I Norwood procedure. Subsequently, the patient may develop acute or chronic HF. Acute failure should be managed by VA-ECMO support whereas for chronic failure, the best solution may be to progress to the second stage of SV pathway to eliminate a volume-loaded circulation. The use of VA-ECMO support after neonatal palliation with systemic-to-pulmonary artery shunt warrants a balance between systemic and pulmonary perfusion in order to prevent myocardial and systemic ischemia, caused by excessive runoff into the low-resistance pulmonary bed through the shunt.Early reports of VA-ECMO suggest that outcomes for patients with SV circulation are substantially worse than those with 2-ventricle circulation, and survival to discharge after Stage I Norwood procedure supported with VA-ECMO was only 31% , 21. RecUngerleider et al. have advocated the routine use of centrifugal short-term VADs for circulatory support following stage I Norwood for palliation of hypoplastic left heart syndrome (HLHS) . Berlin Weinstein et al. reviewed the EXCOR Investigational Device Exemption study database and analyzed outcomes of patients with SV supported with BHE. Amongst 26 children, 9 were supported after palliative neonatal surgery with BHE, in which it served as a UVAD in 8 cases and provided biventricular support in one case, with only one surviving to orthotopic heart transplantation (OHTx) . De RitaFigure The second operation in the SV pathway involves a superior cavo-pulmonary connection (SCPC) commonly called the “Glenn” shunt, where superior systemic venous return is directed to the pulmonary bed. The main reasons of circulatory failure at this stage are elevated mean pressure in the SCPC, significant atrio-ventricular valve regurgitation, younger age, lower weight, longer bypass time, and re-intubation; whereas, inter-stage mortality was mainly influenced by moderately impaired ventricular function, prolonged hospital stay and poor weight gain , 31.SV patients with SCPC present unique challenges when considering MCS. Since the SVC is connected to the pulmonary artery, decompression of the systemic pumping chamber may not guarantee adequate venous drainage and may result in ongoing venous hypertension, which encourages the development of aberrant veno-venous connections and subsequently worsening cyanosis. Thus the management of circulatory failure at SCPC palliation is mainly medical management, either to recovery or as a bridge to OHTx, with conversion to total cavo-pulmonary circulation or to biventricular repair on rare occasions and subsequent central VA-ECMO or VAD support , 32. ParRecent report on the usage of VA-ECMO in SCPC showed an improved survival to hospital discharge (41%) compared to earlier data, but there was still a high incidence of neurological complications . There hRecent trends in the management of acute univentricular HF with SCPC advocate the use of BHE cannulae connected to a centrifugal pump with an oxygenator and either conversion to a BHE pulsatile pump or maintenance of a continuous flow pump and oxygenator and progress to extubation. Alternatively, the use of an implantable continuous-flow VAD, such as the HVAD Heartware or Heartmate II, may represent a more suitable option due to the ability for discharge to home, 38. RegFigure The inferior systemic venous return is directed to the lung following TCPC. Aim of this stage is that all systemic venous blood flows passively through the pulmonary vascular bed bypassing the SV. The final objective is to achieve normal volume and pressure workload for the SV and nearly normal oxygen saturation of the systemic blood. Prerequisites to a successful TCPC include low PVR and good ventricular function with low end-diastolic pressure . After FCurrently, there is no medium or long-term mechanical assist device as bridge-to-transplant or bridge-to-recovery, which has been found suitable for the failing Fontan circulation. VA-ECMO has been used in acute settings in the past, with disappointing results. Rood et al. reported a survival to discharge of 35% in patients with Fontan failure supported with VA-ECMO . In the BHE has been used in Fontan failure as well, though mainly as a UVAD. In the group described by Weinstein and colleagues, 5 patients with Fontan circulation were supported with BHE as a UVAD and 3 survived to transplantation . SandicaPrêtre et al. reported a right ventricular assist device (RVAD) with BHE in a 27-year-old patient with the primary diagnosis of tricuspid atresia, extracardiac Fontan and preserved ventricular function, who was eventually transplanted successfully . VanderPFew other devices have been attempted in the failing Fontan circulation including the Thoratec Paracorporeal Pulsatile VAD , which was used in a case, reported by Newcomb et al. from Melbourne who survived to transplantation and in another case, reported by Arnaoutakis et al. who did not survived to heart transplantation , 54. RusThe management of SV failure is a very difficult task for surgeons and physicians, as it involves a complex underlying pathophysiology often confounded by other medical and surgical issues. The mode, timing, and mechanism of SV failure as well the patient size are equally important factors in deciding the management strategy. The algorithm proposed by Horne et al. is a valid attempt to rationalize the care in SV failure, but frequently an individualized approach is warranted in view of other factors .End-organ failure, specifically renal and hepatic, often develop due to long-standing suboptimal circulation. This constitutes a considerable problem when dealing with SV physiology and also plays an important role in candidacy for future transplantation. The ability to preserve the liver's synthetic and metabolic functions is paramount for the success of cardiac transplantation, especially in patients with Fontan failure.Short-term device use for initial MCS support is often necessary in SV patients with acute HF. This is beneficial as it can be used as a bridge to decision in order to allow full assessment of each major organ system. However, the associated substantial neurological risks are an important consideration , 32. TheAlthough it has been demonstrated that using more than one modality of MCS does not increase the neurological risk, this may not be the case with the SV population . Thus, iRecently there has been an increasing number of mechanical devices available for the surgeons, however MCS in SV failure is centered only on few of those, as reported by the literature , 30, 53.While in the past, the choice between these devices was mainly related to the surgeon's and institution's preferences, this may be changing nowadays. Currently, the choice is dependent on the mode of failure in relation to the mechanism of each device, particularly considering their unloading characteristics. The TAH opens an interesting perspective for the future as it can provide biventricular support with high pump output. Given the ongoing miniaturization, the TAH system will become available even in smaller patients. However, it involves extensive surgery, needs the creation of a venous reservoir for the systemic return, and can be further complicated by anatomical variation as situs inversus, dextrocardia, and isomeric hearts. Thus, it is clear that the MCS support for SV population has not reached the level of sophistication compared to that for normally structured hearts. More clinical experience as well as academic studies are necessary for further improvement in this challenging population.Literature has shown that it is possible to support patients with SV failure using MCS, however the results of such usage are mixed, based on the underlying anatomy. Moreover, the outcomes of MCS in stage I patients are far from optimal. Although cardiac transplantation represents the ultimate goal for SV failure patients, the lack of suitable donors remains a considerable problem. The understanding of the underlying SV pathophysiology and its interaction with MCS devices continues to evolve. Together with the development of new devices, we hope to provide MCS with medium and long-term durability for these patients, with comparable results to those with two-ventricle physiology.MG collected articles, wrote and revised manuscript. RS collected articles, revised manuscript. SJ collected articles, revised manuscript. GP collected articles, wrote manuscript. IA collected articles, wrote manuscript.IA serves as a consultant and proctor for Berlin Heart, Inc., and Heartware, Inc. IA receives a research grant from Abiomed, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Previous studies have reported slightly higher stroke rates in Takotsubo Syndrome compared to acute myocardial infarction. Our goal was to evaluate the temporal course of stroke rates and left ventricular recovery in patients with Takotsubo Syndrome.We retrospectively examined the clinical and imaging data of 72 patients with Takotsubo Syndrome. The data collected came from January 2005 to March 2017. Left ventricular performance was evaluated by cardiovascular magnetic resonance imaging (MRI) in all patients during the acute phase of Takotsubo Syndrome and in a follow-up scan 2 months later. Acute stroke and major adverse clinical events, such as myocardial infarction or recurrence of Takotsubo Syndrome and death, were also determined for each patient at 30 days and 12 months after initial presentation.P < 0.001). We observed 9 (12%) events in the study population within 12 months of the initial diagnosis of Takotsubo Syndrome. Stroke had an event rate of 2.8% after 30 days and 4.2% after 12 months.The MRI scans performed during the acute phase of Takotsubo Syndrome demonstrated apical ballooning with anterior wall motion dysfunction in 65 (90%) patients. Imaging performed 2 months later demonstrated resolution of this in 97% of those patients. Median left ventricular ejection fraction also significantly increased between both scans  contains supplementary material, which is available to authorized users. Large anterior wall myocardial infarction is associated with an increased risk of stroke. . Apical We evaluated 72 patients with TTS in our tertiary care center from January 2005 until March 2017. The diagnosis was established according to the Mayo Clinic diagnostic criteria . The criWe performed the contrast-enhanced cardiac MRI using a 1.5 T MRI scanner  in all patients during the acute phase of TTS in order to analyze global and regional left ventricular function and to assess myocardial injury.The MRI protocol included two-dimensional turbo gradient echo sequences in state of the art steady-state free precession technique. These sequences were performed in short axis, four-chamber, two-chamber and three-chamber views of the left ventricle. For the assessment of myocardial oedema, T2-weighted black blood turbo-spin-echo sequences with fat saturation pre-pulse in short axis and in four-chamber views with slice thickness of 8 mm and gap 0 mm covering the complete left ventricle were performed . These sequences were previously validated [For Late Gadolinium Enhancement (LGE) image acquisition, a three-dimensional inversion-recovery turbo gradient echo sequence of the left and right ventricle was performed in the long and short axis views. LGE images were scanned after an interval of 10–15 min post- injection of 0.2 mmol/kg of gadoteridol .Follow-up MRI scans were performed 2 months after initial presentation to reassess global and regional left ventricular function and myocardial injury.A commercially available software-tool  was used for the cardiac MRI image analysis. Assessment of left ventricular functional parameters included determination of global left ventricular ejection fraction (LVEF), left ventricular end-diastolic volumes and wall motion abnormalities (WMA). The WMA were classified as apical, midventricular, or basal ballooning of the left ventricle. Apical ballooning was specifically defined as WMA of the left ventricular apex, all four apical segments, and a minimum of four affected midventricular segments, which was based on the AHA 17-segment model for the analysis of regional left ventricular function . MidventA region was quantitatively described as having myocardial oedema when the signal intensity threshold was > 2 standard deviations (SD) above that of remote normal myocardium in T2-weighted sequences .MyocardiLGE was defined as hyperenhancement of myocardium that was ≥5 SD above that of the signal intensity threshold of remote normal myocardium, as previously described . A semi-The local ethics committee (University Witten/Herdecke) approved this study and patients gave written informed consent. Patients or their treating physicians were contacted by telephone for the standardized interview used for MACE assessment.P value of less than 0.05 was considered to indicate statistical significance.Statistical analysis was performed using STATA/IC 14.2 software . Categorical variables are described by frequencies; continuous data are expressed as median with maximum – minimum or interquartile range or with mean and standard deviation. To test if distribution of parameters of the two MRI scans were different Wilcoxon matched-pairs signed-ranks test was used. A two-sided Patients had a mean age of 68.8 ± 17.5 years. The majority were female patients (93%). Patient characteristics are presented in Table Video S1. Steady-state free precession CINEimaging of the cardiac three-chamber view in a patient with Takotsubo Syndrome. Apical ballooning with leftventricular thrombus formation is evident. (AVI 616 kb)Additional file 1: Initial MRI was performed in all patients shortly after presentation with TTS , and a follow-up scan was conducted 2 months later IQR 1.3–2.9) in 63 (88%) patients. Apical ballooning was initially observed in 65 (90%) patients and resolved in 97% of those patients within 2 months (Table –2.9 in 6P < 0.001). Myocardial oedema decreased significantly between the two MRI scans. LGE was not detected in these TTS patients  in TTS patients within the first 30 days. One explanation for this might be that we also found more apical ballooning with severe anterior WMA. The most common WMA in our study were associated with apical ballooning, which was found in 90% of patients and resolved in 97% of them. Previous studies support this finding; although, the percentage of TTS patients with apical ballooning in these studies was found to be approximately 82% . The higAt this time, there are no standard therapeutic recommendations for TTS available. We propose that oral anticoagulation for 2 months or until recovery of ventricular function might decrease the risk of stroke in TTS.A limitation of the study is its retrospective design and the relatively small, single-center cohort. A larger, prospective, multicenter study would be better powered to confirm our hypothesis.In conclusion, our findings suggest that apical ballooning with severe anterior WMA followed by a rapid improvement in left ventricular morphology and function may facilitate the formation of cardiac emboli and consequently increase stroke rates in TTS. No guidelines currently exist for the treatment of TTS, but our results point to a potential role for oral anticoagulation in high-risk patients until recovery of left ventricular function.


Antiphospholipid syndrome (APS) is an autoimmune disorder that has a strong propensity for a hypercoagulable state and is known to be associated with venous and arterial thromboembolism. We describe an uncommon case of APS in the setting of non-Hodgkin’s lymphoma, with thromboembolism, and a rare complication after an uncommon etiology of myocardial infarction. This case highlights the importance of early and appropriate type of anticoagulation to reduce the morbidity and mortality in patients with APS. Three months prior, he had an episode of NSTEMI. Coronary angiogram showed no significant atherosclerotic disease . Direct On admission, the patient was afebrile, heart rate 91 beats/min, blood pressure 122/77 mm Hg, respiratory rate 18 breaths/min, and an oxygen saturation of 95% on 1.5 liters by nasal cannula. Physical examination revealed a significantly elevated jugular venous distention measuring approximately 15 cm, with a positive hepatojugular reflux. Auscultation revealed a grade 4/6 holosystolic murmur, heard best at the left ventricular apex, with an S3 gallop. There was trace pitting edema bilaterally, along with extensive necrotic skin lesions across the anterior chest and abdominal wall. Electrocardiogram showed normal sinus rhythm at 95 beats per minute with left anterior fascicular block.A transthoracic echocardiogram TTE) showed severe MR with a flail A2/A3 mitral valve leaflet and an eccentric and posteriorly directed MR jet, and mitral regurgitant volume was 73 mL/beat. The left ventricular ejection fraction of 42% with a significantly elevated right ventricular systolic pressure of 85 mm Hg  and E. A showed sCardiac magnetic resonance imaging (CMR) demonstrated subendocardial late gadolinium enhancement involving basal to mid-inferolateral wall of the left ventricle . The stuLaboratory markers were positive for aPL and β-2 glycoprotein I antibody (β-2GPI) consistent with antiphospholipid syndrome. Antiphospholipid antibody immunoglobulin (Ig) M and β-2GPI IgM were both more elevated at a value of 28 and 22.2 MPL (IgM Phospholipid Units) than IgG levels of 9.8 and 9.4 GPL (IgG Phospholipid Units), respectively. Guideline-directed medical therapy was initiated, and the patient subsequently received a 31/33 On-X mechanical mitral valve  replacement. He was discharged on lifelong warfarin therapy along with aspirin. One year postoperatively, he is currently New York Heart Association (NYHA) functional class I.2 The presence of aPL in APS has a greater risk of developing thromboembolism and cardiac valvular disease.3 Although there have been reports of antibody immune complex deposition causing valvular damage and insufficiency in most APS patients, MR after a non-atherosclerotic myocardial infarction is rare. Patients with APS experience a higher incidence of arterial compared with thromboembolic events.4 Thrombotic events are typically seen in solid tumor malignancies rather than lymphoid-derived neoplasm.5Antiphospholipid syndrome is an autoimmune disorder in which patients are at high risk of developing a hypercoagulable state leading to thrombosis.6 Miranda and colleagues reported a case of thrombosis of the anterior descending artery as a clinical complication of APS in a patient presenting with acute myocardial infarction.7 Another case by Park and colleagues demonstrated a patient with systemic lupus erythematosus and APS who developed an inferior myocardial infarction that was complicated by severe MR caused by posterior papillary muscle rupture.8 The provoking factors in many of these cases involve presence of aPL, which are directly involved in the pathogenesis of thrombosis. The aPL have been reported to be positive in 11% of cases with myocardial infarction.9 In our patient, the cardiac MR results were consistent with subendocardial infarction in the basal to mid-inferior/inferolateral wall of the left ventricle most likely from an embolus from the nonbacterial thrombotic endocarditis, which in turn was the result of APS.Cardiac manifestations of APS have been widely recognized including valvular abnormalities, occlusive arterial diseases, intracardiac emboli, and coronary thromboembolism.10 Management with VKAs in patients with APS can be challenging because of their multiple food and drugs interactions, which necessitates frequent monitoring of adequate anticoagulation. The variable response of thromboplastin reagents to aPL may potentially influence the validity of prothrombin time/international normalized ratio, thus complicating monitoring.11Furthermore, our patient was not anticoagulated at the time of these events, increasing the risk of developing thrombosis. The risk of thromboembolic events significantly increases in patients positive for APS antibodies like β-2GPI; therefore, prolonged anticoagulation is recommended. The first-line guideline therapy by the 14th International Congress on Antiphospholipid Antibodies Task Force Report on APS treatment trends for patients with thrombotic APS is with vitamin K antagonists (VKAs) like warfarin.12 However, its use in high-risk patients with antiphospholipid syndrome has been shown to be associated with increased rates of adverse effects with no benefit.13 A clinical trial by Pengo and colleagues demonstrated a 12% rate of thromboembolic events in patients randomized to rivaroxaban compared with 0% in the warfarin group.13 The role of direct oral factor Xa antagonists in APS and other inherited thrombophilias remains unclear, and further studies on large cohorts are needed to establish the safety and efficacy of its use over traditional VKAs.The rivaroxaban in antiphospholipid syndrome randomized controlled trial suggests that rivaroxaban has the potential to be a convenient and effective alternative to warfarin in thrombotic APS patients requiring standard anticoagulation therapy.In our patient, coronary thromboembolism most likely contributed to the valvular lesions of non-thrombotic bacterial endocarditis, which is seen in patients with acquired APS. Subsequent embolism down the right coronary artery resulting in posterior circulation myocardial infraction, with papillary muscle rupture, and ensuing severe MR was the etiology for the patient’s symptoms. Multimodality imaging with TTE, TEE, and CMR confirmed these findings. Optimal long-term anticoagulation based on guidelines is with VKAs. Early and appropriate anticoagulation must be made soon after diagnosis to reduce morbidity and mortality in patients with APS.


Hypotonic hyponatremia is a common electrolyte disorder defined by a blood serum sodium value of less than 136 meq/L. A challenge in managing hyponatremia is accurately determining the etiology for the free water excess as management can markedly differ. Accurate diagnosis of the etiology of hypotonic hyponatremia requires precision in the determination of extracellular volume status. Determination of volume status has traditionally relied on physical examination, imaging modalities, and clinical gestalt, all of which are inaccurate. Portal vein pulsatility is an easy to perform bedside ultrasound imaging study which can be used as a marker for hypervolemia and venous congestion. We present 2 cases of hypervolemic hyponatremia in which portal vein pulsatility was used in the diagnosis and management and as a marker for efficacy of treatment. Hypotonic hyponatremia is a pervasive electrolyte disorder that represents an excess of free water as compared to sodium . ConditiA 54-year-old male presented to the emergency department after a pulseless electrical activity (PEA) cardiac arrest at home with an estimated downtime of 20 minutes. He received a total of 5 mg of IV epinephrine, 2 mg of IV magnesium, and 200 mEq of sodium bicarbonate. After achieving a return of spontaneous circulation (ROSC), the hypothermia protocol was initiated, and the patient was transferred to the intensive care unit. He was on mechanical ventilation with an initial fraction of inspired oxygen requirement of 100% on a positive end-expiratory pressure of 12 cm H20. He was on norepinephrine of 20 mcg/min to maintain a mean arterial pressure of greater than 65 mmHg. Initial labs were notable for a white blood count of 19000 cells per cubic millimeter (4.5-11000), sodium 115 meq/L (135-145 meq/L), and a N-terminal pro b-type natriuretic peptide of 12100 pg/ml (1-850 pg/ml A 95-year-old male with a past medical history of heart failure with reduced ejection fraction, atrial fibrillation, and hypothyroidism presented to the hospital with shortness of breath and increased work of breathing requiring noninvasive positive pressure ventilation. Laboratory values were remarkable for a serum sodium of 120 meq/L, serum creatinine of 1.91 mg/dl, and an NT ProBNP above 15000 pg/ml . BedsideHyponatremia secondary to congestive heart failure is a prognostic marker for mortality . CongestUrine electrolytes in case 1 indicates a sodium avid state, as the urine sodium value was < 5, which indicates a low ECF, and does not differentiate hypervolemia or hypovolemia. The initial portal vein study was biphasic in both cases, which denotes severe venous congestion and more consistent with hypervolemia. Once a diagnosis of hypervolemic hyponatremia was made, we felt that achieving a negative fluid balance would lead to an improvement in renal venous congestion with possible concurrent renal interstitial edema and intra-abdominal hypertension. We were able to demonstrate significant improvements in pulsatility that coincided with the improvements in sodium as we diuresed the patients. Both patients either maintained or improved their creatinine levels with diuresis that was guided by improvements in pulsatility. We believe that following portal vein pulsatility improvements could potentially avoid acute kidney injury from overdiuresis.The use of portal vein pulsatility to identify patients with hypervolemic hypotonic hyponatremia would portend an essential advance in the diagnosis of the condition, which has mostly remained unchanged for decades. Differentiation between hypervolemia and hypovolemia, particularly when it comes to venous congestion, remains challenging with the traditional methods of physical exam and chest X-ray. Furthermore, repeat measurements of pulsatility allow for the clinician to assess for improvements in organ congestion, potentially avoiding excessive diuresis. Prior studies have demonstrated a high success rate and good interobserver variability which bolster the case for the more pervasive use of portal vein pulsatility in the management of hyponatremia . A propoThere remain significant limitations to our proposal for the use of portal vein pulsatility to diagnose and follow therapeutic efficacy for hypervolemic hyponatremia. First, though the physiology is viable, there needs to be a more extensive proof of concept study performed, as we are still in the hypothesis phase. Secondly, though prognosis appears to be worse in heart failure patients with hyponatremia, there is little evidence that modification of the hyponatremia would improve mortality outcomes. Instead, the goal is to improve symptoms and morbidity; for example, sodium levels below 120 meq/L can alter mentation and predispose to seizures, and correction can improve these outcomes.We present two cases of hypervolemic hyponatremia. Hypervolemic hypotonic hyponatremia is both challenging to diagnose and manage. We propose portal vein pulsatility as a means to diagnosis and as an indicator for efficacy of therapeutics. The study is relatively simple to perform with excellent interobserver variability. Our case series is hypothesis generating, and a more extensive study will need to be performed to further corroborate the use of portal vein pulsatility index in the management of hypervolemic hyponatremia.


Cardiac morphology changes in heart failure and provides information on the state of the heart. We hypothesized that pre-implant left ventricular (LV) morphology differs significantly between responders and nonresponders to cardiac resynchronization therapy (CRT). To this end, the LV morphology of 50 subjects selected for CRT was studied from cardiac magnetic resonance by building a statistical 3-dimensional (3D) anatomic atlas.Fifty consecutive subjects—39 men, 69.3 ± 11.2 years of age, 46% with ischemic etiology, and 92% with left bundle branch block (LBBB)—underwent a cardiac magnetic resonance anatomic study: electrocardiogram-gated free-breathing steady-state free-precession 3D anatomic sequences with nearly isotropic spatial resolution (median of 0.89 × 0.89 × 1.00 mm) before the CRT implantation procedure with a lead in a lateral or posterolateral vein as per standard clinical practice. They were all clinically assessed at baseline and followed up 6 months after implantation: LV end-systolic volume change on echocardiography defined CRT response, positive with a reduction in LV end-systolic volume of >15% A statistical anatomic atlas was built from the 50 steady-state free-precession datasets involving: 1) a semiautomatic segmentation of the LV by 2 observers, reaching a Dice similarity metric with fully manual approach of 0.74 ± 0.05; 2) the automatic construction of 3D models LV shape changes due to a variety of factors, and the goal was to identify the LV morphological pattern that is most associated with CRT response. We thus found the linear combination of principal component analysis modes that best differentiated response to CRT through a linear discriminant analysis. Linear discriminant analysis performance was evaluated by cross-validation , identifying the combination that maximized the area under the curve of the receiver-operating curve, finding an area under the curve of 0.7603 ± 0.0162, and a sensitivity and specificity of 77% and 82%, respectively, at the optimal working point. The visual inspection of the remodeling signature that was predictive of CRT response  revealedThe presence of a thicker lateral wall in the responder suggests a larger workload localized in this region causing the localized thickening. This is supported by earlier studies using positron emission tomography, which demonstrated metabolism was highest in the lateral wall and lowest in the septum at baseline in all patients In conclusion, a specific morphological signature, with asymmetric thickness in the pre-implant LV shape, was found to be an independent predictor of a favorable remodeling response to CRT. LV shape may represent a potential new criterion for CRT patient selection.


We aimed to investigate the association of smoking and physical exercise on ventricular function and structure, determined by cardiac magnetic resonance imaging (CMR), in subjects without known cardiovascular diseases. A total of 381 participants (median age 57 years) of the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort underwent CMR. The participants’ smoking and sporting habits were measured by a questionnaire. Physical inactivity was associated with a reduction of left ventricular ejection fraction (LV-EF), stroke volume, early diastolic peak filling rate and peak ejection rate of the left ventricle as well as right ventricular stroke volume. LV-EF was reduced in subjects with almost no physical activity compared to subjects with regular physical activity . Smokers had lower right ventricular end-diastolic volumes  but higher extracellular volume fractions (ECV) and fibrosis volumes . We conclude that asymptomatic individuals without known cardiovascular diseases show differences in cardiac function and structure depending on their physical activity and smoking habits. This underlines the importance of prevention and health education. Smoking and physical inactivity are among the main modifiable risk factors4. In several clinical and population-based studies, smoking and physical inactivity were independently associated with advanced cardiovascular disease such as heart failure, myocardial infarction and stroke as well as cardiovascular mortality12. The prevalence of smoking declined in the last 25 years, but still about 21% of men and 6% of women worldwide were smoking in 201510. More than 35% of adults have a sedentary life style with low physical activity10.Deaths due to cardiovascular disease increased by 12.5% globally between 2005 and 201516. However, there is only limited data on the association of smoking and physical inactivity on subclinical cardiovascular changes in asymptomatic individuals without a history of cardiovascular disease. Even less data is available about the influence of cardiac risk factors on diffuse myocardial fibrosis or myocardial scarring in asymptomatic individuals.Some studies have also linked smoking and physical inactivity to reduced myocardial function and reduced ventricular mass19. Furthermore, it allows to evaluate myocardial scarring and diffuse fibrosis20.Cardiac magnetic resonance imaging (CMR) is the standard of reference for the evaluation of right ventricular function and is less patient- and investigator-depended than echocardiography concerning left ventricular structure and functionThus, we aimed to investigate if smoking and physical inactivity are associated with changes in cardiac structure and function as determined by CMR in asymptomatic individuals without known cardiovascular diseases.We hypothesized that smoking and physical inactivity are independent risk factors for elevated left and right ventricular mass, decreased left and right ventricular function and increased amounts of myocardial fibrosis and scarring.Out of the 400 participants in our sub-study, a total of 381 participants were included in the analysis. Nineteen examinations had to be excluded because for poor image quality or missing left ventricular data. The right ventricular data was available in 337 subjects. In 35 cases, data were incomplete due to software problems during the MRI scan or because the examination was aborted by the study participant. For 28 subjects, short axis images did not completely include the basal part of the right ventricle and were therefore excluded from the final evaluation. Data of 260 subjects were included in the calculation of extracellular volume fraction (ECV) and 257 subjects in the fibrosis calculation, the others had to be excluded due to artifacts, incomplete measurements or missing haematocrit levels. In 368 subjects, Late Gadolinium Enhancement (LGE) measurements could be analysed – 32 examinations had to be discarded due to missing data or poor image quality. Baseline characteristics of the study population are shown in Table 21. A total number of 11 individuals (2.9%) showed LGE and mean ECV and fibrosis volume were 0.24 ± 0.03% and 31.8 ± 8.2%, respectively.Overall, mean left and right ventricular parameters of the study population were within normal limits (left ventricular end-systolic volume (LV-ESV): 40.7 ± 18.1 ml, left ventricular end-diastolic volume (LV-EDV): 129.1 ± 32.9 ml, left ventricular ejection fraction (LV-EF): 69.2 ± 8.2%, left ventricular stroke volume (LV-SV): 88.3 ± 20.7 ml, left ventricular (LV) myocardial mass: 140.7 ± 35.0 g, right ventricular end-diastolic volume (RV-EDV): 165.5 ± 39.8 ml, right ventricular end-systolic volume (RV-ESV): 79.1 ± 25.9 ml, right ventricular stroke volume (RV-SV): 86.4 ± 19.5 ml and right ventricular ejection fraction (RV-EF): 52.8 ± 7.0%) with some subjects with reduced LV-EF  or RV-EF  or increased LV volumes  or RV volumes Multivariable linear regression analysis revealed that physical inactivity was associated with a decrease in LV-SV, LV-EF, Peak Ejection Rate (PER) and early diastolic filling rate PFR1). There was a decrease in LV-EF from subjects with regular 2 h exercise per week  to subjects with almost no exercise  (p = 0.044). All LV-EF values of the different physical activity groups are displayed in Fig. . There wThere were no significant associations between smoking status and left ventricular function Table . HoweverRV-EDV was significantly lower in current smokers  than in never-smokers  (p = 0.048). Smoking status showed no significant associations with RV-ESV, RV-SV and RV-EF  and fibrosis volumes  Table .Table 7SIn this cross-sectional study, we examined the association of physical inactivity and smoking habits on cardiac function and structure as assessed by CMR in subjects without known cardiovascular disease. Parameters for left and right ventricular function were within normal limits for the vast majority of participants. However, we found that physical inactivity is associated with a reduction of LV and RV systolic and LV diastolic function. Furthermore, smoking was associated with a reduction of RV-EDV and with elevated ECV and fibrosis volumes.16. In MESA as well as in our study, LV-SV increased with exercise. In contrast to MESA, we have also found a positive effect on LV-EF. Potentially these results could be explained by differences in the assessment of physical activity or differences in the ethnicities of the study (the KORA population being completely Caucasian). Furthermore, we used a 3-Tesla MRI system, which offers an increased signal-to-noise-ratio and contrast-to-noise-ratio compared to 1.5-Tesla22.These findings are in line with results of the Multi-Ethnic Study of Atherosclerosis (MESA)et al. showed that older and untrained subjects had a lower PFR123. This correlates with our results, where subjects with the highest physical activity per week had the highest PFR1. In our study subjects with more than 2 hours of physical activity per week had the highest PER, as was already demonstrated by Stratton et al.24, where untrained men had lower PER.Levy et al. in the MESA trial15. The higher RV-SV could be caused by hypertrophy of cardiomyocytes due to physical activity, causing higher left and right SV25.Our study shows that physical activity has a significant positive effect on RV-SV. Regular physical activity also positively influenced RV-EDV and RV-EF, but these results were not significant. This is in line with the results of Aaron 26, but more LGE27, while in our study physical activity had no significant effect on fibrosis volumes, ECV or LGE. As physical activity influences cardiac function and hypertrophy, fibrosis and ECV could also be affected, whereas presence of LGE should not differ between subjects with more or less physical activity. These partly differing results need more research in the future.In former studies, subjects with higher physical activity rates showed no difference in cardiac fibrosis volumes28. In contrast, the LARGE study found a smaller left ventricular mass in smokers, maybe due to the special cohort of the LARGE study, which comprised only healthy young men29.We observed a trend towards increased left ventricular mass in smokers, a result that is in line with MESA and other studies32. Cigarette smoke includes several toxic substances that cause aging of cardiomyocytes and thus reduced compliance of the right ventricle33. Smoking can lead to chronic obstructive pulmonary disease, which causes hyperinflation of the lungs32. Both mechanisms can thus reduce RV filling.Analogous to the MESA study, RV-EDV was lower in smokers34. In MESA, smokers also had more LGE35, whereas in our study smokers had less LGE, but this result was not significant. It is known that smokers are more vulnerable concerning coronary heart disease so it could be expected that smokers and ex-smokers show more LGE than never-smokers. This, too, needs further research with larger cohorts.We were able to demonstrate that current smokers had significantly higher ECV and fibrosis volumes compared to non-smokers, which can be explained by oxidative stress and inflammation causing cardiac remodeling in smokersAs this is a cross-sectional study, we can only show correlations; it is not possible to draw conclusions about causations. As opposed to the LARGE study  or the MESA study  our subjects were aged 38–72, caucassian, and were approximately 50% females. As a result, our cohort is better suited for the population in Germany than the LARGE or MESA cohorts. Our results are in general in line with the results of other large cohort studies examining subclinical cardiovascular changes depending on risk factors.Smoking status was assessed via questionnaire, so there was no biochemical confirmation of smoking status. Whereas subjects with known cardiovascular diseases were excluded from the KORA study, participants with known pulmonary diseases that could affect the right ventricle, were not excluded. Another limitation is that the subjects’ amount of physical activity was based on an interview and not validated via ergometry, resting heart rate or electronic activity trackers like wristbands.The differences between the examined groups were small and most probably have no clinical significance but may represent early manifestations of potentially progressive disease.36. Especially when measuring LV-EF using the Simpson method, echocardiography has its limitations because frequently the endocardial contours are often not clearly visible when not using contrast agents17. Whereas cardiac magnetic resonance imaging (CMR) has lower inter-observer variabilities, is less dependent on acoustic windows and shows better contrast between endocardium and blood in order to properly measure endocardial contours to measure left ventricular volumes and calculate left ventricular ejection fraction37. For left ventricular hypertrophy, CMR has higher sensitivity rates than echocardiography38. Furthermore, it was shown that CMR has higher reproducibility rates in right ventricular parameters40. CMR can therefore be called the standard of reference for detecting the smallest, but still significant changes in cardiac function and mass parameters19.Most studies about the impact of cardiac risk factors used echocardiography, for example the Framingham Study. Echocardiography is a widely available method, it is fast, cost-effective and does not use radiation. Unfortunately, echocardiography is more dependent on the patient’s constitution, depending on the patient’s acoustic windows, and has quite a high inter-observer variabilityUsing CMR, our study showed that in subjects without a history of cardiovascular diseases, parameters of left and right ventricular function increase with physical activity and decrease with smoking. In addition, we were found increases in ECV and fibrosis volumes in smokers. These results underline once more the importance of prevention and health education in order to prevent subclinical and in hereafter symptomatic cardiovascular changes.Kooperative Gesundheitsforschung in der Region Augsburg”, Cooperative Health research in the region of Augsburg) S4 cohort. S4 is a health survey (1999–2001) comprising 4,261 individuals, 25 to 74 years of age, in the region of Augsburg in the south of Germany. The first follow-up (F4) was conducted between 2006 and 2008 with 3,080 participants and the second follow-up (FF4) took place in 2013/2014 with 2,279 participants41.Study participants were recruited from the second follow-up (FF4) of the population-based KORA , any implanted device , pregnant or breast feeding female subjects, claustrophobia, known allergy against gadolinium compounds and serum creatinine ≥1.3 mg/dl. The inclusion criteria were: willingness to undergo whole-body MRI and qualification in the diabetics, prediabetics or control group according to the World Health Organization criteria43. In total, 400 subjects aged 38–72 years were included in this study. The study was approved by the institutional review board of the Ludwig-Maximilians-University, Munich, and all participants provided written informed consent42. All methods were performed in accordance with the relevant guidelines and regulations.The current study population was drawn from a sub-study that aimed at examining MRI-derived subclinical cardiovascular disease burden in diabetics, pre-diabetics and controls without a history of cardiovascular diseaseAll images were obtained with the same 3-Tesla MR system  in the Institute of Clinical Radiology of the Ludwig-Maximilian University Hospital in Munich. Imaging was performed using an 18-channel body coil in combination with the table-mounted spine matrix coil. The MRI examination was performed within three months after the FF4 visit at the study center. The protocol comprised imaging of the neurocranium, the carotid vessels, liver and whole-body fat imaging as well as cardiac imaging. Total acquisition time was approximately one hour. The full protocol is shown in Supplementary Table Left ventricular function was assessed using cine-steady state free precession sequences which were acquired in four chamber view and short axis stack with 10 slices and 25 phases using the following parameters: slice thickness 8 mm, in-plane voxel size 1.5 × 1.5 mm², field of view 297 × 360 mm², matrix 240 × 160, repetition time 29.97 ms, echo time 1.46 ms, flip angle 63°.44 by two readers blinded to any information regarding the subjects’ risk factors and clinical status. After automatic contouring of the endo- and epicardial contours, the outlines were corrected manually, if necessary. The papillary muscles were excluded from the myocardial mass and included in the ventricular volumes. The position of end-diastolic and end-systolic phase were chosen automatically by the software. The derived parameters were: end-systolic volume (LV-ESV), end-diastolic volume (LV-EDV), stroke volume (LV-SV), ejection fraction (LV-EF), systolic and diastolic myocardial mass, cardiac output, and left ventricular wall thickness. An example of the LV contouring is given in Fig. Evaluation of cardiac function parameters was performed using a dedicated software package , Circle Cardiovascular Imaging Inc., Calgary, Canada). The left ventricular short-axis and four chamber view images were analyzed semi-automatically. The reading was performed according to standardized post-processing guidelines of the Society for Cardiovascular Magnetic Resonance44. The largest and smallest right ventricular volume were defined as end-systolic and end-diastolic phase. Papillary muscles were included in the ventricular volume. Parameters included: end-diastolic (RV-EDV) and end-systolic volume (RV-ESV), stroke volume (RV-SV), cardiac output, ejection fraction (RV-EF).Right ventricular volumes and function were analyzed by manual tracking of the endocardial contour on short-axis and manual detection of the apex and tricuspid valve on four chamber view images according to current guidelines45.Late gadolinium enhancement (LGE) sequences were acquired 10 minutes after administration of gadopentate dimeglumine  as Fast Low Angle Shot (FLASH) inversion recovery sequences with slice thickness 8 mm, FOV 300 × 360 mm, Matrix 256 × 140, TR 700–1000 ms, TE 1.55 ms and FA 20–55°. Analysis of late gadolinium enhancement (LGE) was performed by two experienced readers using the same software also used for the cardiac function analysis . In case of discrepancy, a consensus reading was performed. The presence and distribution pattern  of LGE was documented using the AHA 17-segment model46 to omit influence of surrounding fat or blood by two blinded readers. Segments with obvious artifacts or presence of LGE were discarded. Another region of interest was placed in the blood volume. ECV as a measure of the amount of extracellular matrix was calculated from the T1 relaxation times pre and post contrast by taking into account the haematocrit. Fibrosis volume was derived using the following formula:ΔR1myocardium = 1/T1myo-post − 1/T1myo-preΔR1 blood = 1/T1blood-post − 1/T1blood-preMyocardial partition coefficient (λ)  = (ΔR1myocardium/ΔR1 blood)ECV =  (1 − haematocrit level) × λFibrosis volume = ECV*LVmass/myocardial density [myocardial density = 1.05 g/mL]For measuring myocardial fibrosis, T1 ECG-gated steady-state free-precession-based modified Look-Locker inversion-recovery (MOLLI) sequences with 5(3)3 pattern  were acquired pre- and 10 minutes post contrast. These sequences were acquired on short axis at the mid-ventricular and basal short-axis plane (segments 1–12) with the following parameters:: Slice thickness 8 mm, spatial resolution: 1.5 × 1.5 mm2, acquired voxel size: 2.25 × 1.5 mm2, FOV: 323 × 380 mm using a 256 × 144 mm matrix, TE: 1.1, TI: 100–3500 with a 35° flip angle. T1 relaxation times were calculated per segment (1–12 of the 17 segments of AHA classification). The inner and outer contour of the left ventricular myocardium was segmented following recommendationsSmoking habits and physical activity of the subjects were measured in a standardized interview during the FF4 follow-up at the KORA study center. Physical activity was scaled as follows: Physical activity regularly more than 2 hours per week (group 1), regularly one hour per week (group 2), irregularly one hour per week (group 3), almost no activity (group 4). For smoking the scaling was: smoker, ex-smoker, never-smoker. Subjects were classified as smokers if they reported current regular or sporadic cigarette smoking.47. Blood pressure was measured three times at the right arm of seated participants after an at least five-minute resting period. The mean of the second and third measurement was used for the analyses. Arterial hypertension was defined as increased systolic blood pressure (≥140 mmHg) and/or increased diastolic blood pressure (≥90 mmHg) or use of antihypertensive medication under awareness of having hypertension according to 2003 World Health Organization / International Society of Hypertension criteria48.Several co-variates were measured in the KORA FF4 study center by standardized interview, basic health examinations and laboratory analyses. They comprised: age (years), sex , body mass index , waist circumference, body surface area, systolic and diastolic blood pressure, diabetes status , intake of antihypertensive, lipid-lowering or antidiabetic medication. Laboratory measurements including HbA1c, glucose, total cholesterol, high and low density lipoprotein and triglycerides were performed according to KORA standardsBaseline characteristics of the study sample were separately described for women and men by median and interquartile range for continuous variables and absolute numbers and percent values for categorical variables.Associations of physical inactivity and smoking (risk factors = independent variables) with left and right ventricular structure and function parameters (outcomes = dependent variables) were investigated by calculating adjusted predicted outcome means or proportions with 95% confidence intervals by using average co-variable values after separated linear or logistic regression models for each risk factor and each outcome. Adjustments were made for age, sex, body mass index, systolic and diastolic blood pressure as well as diabetes mellitus. Physical inactivity and smoking status were treated as factor variables and each predicted mean was compared with its reference category of regular 2 hours activity per week or never smoking status, respectively. The p-value from t-test of the corresponding β-coefficient from the linear regression model was used to evaluate outcome differences between risk factor groups. Normal distributions of predicted residuals were tested visually. In addition, observed differences of LV-EF between physical activity categories were presented by box plots providing group medians, interquartile ranges and lower and upper adjacent values. All analyses were additionally adjusted for sampling weights considering differences in age, sex and diabetes status between the study sample (n = 400) and the entire KORA cohort  yielding no substantially changed findings. A p-value of <0.05 was considered statistically significant. Statistical analyses were performed using Stata 14.1 .Supplementary Table S1


The aim of the study was to evaluate CMR myocardial first-pass perfusion in the injured region as well as the non-infarcted area in ST-elevation myocardial infarction (STEMI) patients few days after successful primary percutaneous coronary intervention (PCI).220 patients with first time STEMI successfully treated with PCI (with or without postconditioning) were recruited from the Postconditioning in STEMI study. Contrast enhanced CMR was performed at a 1.5 T scanner 2 (1–5) days after PCI. On myocardial first-pass perfusion imaging signal intensity (SI) was measured in the injured area and in the remote myocardium and maximum contrast enhancement index (MCE) was calculated. MCE = (peak SI after contrast—SI at baseline) / SI at baseline x 100.There were no significant differences in first-pass perfusion between patients treated with standard PCI and patients treated with additional postconditioning. The injured myocardium showed a significantly lower MCE compared to remote myocardium . When patients were divided into four quartiles of MCE in the injured myocardium (MCE injured myocardium), patients with low MCE injured myocardium had: significantly lower ejection fraction (EF) than patients with high MCE injured myocardium, larger infarct size and area at risk, smaller myocardial salvage and more frequent occurrence of microvascular obstruction on late gadolinium enhancement. MCE in the remote myocardium revealed that patients with larger infarction also had significantly decreased MCE in the non-infarcted, remote area.CMR first-pass perfusion can be impaired in both injured and remote myocardium in STEMI patients treated with primary PCI. These findings indicate that CMR first-pass perfusion may be a feasible method to evaluate myocardial injury after STEMI in addition to conventional CMR parameters. In patients with acute ST-elevation myocardial infarction (STEMI) the recommended treatment to restore coronary blood flow is percutaneous coronary intervention (PCI) within the first 120 minutes after the STEMI diagnosis has been made . Thus, vCardiac magnetic resonance (CMR) imaging is a sensitive method for evaluation of the microcirculation with high spatial resolution , 7. OverThis study included patients from the Postconditioning in STEMI (POSTEMI) study. Compared with conventional primary PCI, PCI combined with ischemic postconditioning did not influence the primary endpoint of infarct size nor the secondary endpoints of MVO, myocardial salvage and ejection fraction, as determined by CMR . The aimThe study population was recruited from the POSTEMI study  on patients with acute STEMI treated with PCI with or without a postconditioning procedure . The stuThe study protocol is described in detail elsewhere , 20. In Patients were treated with primary PCI (standard treatment) or primary PCI with postconditioning. The postconditioning was performed with balloon inflations, 4 cycles of 1 min reocclusion and 1 min reperfusion, starting 1 min after opening of the occluded coronary artery .All patients were treated with a stent in the IRA and received a GPIIb/IIIa inhibitor.Of the 272 patients randomized in the POSTEMI trial, 220 patients were included in the present study . ReasonsClinical data were collected at one year and a composite endpoint was defined as death, myocardial infarction, unscheduled revascularization >3 months after the index infarction, rehospitalization for heart failure, or stroke.CMR was performed within 2 (1–5) days after the STEMI on a 1.5 T scanner , using five-element synergy-cardiac coil or Sense-cardiac coil, respectively, and vector-based electrocardiography (ECG).For cine imaging the left ventricle was scanned in two-, three- and four-chamber long axis view using balanced fast-field echo sequences for functional analysis, and short axis images were acquired for complete left ventricular volume analysis. T2-weighted imaging was performed with five short axis slices, covering the ventricle from basis to apex using black blood inversion recovery fast spin echo sequences. The most apical and the most basal slices were rejected and the three mid slices were used for analyses.First-pass perfusion at rest was performed using ECG triggered fast T1 enhanced gradient-echo technique with segmented K-space and saturation pre-pulse. Three short axis slices were acquired during breath hold, scanning for one minute. The parameters were: TR (time to repeat) 3.2 ms, TE (time to echo) 1.26 ms, flip angle 20° and saturation prepulse delay 200 ms, trigger delay approximately 210 ms, matrix 128 and field of view 350 mm, slice thickness 10 mm, gap 20 mm.The LGE study was performed 15 minutes after the first-pass study in short axis and two- and four-chamber long axis view, using 3D turbo-field-echo technique with inversion pre-pulses, covering the whole left ventricle. The imaging parameters were: TR 4.5 ms, TE 1.44 ms, flip angle 15° and trigger delay 375–1226 ms, chosen according to the ECG RR interval to fit end-diastole. The optimal T1 for suppression of the myocardium was achieved by the Look-Locker sequence before the diagnostic sequences was performed [In all patients, gadolinium-DTPA  was injected using Spectris power injector. For the first-pass perfusion imaging, 0.05 mmol/kg body weight was injected at the rate of 3 ml/s into the left brachial vein, followed by 25 ml of saline infused at the same speed . For LGEAll image analysis was performed offline on a View Forum workstation, Philips Intera extended MR workspace R2.6.3.1. . First-pass perfusion imaging was analyzed by one reader (AB) with 5 years experience. All other parameters were analyzed by another reader (PH) with an experience >10 years within the field.EF was calculated by assessment of the volumes of the endocardial contours in diastole and systole of the short axis images as per standard practice .AaR was assessed in the T2 images as myocardium with a SI of more than 2 standard deviations above the signal intensity (SI) in remote myocardium. The contour of the area with hyperintense signal was than manually drawn in the central 3 of the 5 short axis slices. As the remote area, myocardium supplied by other arteries than the IRA remote to the infarction was chosen. High-grade stenosis in the remote area was ruled out via coronary angiography findings. Myocardial hemorrhage was assessed visually as a hypoenhanced region within the AaR on T2 imagages. The size of the hemorrhage was not assessed.Myocardial first-pass perfusion was analyzed semi-quantitatively by measuring the SI versus time . SI was line×100 –26. Timeline×100 . AdditioThe IS was assessed as a volume in the LGE images by manually drawing the contour of the hyperenhanced area in short axis slices . The vol)AaR×100 .The readers were blinded to treatment strategy and clinical outcome. The intraobserver reliability estimated by the intraclass correlation coefficients for myocardium at risk and infarct size were 0.876, 95% CI (0.628 to 0.963) and 0.985, 95% CI (0.963 to 0.994), respectively .Within observer consistency and agreement was 0.902, 95% CI (0.716–0.972) and 0.906, 95% CI (0.705–0.972) for MCE injured myocardium and 0.878, 95% CI (0.782–0.962) and 0.883, 95% CI (0.774–0.963) for MCE remote myocardium. The Pearson`s correlation coefficient between observers was 0.960, 95% CI (0.903–0.984) for MCE injured myocardium and 0.759, 95% CI (0.488–0.897).Consistency and agreement between observers was: 0.958, 95% CI (0.919–0.981) and 0.960, 95% CI  for MCE injured myocardium and 0.741, 95% CI (0.395–0.981) and 0.741, 95% CI (0.381–0.981) for MCE remote myocardium, respectively.This substudy was a cohort study of exposed (standard treatment and postconditioning) versus unexposed (standard treatment) patients.Peak troponin is given as median (interquartile range) as the distribution was right skewed. Other continuous data were approximately normally distributed and are presented as mean ± standard deviation, binary data as distribution of categories.To compare patients with different perfusion levels, MCE data of injured myocardium (MCE injured myocardium) were divided into 4 quartiles where quartile 1 represents the highest and quartile 4 the lowest perfusion level. The one-way ANOVA or the chi-square test for categorical variables were used to compare the means of the groups.Normality and homoscedasticity of the residuals was confirmed for MCE injured myocardium . TherefoCorrelation between MCE injured myocardium and the composite endpoint was done with Spearman´s rho.A p-value <0.05 was considered statistically significant. We used IBM SPSS Statistics 24 for all analysis.Baseline characteristics of the 220 patients included in this substudy are shown in CMR first-pass perfusion revealed significantly reduced MCE and delayed TTP in the injured myocardium compared to remote myocardium .When MCE data of the injured myocardium were divided into four quartiles, peak troponin T was higher for patients with lower MCE. However, there were no significant differences in the angiographic data like symptom-to-balloon time, door-to-balloon time, IRA, multi vessel disease, TIMI flow post PCI or the use of thrombectomy related to the level of MCE .Comparing the level of MCE to the functional CMR parameters, patients with high MCE injured myocardium (1. quartile) had significantly smaller EDV and ESV and higher EF compared to patients with low MCE injured myocardium (4. quartile) . CompariPeak SI in the lumen of the left ventricle was not significantly different between the four groups .Analyzes of MCE in the remote myocardium showed that in the 1. quartile MCE in the remote myocardium tended to be lower (not significant) than in the injured myocardium. In all the other quartiles of MCE injured myocardium, MCE remote myocardium was higher than MCE injured myocardium. Data also showed that MCE remote myocardium decreased significantly from the 1. to the 4. quartile .Clinical events were few. Of the 220 patients included in the present substudy 13 patients had a clinical event as defined in the composite endpoint. There was no significant difference between the four groups of MCE injured myocardium .In the present study, the results on CMR first-pass perfusion at rest showed no significant differences between patients treated with PCI with or without postconditioning, which is in accordance with the findings in the main study , 29.Normalized flow in the epicardial arteries, in the absence of high-grade stenosis, gives a comparable blood supply to the entire myocardium. Still, microvascular perfusion in the injured myocardium was significantly lower than in the remote area of the left ventricle. The main findings of the present study are, that the level of MCE injured myocardium was associated with EDV, ESV and EF as well as the IS, AaR, myocardial salvage and the occurrence of MVO at LGE imaging. Furthermore, in patients with low perfusion in the injured myocardium also perfusion in the remote myocardium was significantly impaired. Semiquantitative parameters do not depend on the relative difference between injured and remote myocardium and therefore minor changes in remote myocardium can be detected. Recently, research on STEMI patients has focused more on the remote myocardium  and paraIn patients with acute STEMI and restored TIMI 3 flow in the IRA, TMP grade assessed at final angiography has been shown to have prognostic value , 4. The Despite standardized contrast media dose and infusion rate as well as examination technique and TIMI 3 flow after PCI in the majority of the patients (95.5%), there were significant differences in CMR first-pass perfusion at rest. In the present study, patients with high MCE injured myocardium performed better on functional CMR parameters and presented with significantly smaller IS, and even though they had smaller AaR, they also had higher myocardial salvage. This is in agreement with the findings of Hopp et al. , who alsThe present study also shows that MCE remote myocardium may be impaired after STEMI treated with PCI. As none of the other CMR parameters in our study, such as T2, LGE or cine sequences showed alterations in the myocardium supplied of other than the target vessel, first-pass perfusion appears to be a more sensitive parameter for evaluating the microvasculature. Also previous CMR studies have found alterations in perfusion of the myocardium adjacent to the infarction and also in the remote myocardium. For instance, Bodi et al. found hypoperfusion in the non-infarcted myocardium in 13% of the myocardial segments adjacent to the infarction  and TaylEvolving techniques like T1 mapping have also shown changes in the remote myocardium , 43, 44.The remote myocardium in patients with STEMI has also been evaluated in a series of studies applying other methods than CMR. In a recent study in patients with acute myocardial infarction, Cheng et al.  showed aEchocardiography with circumferential strain could as well show a significant correlation between alterations in the non-infarcted myocardium and diastolic function . It was Several histological studies, both in animals and patients found alterations like focal necrosis not only in the infarcted but also in the remote myocardium early after myocardial infarction , 52. OliSTEMI patients treated with primary PCI do generally have a good prognosis , 55. In However, to prevent left ventricular remodeling patients at high risk and in need for intensified therapy need to be identified at an early point in time. The results of the present study indicate that changes in the remote and injured myocardium are related to outcome. As LGE normally does not show alteration in the remote myocardium, we additionally to the standard parameters propose MCE in the injured and remote myocardium as an early marker for risk stratification in STEMI patients treated with primary PCI. However, more standardization of perfusion in the remote myocardium is needed before clinical application. This can be an interesting research area for future investigations.In the present study first-pass perfusion CMR covers only 3 slices and not the entire left ventricle, which can lead to inaccuracy . Great cSI can vary within different distances to the coil. We accounted for that by relating peak SI to baseline SI. Moreover, IRA was evenly distributed between the different groups.We applied a semiquantitative analysis for the evaluation of first-pass perfusion imaging instead of analyzing the absolute values. However, semiquantitative approaches have been shown to be valuable in STEMI patients , 37.CMR first-pass perfusion can be impaired in both injured and remote myocardium in STEMI patients treated with primary PCI. Impaired first-pass perfusion in the remote myocardium was particularly seen when impairment was larger in the injured myocardium. First-pass perfusion provided additional information to TIMI flow at angiography.S1 Fig(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.