Right ventricular (RV) function has proven to be a prognostic factor in heart failure with reduced and preserved ejection fraction and in pulmonary hypertension. RV function is also a cornerstone in the management of novel clinical issues, such as mechanical circulatory support devices or grown-up congenital heart disease patients. Despite the notable amount of circumferentially oriented myofibers in the subepicardial layer of the RV myocardium, the non-longitudinal motion directions are often neglected in the everyday assessment of RV function by echocardiography. However, the complex RV contraction pattern incorporates different motion components along three anatomically relevant axes: longitudinal shortening with traction of the tricuspid annulus towards the apex, radial motion of free wall often referred as the “bellows effect”, and anteroposterior shortening of the chamber by stretching the free wall over the septum. Advanced echocardiographic techniques, such as speckle-tracking and 3D echocardiography allow an in-depth characterization of RV mechanical pattern, providing better understanding of RV systolic and diastolic function. In our current review, we summarize the existing knowledge regarding RV mechanical adaptation to pressure- and/or volume-overloaded states and also other physiologic or pathologic conditions. Compared to the left ventricle (LV), whose anatomy and function has been the subject of intensive research, right ventricular (RV) morphology and mechanics were traditionally less studied in contemporary science. In the past few decades, novel diagnostic techniques and important epidemiology studies have brought RV function back into the scientific spotlight. RV function has proven to be a prognostic factor in heart failure with reduced and preserved ejection fraction and in pulmonary hypertension. RV function is also a cornerstone in the management of novel clinical issues, such as mechanical circulatory support devices or grown-up congenital heart disease patients. In our current review, we summarize the existing knowledge regarding RV mechanics in different overload conditions and emphasize the role of non-longitudinal contraction of the chamber and its evaluation.The myocardium is a complex three-dimensional network of myofibers in a multiple helical arrangement with important functional consequences. A contraction of these bundles deforms the ventricle and generates ejection, whereas the relaxation aids diastole; moreover, knowing the myofiber orientation helps to understand the pattern of RV contraction in the three-dimensional space. On the epicardial surface, circumferentially oriented myofibers are present; these myofibers are components of the myofiber tracts that are shared with the LV, encompass the subpulmonary infundibulum and advance more or less parallel with the atrioventricular groove. At the apex, this layer spirals into the deep  layer of the RV. However, this subendocardial fiber orientation is rather longitudinal Fig. . In physMechanistically, the RV shows a distinctive, peristaltic-like contraction pattern: the activation starts from the inlet portion and ends at the infundibulum . During Accordingly, three main mechanisms contribute to RV pump function: (1) shortening of the longitudinal axis with traction of the tricuspid annulus towards the apex; (2) inward  movement of the RV free wall, which is often referred as the “bellows effect”; and (3) bulging of the interventricular septum into the RV during the left ventricular contraction and stretching of the free wall over the septum (causing shortening in the anteroposterior direction).Normative data are still lacking regarding the relative contribution of the longitudinal, radial, and anteroposterior components of RV wall motion to global ejection. Under physiological conditions, the longitudinal shortening was suggested to account for the majority of RV pump function ; howeverTwo-dimensional echocardiography is barely capable of thoroughly characterizing RV morphology and function. Still, RV function assessment is often based exclusively on tricuspid annular plane systolic excursion (TAPSE), which refers only to the longitudinal shortening of the chamber. The estimation of RV volumes based on 2D geometrical assumptions (as regarding the LV) are not used routinely; instead, fractional area change (FAC) is calculated. Although this technique is a 2D approach and partially incorporates radial motion direction, FAC describes RV function in a single cut of a very complex 3D structure. Speckle-tracking echocardiography emerged as a valuable tool for a more quantitative, semi-automated approach. Global longitudinal strain is showing an established diagnostic and prognostic value regarding LV pathologies , and proAs a recent advancement, 3D echocardiography may overcome these shortcomings. Several software solutions are available to reconstruct the endocardial surface of the RV for a better appreciation of its geometry and to allow the measurement of volumes and subsequent ejection fraction. In addition, novel postprocessing solutions have become available for a deeper analysis of shape and function. Beyond 3D speckle tracking, curvature analysis and the separate quantification of the different motion components  are promising in terms of obtaining a deeper understanding of RV physiology and pathophysiology , 11.In conditions accompanied by pressure overload, the challenge for the RV is to remain coupled to the increased afterload. The major mechanisms include adaptive myocardial hypertrophy, which leads to increased wall thickness and reduced wall stress, and alterations of muscle properties, such as myocardial fiber orientation and also RV shape . The relRV-LV interactions should not be neglected in pulmonary hypertension. There is a parallel interaction via the leftward bowing of the interventricular septum and an in-series interaction as the RV fails to supply an adequate LV preload. Another interesting aspect of ventricular interdependence is functional linkage via common myofibers. In experimental models of pulmonary artery banding, the addition of a mild aortic band increases the contractility of the pressure-stressed RV, and this change is probably attributable to the Anrep effect and the continuity of myofibers . Better Although pressure overload induces prominent changes in RV structure and function, RV remodeling seems to be highly reversible, and the recovery of RV function could be observed after appropriate treatment. Patients with pulmonary hypertension showed markedly improved RV function and decreased RV wall thickness after lung transplantation, even with severe preoperative RV dysfunction . The degWhen RV preload increases, wall stress is maintained by dilation of the chamber, along with preserved end-systolic volumes in the early stages; these observations suggest increased contractile function through the Frank-Starling law, which effectively compensates for altered hemodynamic conditions. Clinical experience includes an accompanying increase in RV longitudinal shortening. The significant elevation of RV preload may be also tolerable with maintained global function in acute and chronic settings, and these observations led to the conclusion that RV volume overload is a benign condition that lacks hemodynamically detrimental consequences. However, there is growing evidence from tricuspid and pulmonary regurgitation patients that strongly emphasizes the negative effects of RV volume overload –21.In the clinical setting, the main etiologic factors of RV volume overload are tricuspid regurgitation (TR), pulmonary valve regurgitation, and left-to-right shunts. The latter two entities are almost exclusively associated with congenital heart diseases; for such diseases, in addition to the presence of RV volume overload, other complex structural and functional aspects must be taken into consideration and will be discussed later. Approximately 80% of TR is functional, and the nature of the primary disease also significantly affects pathophysiology and presentation . The majCongenital heart diseases (CHD) represent a wide range of cardiac malformations, in which RV characteristics are also the cornerstones of disease presentation and progression. Depending on the nature of the abnormality, the RV may be exposed to severe pressure and/or volume overload. In certain types of defects, the myofiber architecture also differs from the physiological architecture , and thiIn isolated atrial septal defect (ASD) patients, increased preload results in the dilation of the RV, along with maintained/increased contractility in compensated state . Global In intracardiac shunts, the main driver of RV geometric and functional remodeling is the altered loading conditions of the ventricle, whereas in complex malformations of the heart, such as tetralogy of Fallot (ToF), the RV myoarchitecture is primarily affected. In contrast with healthy individuals, in ToF patients, a prominent middle layer with circumferentially oriented myofibers is also found, similar to the LV architecture. Consequently, we may hypothesize a relative dominance of radial RV function. In the current era of ToF management, total surgical repair is performed in the first years of life. Still, pulmonary regurgitation as a consequence of the repair procedure is a common finding. This volume overload of the RV may be tolerated for the long term; however, current data support the finding that the restoration of valve function must be performed to preserve RV function . In the Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy that predominantly affects the RV. While the genetic background of AC is established, other factors, such as the volume load of the RV, may precipitate the disease and accelerate progression . VentricIn heart failure with preserved ejection fraction (HFpEF), it has been shown that more than 50% of total deaths are attributable to right heart failure . In the In heart failure with reduced ejection fraction (HFrEF), right heart failure develops because of gradual increases in afterload due to pulmonary hypertension and because of tricuspid regurgitation accompanied by volume overload. Due to the given pericardial space, the enlargement of one ventricle will affect its counterpart. Moreover, in the presence of overload conditions, misalignment of interventricular interactions and normal cardiac cycle events can lead to mechanical dyssynchrony. Geometrically, this change often means that in the early stages, the bulging of the septum will be more prominent, and the space for RV volume will drop. This effect may imply a heavier dependence on longitudinal shortening of the free wall, as seen in other conditions in which a heavily distorted RV geometry is present . RV failChanges in RV mechanical pattern in conduction abnormalities and during RV pacing also attract scientific interest. Pacing from the RV results in a contraction pattern that is similar to a left bundle branch block . This efThe assessment of RV function by echocardiography is also key in the selection of candidate patients for ventricular assist device implantation. The presence of RV dysfunction is unequivocally associated with worse outcomes. Carluccio et al. investigated and followed up 200 patients with HFrEF but normal TAPSE . RV freeLeft-sided valvular diseases subsequently affect the right heart through the varying burden of pressure- and/or volume overload. However, RV function is commonly found to be significantly altered following cardiac surgeries, such as coronary artery bypass grafting (CABG), surgical valve repair, or heart transplantation , 42. TheThe evaluation of RV function following orthotropic heart transplantation deserves special attention because RV failure is still one of the major determinants of cardiac complications and mortality during the early postoperative period . The altIn conclusion, the decline in RV longitudinal function after cardiac surgery does not necessarily indicate a reduction in global RV systolic function. Therefore, reporting of RV parameters that also incorporate radial function is highly recommended .Regular exercise training is associated with significant changes in cardiac dimensions and function, which are also referred to as athlete’s heart . TraditiAlthough very few prospective follow-up studies were performed in the field, current data suggest that the volumetric adaptation of the RV to exercise is more pronounced than that of the LV and that the eccentric type of hypertrophy is expected at all levels of training . RestingIn our review, we have provided a brief summary of the existing literature regarding the mechanical adaptation of the RV to different overload conditions. The RV, which is often referred to as the “forgotten chamber”, has emerged as an important factor and prognosticator for several cardiovascular conditions. The avoidance of RV failure is now a major and explicit goal, for instance, in pulmonary hypertension, HFpEF, and CHD patients.Echocardiography is the first-line modality for assessing and monitoring RV morphology and function. However, 2D approaches fail to provide a good estimation of the non-longitudinal contraction of the chamber. Notably, the subepicardial layer of the RV myocardium consists of circumferentially oriented myofibers, which play a significant role in the complex contraction pattern. Nevertheless, further prospective studies are needed to assess the clinical value of in-depth characterization of RV mechanics. While pressure overload seems to affect the RV in a uniform way, the mechanical characterization of a volume-overloaded RV is more complex. Beyond contractility, the preload and afterload determine RV function, and the effect of pericardial constraint should not be neglected. Surgical procedures induce an instant shift in the functional pattern.To provide a clinical recommendation on the assessment of RV function, it is important to emphasize that the sole evaluation of longitudinal shortening does not grant sufficient information concerning the majority of RV-related pathological conditions Table . If applUsing advanced imaging modalities, the knowledge gap in our understanding of the adaptation of RV shape and function appears to be narrowing. As for the LV, segmental and subsequent motion pattern analyses are the next steps in RV research activity.


The mechanical reinforcement of the ventricular wall after a myocardial infarction has been shown to modulate and attenuate negative remodeling that can lead to heart failure. Strategies include wraps, meshes, cardiac patches, or fluid-filled bladders. Here, we review the literature describing these strategies in the two broad categories of global restraint and local reinforcement. We further subdivide the global restraint category into biventricular and univentricular support. We discuss efforts to optimize devices in each of these categories, particularly in the last five years. These include adding functionality, biomimicry, and adjustability. We also discuss computational models of these strategies, and how they can be used to predict the reduction of stresses in the heart muscle wall. We discuss the range of timing of intervention that has been reported. Finally, we give a perspective on how novel fabrication technologies, imaging techniques, and computational models could potentially enhance these therapeutic strategies. Over one million people suffer a myocardial infarction (MI), or heart attack in the U.S. every year . An MI oFor patients that survive an MI, preventing or hindering the development of HF is the main goal. Current clinical practices include medication and lifestyle changes in the post-MI stages. If patients progress to HF, left ventricular assistive devices (LVADs) can act as a bridge-to-transplant or a bridge-to-destination, but have inherent limitations, such as a propensity for thrombogenicity, and limited long-term success. Mechanical reinforcement strategies, where part or all of the heart is reinforced or restrained with an epicardially placed wrap or patch, have been proposed as promising therapeutic approaches. By supporting the diseased myocardium, these strategies can lead to an improved ventricular function by either preventing or hindering pathological left ventricle (LV) remodeling in the infarcted heart .The epicardial restraint field was pioneered with cardiomyoplasty, a surgical procedure that aimed to restrain dilation and aid ejection in the failing heart by wrapping the epicardium with the latissimus dorsi muscle (from the posterior trunk) and stimulating the wrap to contract. Clinical studies showed that the efficacy of this procedure relied on the passive restraint exerted by the wrap . AlthougOne of the widely studied hypotheses in recent years has been whether the localized mechanical reinforcement of the infarct can limit LV dilation or prevent a progression to HF by limiting infarct expansion in the short-term following a heart attack . With thConstant improvements of this therapeutic strategy are being reported in the literature. Motivated by one of the key limitations associated with early mechanical global and local restraint devices or patches—the inability to adapt the level of restraint—adjustable and quantifiable ventricular restraint  has receTo identify studies to be included in this review—those describing epicardially placed mechanical support strategies post-MI—a chronological review of literature databases , was conducted from 2013 to the present. The keywords used as search entries were ‘ventricular restraint’. Only search results pertaining to the cardiovascular field were considered and further filtered by criteria such as the nature of epicardial placement including global or local mechanical support.The Paracor HeartNet CSD is a passive, biventricular restraint device consisting of a NiTinol wire mesh. It is designed to be flexible and elastic, to achieve a high degree of conformability to the heart when appropriately sized . One benOne of the drawbacks of biventricular restraint is the possibility that the initial restraint level, while reinforcing the infarct region and preventing ventricular dilation, also inhibits diastolic filling. To address this, Ghanta et al.  developeFollowing the validation of the aforementioned devices, the further optimization of ventricular support has been pursued. Efforts at enhancing this therapeutic strategy include the addition of functionality, the variation of the duration of restraint and the use of biomimetic materials to match the mechanical properties of heart muscle. For instance, in terms of added functionality, the validation of a new mechanism aiming to modulate diastolic filling was realized by Snowden et al. . FurtherAnother knitted biventricular device was shown to positively impact LV remodeling and mitral regurgitation following MI creation. Okada et al.  report CSalvia miltiorrhiza [A biventricular CSD that simultaneously acted as a mechanical reinforcement device and a replenishable delivery system was first developed by Zhou , and teriorrhiza  and boneiorrhiza .The use of soft robotics to manufacture implantable devices that can augment cardiac function was first introduced in 2016 by Roche et al.  and was Two clinically approved LV restraint devices are the Myosplint (Myocor) and the CardioClasp . These devices interact with the LV only and their implantation procedure, which consists in reshaping the LV, does not allow them to be used as post-MI therapies, likely due to the risk of rupturing the weakened ischemic region . HoweverThe CardioClasp is another device that aims to reduce LV dilation by reshaping. It consists of two rigid bars connected through the LV cavity by an adjustable tether . The barThe group that developed the QVR and AMVR was the first to investigate whether ventricular restraint therapy was affecting both the RV and the LV in the same fashion and whether having the ability to adjust the level of restraint would positively change hemodynamic parameters . In an aConsistent with design optimization strategies for biventricular restraint; adding functionality, varying the duration of restraint, and using biomimetic materials are features that have been explored. For instance, Kalogerakos et al.  developeFinite element analysis (FEA) has been used to study various types of ventricular constraint devices. More sophisticated, patient-specific models were also used to study ventricular restraint devices. Carrick et al.  showed tLocally restraining the infarct region to prevent infarct expansion and post-MI remodeling using synthetic patches has been evaluated as early as 1999 . In receDue to increasing interest in the promise of cardiac regeneration over the last few decades, a multitude of studies have utilized tissue engineering patches or biological or synthetic matrices loaded with therapeutic agents while providing local mechanical reinforcement to the post-MI ventricle. For instance, Rodness et al.  observedOne group has conducted studies utilizing a commercially available extracellular matrix (ECM) biomaterial patch procured from porcine small intestine submucosa, named CorMatrix–ECM  for its intrinsic bioactive properties and as a carrier of bioagents. For instance, in one study, they enhance the CorMatrix–ECM patch with basic fibroblast growth factor (bFGF), a potent inhibitor of fibrosis, to study its effects on myocardial fibrosis, chamber dilation, and progression to heart failure in a rat MI model 16 weeks post-treatment. They report improved ejection fraction following treatment bFGF-enhanced CorMatrix–ECM patch when compared to the control group as well as a significant reduction in LV dilation when compared to both the control group and the nonenhanced CorMatrix–ECM patch, suggesting the addition of bFGF was beneficial . On a diIn addition to delivering therapeutic proteins, epicardially placed synthetic and natural patches can be used as scaffolds to deliver cells, or act as scaffolds for transplanted cells, enabling delivery of paracrine factors to the infarcted heart. In one such study, researchers implanted an elastic, biodegradable cardiac patch made of poly(ε-caprolactone)/gelatin (PG) nanofibers and loaded with mesenchymal stem cells (MSCs) one week post-MI in rats . The comIn order to address some of the limitations associated with the sustained delivery of biological agents and cell therapy to the epicardial surface, our group developed a replenishable reservoir that, when implanted into the epicardial surface following MI, improved cardiac function following the repeated administration of MSCs . We obseApart from the incorporation of biological therapy to cardiac patches, two different groups also utilized conductive nanomaterials to improve electrical implant integration and compatibility with the myocardium as well as cardiac function ,65. One As with global restraint devices, an approach taken to optimize the local reinforcement of the infarct was to make the level of restraint adjustable to better understand how this parameter affects LV function and remodeling. In 2013, Koomalsingh et al.  used a dThe aforementioned studies use patches, scaffolds, and devices localized to the infarct area to better limit LV remodeling with mechanical reinforcement in conjunction with biological therapy delivery or electrical coupling, and in some cases, with adjustable mechanical restraint. Purely biomechanical studies have also been conducted to isolate and elucidate how global and local heart mechanics alter scar composition, a key determinant of the degree of pathological remodeling. Recently, Caggiano et al.  tested hAs described in this review, ventricular restraint and infarct reinforcement are promising therapeutic approaches that can reduce or prevent LV remodeling post-MI. Global, biventricular restraint was the first approach tested clinically and has been studied in detail. Adjustability incorporated in these devices is highly beneficial, as the optimal level of restraint required to provide mechanical reinforcement yet avoid restriction of filling and tamponade can change over time as the heart adapts post-therapy. Currently, devices that can quantify and adjust the level of restraint consist of simple, fluid-filled bladders. Potentially, with the advent of 3D printing and soft robotic techniques, we can achieve a higher fidelity biomimetic mechanical reinforcement that conforms to the heart, moves with the heart wall, and has adaptable mechanical properties that can be tuned and adjusted over time. Using soft robotics, we could also achieve a finer control over spatial regions of supporting structures, for example to provide variable stiffness or anisotropy to optimize regional mechanical benefit to the infarcted heart. These techniques increase the potential design space for smart, customized biventricular reinforcement. Of course, further study is warranted to see the level of improvement in functions enabled by this higher granularity, and how much clinical improvement would result. In terms of univentricular support, various studies corroborate the fact that the ventricles respond differently to restraint. This further motivates the design of a smart, tunable device that that imparts different levels of restraint to each ventricle.In terms of local post-MI reinforcement, literature in recent years has largely focused on the implantation of cardiac patches or scaffolds that also exert a mechanical effect. While results are promising, tools for minimally invasive delivery are desirable to accelerate these strategies along the path to clinical translation. The use of anisotropic patches that control how the infarct area is mechanically deformed demonstrate the importance of the effect of the mechanical environment on scar structure and LV remodeling. To date, researchers have limited deformation in circumferential or apicobasal directions. Finer control over material anisotropy in reinforcing patches may enable studies with patches with anisotropic properties parallel or perpendicular to the epicardial fibers. Indeed, further study is necessary to fully understand how patient-specific reinforcement might yield optimal therapeutic effects. Incorporating high resolution imaging techniques and computational modeling to make patient-specific patches could help elucidate whether this level of customization leads to better functional effects post-MI or if a more global approach to mechanical intervention is sufficient to see functional benefits. For example, patches that include specific fiber orientation could be designed based on DTI data, and computational modeling, as described in this review, could aid with optimization of patch/device design. Indeed, in vivo tracking of structural changes in the infarct region and the surrounding tissue has been reported in various studies using DTI ,75,76,77


Takotsubo cardiomyopathy is rare in pregnancy and is characterized by left ventricular dysfunction with apical ballooning. This transient cardiac dysfunction may affect women of childbearing age in the antepartum, intrapartum or postpartum period. Most patients respond well to medical management with resolution of cardiac dysfunction within weeks.A 35-year-old female in her second pregnancy presented with severe preeclampsia at 31 weeks of gestation. She subsequently developed severe substernal chest pain and workup showed a stress induced cardiomyopathy prior to her delivery via caesarean section. She had full recovery of her cardiac function by 12 weeks postpartum after medical management.Stress induced cardiomyopathy, though rare, should be considered after acute myocardial infarction has been ruled out in gravid females presenting with acute chest pain. Management should involve a multidisciplinary team. Cardiac function recovery is common within 4 weeks although some patients may require long term heart failure management. Takotsubo cardiomyopathy (TCM) also known as stress induced cardiomyopathy is characterized by new onset left ventricular dysfunction with variable wall motion abnormalities in the absence of significant coronary artery disease –3. CardiIn this article, we present a case of a 35-year-old female who presented with severe preeclampsia at 31 weeks of gestation and subsequently developed TCM during her hospitalization. We further review the current literature on stress-induced cardiomyopathy in pregnancy.A 35-year-old Indian female, para 1 + 0 gravida 2, was admitted with severe preeclampsia at 31 weeks of gestation after complaints of anasarca for 1 week. She reported normal fetal movements with no epigastric discomfort, headaches or visual blurring. She had a blood pressure of 190/110 mmHg with a regular pulse rate at 70 beats/minute palpable on all extremities. She was afebrile at 36.7°C, had a respiratory rate of 18 breaths per minute and peripheral oxygen saturation of 99% on room air.Six years prior, she had had severe preeclampsia and a preterm delivery by caesarean section at 29 weeks of gestation. The baby died of infant respiratory distress syndrome shortly after birth causing the patient significant psychological distress requiring counselling. This made her defer the possibility of a pregnancy for years sighting psychological trauma.This pregnancy, she presented in the first trimester for antenatal care. Her blood pressure was 110/70 mmHg and antenatal profile was unremarkable: Hemoglobin 13.0 g/dl; Hepatitis-B surface Antigen, H.I.V. and Venereal Disease Research Laboratory (VDRL) were negative. Her blood group was O with positive Rhesus factor. The dating scan confirmed a 12-week-old gestation and she was placed on aspirin 75 mg throughout her pregnancy. Subsequent antenatal visits at 16, 20, 24, 28 and 30 weeks were uneventful with normal blood pressures. An anomaly obstetric scan at 20 weeks gestation showed no fetal anomalies with subsequent growth scans at 24 and 28 weeks showing normal growth with normal umbilical and middle cerebral artery doppler flows.On admission, she had macro albuminuria with elevated urine albumin creatinine ratio of 422 mg/mmol. Her hemoglobin was 12.1 g/dl and the platelet count was 194,000/ml. The renal and liver functions were normal.She was started on intravenous (IV) magnesium sulphate infusion as per the Zuspan regime   revealed a sinus rhythm with ST elevation in the anteroseptal leads (V1–4), Q waves in the septal leads (V1–2) and peaked T waves in V2–4 indicating an acute anteroseptal ST-Elevation Myocardial Infarction (STEMI)  of 0.57 necessitating delivery by caesarean section. The infant weighed 1 .5kg with Apgar score of 9 at 1 min and 10 at 5 min. Left cardiac catheterization was subsequently done on day 3, approximately 18 h after the last dose of LMWH and showed left ventricular apical ballooning with no evidence of atherosclerosis in the coronaries.The LMWH thromboprophylaxis (0 .5mg/kg once daily) was restarted 12 h post-delivery for one week. The blood pressure was controlled with amlodipine (10 mg once daily). Postpartum, she remained normotensive and anti-hypertensive medication was stopped after 6 weeks. Cardiac injury biomarkers normalized by the 10th postpartum day. The ECG done at 6 weeks postpartum showed frontal QRS complex of + 100 degrees with QS complexes from V1 to V3 consistent with recent antero-septal myocardial infarction Fig. . The echTakotsubo cardiomyopathy (TCM) is a rare life-threatening illness that can affect pregnant women. It should be considered a cardiac emergency as it mimics myocardial infarction, peripartum cardiomyopathy, acute myocarditis, and dilated cardiomyopathy and is a diagnosis of exclusion. Takotsubo cardiomyopathy (TCM) typically presents with acute retrosternal chest pain, palpitations and diaphoresis . AffecteThe common triggers of TCM include psychosocial stressors with greater occurrence in those with premorbid psychiatric illnesses , 13. OurDiagnostic evaluation of TCM includes an electrocardiogram (ECG), cardiac biomarkers, echocardiography and left heart angiography. The ECG abnormalities commonly encountered include ST segment elevation in the anterior and precordial leads with some having ST segment depression , 16. A fThe typical findings on transthoracic echocardiography include a large area of regional wall motion akinesia of the LV extending beyond the territory of a single coronary artery . There iThe diagnosis of TCM is based on the Mayo clinic diagnostic criteria . This inUp to 25% of TCM cases may develop Left Ventricular Outflow Tract (LVOT) obstruction due to the increased contractility of the base of the heart , 19. ProMost patients recover normal cardiac function within 4 to 8 weeks , 16. OurThe resolution of physical or emotional stress usually results in rapid resolution of symptoms though some patients may develop acute complications such as acute heart failure and cardiogenic shock requiring coronary cardiac unit admission and need for invasive techniques such as intra-aortic balloon pump and cardiopulmonary support .The decision on the timing and mode of delivery should be guided by obstetrical reasons. It should involve a multidisciplinary team of cardiologists, obstetricians, neonatologists and psychologists.Recurrence of TCM in premenopausal women is rare . Close fIn conclusion, TCM is a rare cardiac condition especially in pregnancy. Management challenges for ongoing pregnancies are crowded by safety concerns of the drugs used for managing acute myocardial infarction. Longitudinal studies are needed to evaluate the reproductive history of women with TCM and further assess its association with preeclampsia. However, we strongly advocate for a multidisciplinary approach in order to optimize outcomes for the mother and child.


To evaluate the relationship between extension or texture features of late gadolinium enhancement (LGE) and ventricular tachyarrhythmias in hypertrophic cardiomyopathy (HCM). Twenty-three patients with HCM were enrolled in this IRB-approved study. The extension of LGE was determined based on the American Heart Association segments model. Texture analysis was performed for 43 myocardial LGE using an open-access software . The relationship between the extension or texture features of LGE and ventricular tachyarrhythmias was evaluated using unpaired test and receiver-operating characteristic (ROC) analysis.p < 0.01). Among 4 texture features, entropy LL was the only discriminator between the 2 patient groups . An ROC analysis gave the number of segments showing LGE a better result  for identification of HCM patients with ventricular tachyarrhythmias than the entropy LL of LGE. Six of 23 patients had a history of ventricular tachyarrhythmias, and 16 patients had LGE. All of the 6 patients with the arrhythmias had more than 4 LGE segments and more LGE segments than those without ( Patients with HCM and a history of ventricular tachyarrhythmias had a wider extension of LGE, and their entropy LL of LGE was significantly lower than those without. The extension of LGE and texture analysis may provide information about LGE related to ventricular tachyarrhythmias in HCM. Hypertrophic cardiomyopathy (HCM) is a relatively frequent, autosomal dominant transmitted myocardial disease . VentricTexture analysis is a quantitative analysis of medical images –18. The This retrospective, cross-sectional, observational study was approved by our institutional review board, and informed consent was given by all the patients. Twenty-three consecutive patients HCM were referred to cardiac MR imaging examinations between August 2011 and April 2017 and enrolled in this study. They were 19 men and 4 women, ranging in age from 38 to 90 years . The phenotypes of HCM were basal asymmetrical septal hypertrophy , midventricular obstruction (MVO) combined with apical HCM , APH (n = 4), dilated phase HCM (n = 3), and basal ASH combined with MVO (n = 1). One patient had an apparent family history of HCM. In all 23 patients, cine MR imaging at end-diastole showed a maximum myocardial thickness of > 15 mm in the absence of other myocardial diseases leading to myocardial hypertrophy.2, and slice thickness 10 mm followed by 5 mm interpolation. The inversion time nullifying the myocardium effectively  was determined in each patient based on T1-weighted scout (Look-Locker) MR imaging.Cardiac MR imaging examinations were performed using a 3.0 T scanner (n = 12) or a 1.5 T scanner (n = 11) . Breath-hold 2-dimensional (2D) cine steady-state free precession imaging was performed on the short-axis, and in the 2-, 3- and 4-chamber view planes. A single-breath-hold 3D LGE MR imaging was performed on the same view planes as cine imaging approximately 10 min after an injection of 0.10 mmol/kg gadolinium-based contrast agents. The typical imaging parameters of the 3D LGE imaging included repetition time 3.7-4.2 ms, echo time 1.12-1.8 ms, flip angle 15°, in plane resolution 1.40-1.59 × 2.05-3.17 mmThe left ventricular myocardium was divided into 17 segments according to the American Heart Association (AHA) statement . Therefo t-test or Welch's t-test was used to evaluate the differences in the quantitative data between patients with and without ventricular tachyarrhythmias. The p-value less than 0.05 was defined as significant. Third, the threshold of the number of LGE segments or texture features to identify the history of tachyarrhythmias was assessed using a receiver-operating characteristic (ROC) analysis.First, the difference in the numbers of LGE myocardial segments was assessed between the patients with and without the history of ventricular tachyarrhythmias, such as nonsustained ventricular tachycardia (NSVT) and ventricular fibrillation (VF). Second, we evaluated the differences in the 4 texture features between the patients with and without ventricular tachyarrhythmias. An unpairedSix (26.1%) of the 23 patients had a history of ventricular tachyarrhythmias: the one had a history of cardiac arrest because of VF and the other 5 patients showed NSVT. The remaining 17 of 23 patients did not have any histories of ventricular tachyarrhythmias. Eighty-two (21.0%) of the 391 myocardial segments showed LGE in 16 (69.6%) of the 23 patients, ranging from 0 to 13 myocardial segments per patient. For texture analysis, 43 ROIs were placed on the LGE segments because there were some LGE covering 2 or more segments contiguously and there were spotty LGE where we could not place ROI appropriately. p = 0.0002). Six patients with HCM and ventricular tachyarrhythmias had 21 ROIs for the texture analysis, while the remaining 17 patients had 22 ROIs. Among the 4 texture features, entropy LL was significantly smaller in patients with the arrhythmias (14970 ± 9108) than in those without . There were no significant differences in the other 3 texture features between the 2 patient groups. The ROC analysis showed that the 4 segments with LGE (area under the curve [AUC] = 0.96) and the entropy LL of 19624 (AUC = 0.72) were appropriate thresholds to discriminate the patients with and without a history of ventricular tachyarrhythmias  or inhomogeneous LGE, probably reflecting the mixture of fibrosis and normal myocardium, is significantly related to serious ventricular arrhythmia associated with ischemic cardiomyopathy and HCM . By contThere were some limitations to the present study. First, the sample size of HCM was relatively small. Nonetheless, we were able to analyze 4 texture features of 43 ROIs on the 82 LGE areas in the HCM patients. Second, 2 types of magnetic field strength were used. Therefore, we assessed the extension of LGE according to the AHA segmentation model rather than the LGE mass, whereas the same 6SD threshold was used to identify LGE both on 1.5T and on 3.0 T. Nevertheless, the present study showed that the numbers of LGE segments and entropy LL were significantly related to ventricular tachyarrhythmias in patients with HCM. Third, we did not analyze all texture features acquired with the software, because the data handling may be too excessive  to be used clinically , 17. FurIn conclusion, HCM patients with a history of ventricular tachyarrhythmias had a wider extension of LGE, and the entropy LL of LGE was significantly less than in those without. The extension of LGE and texture analysis may provide information about LGE related to ventricular tachyarrhythmias in HCM. Based on the present ROC analysis, the extension of LGE may provide a better result than texture analysis in relation to the history of ventricular tachyarrhythmias associated with HCM.


In patients with heart failure with reduced ejection fraction (HFrEF) on sub-optimal doses of beta-blockers, it is conceivable that changes in heart rate following treatment intensification might be important regardless of underlying heart rhythm. We aimed to compare the prognostic significance of both achieved heart rate and change in heart rate following beta-blocker uptitration in patients with HFrEF either in sinus rhythm (SR) or atrial fibrillation (AF).We performed a post hoc analysis of the BIOSTAT-CHF study. We evaluated 1548 patients with HFrEF . Median follow-up was 21 months. Patients were evaluated at baseline and at 9 months. The combined primary outcome was all-cause mortality and heart failure hospitalisation stratified by heart rhythm and heart rate at baseline.p < 0.001; AF: 0.89 (0.81–0.98), p = 0.018], whereas the relationship was less strong for achieved heart rate in AF . Achieved heart rate at 9 months was only prognostically significant in AF patients with high baseline heart rates (p for interaction 0.017 vs. low).Despite similar changes in heart rate and beta-blocker dose, a decrease in heart rate at 9 months was associated with reduced incidence of the primary outcome in both SR and AF patients [HR per 10 bpm decrease—SR: 0.83 (0.75–0.91), Following beta-blocker uptitration, both achieved and change in heart rate were prognostically significant regardless of starting heart rate in SR, however, they were only significant in AF patients with high baseline heart rate. Heart rate is a risk factor in patients with heart failure with reduced ejection fraction (HFrEF) that, when reduced, provides outcome benefits , 2. HoweOne strategy for reducing heart rate is the use of beta-blockers, a mainstay of therapy in HFrEF , 10. AltTo the best of our knowledge, the relative effects of change in heart rate following intensification of beta-blocker therapy have not been previously examined. Given the frequent co-existence of AF and HFrEF, it is important to determine whether patients in AF derive the same benefit from heart rate reduction and beta-blocker uptitration as those in SR, and whether this effect is modulated by changes in beta-blocker dose. We utilised the systems BIOlogy Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) dataset to compare the prognostic importance of changes in heart rate following beta-blocker uptitration in HFrEF patients in AF versus those in sinus rhythm (SR).The BIOSTAT-CHF study design has been published previously . BrieflyIn the first 3 months after recruitment, treating clinicians aimed to initiate and/or uptitrate ACEI/ARBs and beta-blockers to recommended target doses which have been previously published by the European Society of Cardiology . ReasonsHeart rate and rhythm were assessed by ECG with all patients supine and rested for at least 5 min. In BIOSTAT-CHF, all patients were followed up for clinical outcomes. After the scheduled visits at baseline and 9 months, patients were contacted by telephone every 6 months.The primary outcome for this study was the combined endpoint of all-cause mortality or HF hospitalisation. HF hospitalisation was determined as admission to hospital ≥ 24 h due to worsening HF requiring either intravenous or increased dose of oral diuretics.t test and categorical variables were tested using the Chi square test. Heart rate and beta-blocker dose at baseline and 9 months were analysed for their association with the primary outcome and all-cause mortality using the Cox proportional hazard model and Kaplan–Meier analysis. Competing risks regression with death as a competing risk was used to determine hazard ratios for hospitalisation alone. To adjust for treatment indication bias inverse probability weighting was used, the method of which has been explained in detail previously , including 324 deaths  and 337 hospitalisations  (Table p = 0.60), however, higher baseline heart rate was significantly associated with improved outcome in patients with AF . There were no significant associations for the individual endpoints of mortality and HF hospitalisation .ECGs at the 9-month visit were available for 1155 patients. 198 patients died prior to their 9 month visit, while 195 patients did not have an ECG available. After exclusion of 125 patients with paced rhythms, 1030 patients remained for analysis, of which 734 (71.3%) were in sinus rhythm and 296 (28.7%) were in AF. Heart rate-lowering medication use at 9 months is shown in Table p < 0.001). Higher baseline heart was significantly associated with a greater reduction in heart rate at 9 months  and an increase in beta-blocker dose at 9 months . After adjustment for the BIOSTAT risk prediction model and likelihood of uptitration, a higher achieved heart rate at 9 months was significantly associated with increased likelihood of the primary outcome in SR patients  but not in AF  . In multivariable analysis, a decrease in heart rate was significantly associated with reduced likelihood of the primary outcome in both SR and AF  (Table p = 0.046).There was no significant difference in change in heart rate at 9 months between SR and AF patients  Table . A decrep < 0.001; ≤ 85 bpm: HR 0.99 per 10 bpm higher; 95% CI 0.80–1.22, p = 0.94, p for interaction 0.017) (Fig. Among the patients assessed at 9 months, baseline heart rate was 77 bpm in those in SR and 85 bpm in those in AF. Higher achieved heart rate and change in heart rate were significantly associated with outcome regardless of baseline heart rate in sinus rhythm Fig. , howeverIn this multi-national, multi-centre contemporary study of HF patients with left ventricular systolic dysfunction on sub-optimal doses of beta-blocker therapy subjected to treatment intensification, we found that both achieved heart rate and change in heart rate at 9 months are strongly associated with outcome in HFrEF patients in SR regardless of baseline resting heart rate. In contrast, only a decrease in heart rate was significantly associated with improved outcome in AF patients, and in particular only in those with higher baseline heart rates.HF and AF frequently co-exist and present an additional layer of complexity in management . EstabliA major part of our study was to examine the effect of a change in heart rate in conjunction with changes in beta-blocker dose. We found that despite similar reductions in heart rate and similar increase in beta-blocker dose, the prognostic significance of both achieved and changes in heart rate were only seen in AF patients at higher baseline heart rates. It is not completely clear why heart rate reduction using beta-blockers should not be associated with improved outcome in HFrEF patients in AF regardless of baseline heart rate, as it is in SR. It has been postulated that higher heart rates in patients with AF is beneficial to compensate for the loss of atrial ejection and reduced left ventricular diastolic filling . It may We found however that there were benefits in targeting heart rate in AF patients with higher baseline heart rate. A common clinical question in treatment of HFrEF in patients AF is whether the AF is secondary to HF or vice versa . It may Heart rate reduction by other mechanisms generally appears to have limited benefit in AF-HFrEF patients. Digoxin is, at best, neutral in terms of clinical outcome in AF patients with HFrEF, though it might provide some symptomatic benefit, while non-dihyrdopyridine calcium channel blockers are contra-indicated in HF . AlternaOur study has some limitations. First, this is a post hoc analysis of a prospective study. However, one of the strengths of the study was that as well as being an observational study, the protocol also mandated uptitration of HF therapy, thus adding some of the benefits of a clinical trial element. Second, we only obtained resting heart rhythm and rate at two separate time points. It is possible that patients may have been in paroxysmal AF at the time of their visit, while in SR the majority of time in the interim or vice versa. Further insights into the effect of heart rate on prognosis may have been obtained by more frequent heart rate monitoring. Third, we did not have any information on changes in heart rate or beta-blocker dose beyond 9 months, which might have had an impact on clinical outcomes. Additionally, despite the overall size of this study, there were a relatively low number of patients in AF at 9 months, thus we cannot exclude that interactions may have become significant with larger numbers. Further studies specifically examining beta-blocker uptitration are required to confirm these findings. Finally, due to the number of patients, we did not further stratify the cohort based on cardio-selectivity of prescribed beta-blocker. Larger cohorts should be evaluated with the specific aim of determining whether heart rate reduction mediated by cardio-selective beta-blockers is more beneficial in AF patients with HFrEF.In HFrEF patients in SR both achieved and change in heart rate following beta-blocker uptitration were associated with improved outcomes, regardless of heart rate at baseline.Despite a similar increase in beta-blocker dose and baseline heart rate reduction in HFrEF patients in AF, achieved and decrease in heart rate from baseline were only prognostically significant in patients with higher baseline heart rates.


T1 mapping with full left ventricular coverage may be desirable when spatial T1 variations are expected. This would require multiple breathholds, increasing patient discomfort and prolonging scan time.Conventional myocardial T1 mapping (FAST1) technique for full left ventricular coverage.To develop and characterize a novel FASt single‐breathhold 2D multislice myocardial TProspective.2 phantom, 9 healthy volunteers, and 17 patients.Numerical simulation, agarose/NiCl1.5T/FAST1.Two FAST1 approaches, FAST1‐BS and FAST1‐IR, were characterized and compared with standard 5‐(3)‐3 MOLLI in terms of accuracy, precision/spatial variability, and repeatability.t‐tests, Pearson correlation analysis, and Bland–Altman analysis.Kruskal‐Wallis, Wilcoxon signed rank tests, intraclass correlation coefficient analysis, analysis of variance, Student's 1 error) of 0.2%/4%, 6%/9%, and 4%/7%, respectively, while FAST1‐BS and FAST1‐IR had a precision penalty of 1.7/1.5 and 1.5/1.4 in comparison with MOLLI, respectively. In healthy volunteers, FAST1‐BS/FAST1‐IR/MOLLI led to different native myocardial T1 times  and spatial variability . There were no statistically significant differences between all techniques for T1 repeatability (P = 0.18). In vivo native and postcontrast myocardial T1 times in both healthy volunteers and patients using FAST1‐BS/FAST1‐IR were highly correlated with MOLLI (Pearson correlation coefficient ≥0.93).In simulation/phantom, FAST1‐BS, FAST1‐IR, and MOLLI had an accuracy (expressed as T1 mapping with full left ventricular coverage in three separated breathholds. In comparison with MOLLI, FAST1 yield a 5‐fold increase of spatial coverage, limited penalty of T1 precision/spatial variability, no significant difference of T1 repeatability, and highly correlated T1 times. FAST1‐IR provides improved T1 precision/spatial variability but reduced accuracy when compared with FAST1‐BS.FAST1 enables myocardial TLevel of Evidence: 1Technical Efficacy: Stage 3J. Magn. Reson. Imaging 2020;51:492–504. In these conditions, myocardial T1 mapping with full LV coverage requires repeated breathheld acquisitions, each for one slice, thus increasing patient discomfort, prolonging scan time, and resulting in potential slice misalignment if 3D processing is necessary.Several methods have been proposed for myocardial T1 mapping with full LV coverage.1 mapping approaches may need to compromise between spatial resolution and/or artifact level due to limited breathhold duration and limited acquisition window within the cardiac cycle.1 mapping require long scan times and advanced motion correction strategies, which can result in reduced map quality and increased intersegment variability compared with standard breathheld techniques such as MOLLI.3D or advanced 2D multislice techniques can be used to achieve native myocardial T1 mapping (FAST1) for myocardial T1 mapping with full LV coverage in three breathholds at 1.5T.In this work, we sought to develop and characterize a novel FASt single‐breathhold 2D multislice myocardial T1 maps are acquired in one breathhold. A slice‐selective inversion pulse (phase‐modulated hyperbolic secant) is applied in the first heartbeat (HB). Two ECG‐triggered single‐shot images of the same slice are then acquired over the first and second HBs at TIs of TI1 and TI2, respectively. The delay time between the slice‐selective inversion pulse and the first image (TI1) is minimized to reduce the impact of motion. This imaging block is then repeated five times for different slices within the same breathhold.The FAST1 pulse sequence diagram is illustrated in Fig. THK. Furthermore, the five imaging blocks were acquired in a slice‐interleaved fashion using the following slice order  and a slice gap (twice the imaging slice thickness in this work) to minimize slice crosstalk.To reduce the slice mismatch in the presence of residual motion occurring between the inversion and imaging, the ratio of inversion to imaging slice thickness was increased from one to a factor of RTHK values and thus improved robustness against motion while minimizing slice crosstalk, recovery HBs were inserted between the third and fourth imaging blocks . The number of recovery HBs (NR) is adjusted based on each subject's heart rate (HR) to ensure quasi full recovery of the longitudinal magnetization of the last two slices  before application of their associated slice‐selective inversion pulses. This adjustment is achieved based on a worst‐case scenario defined as one slice‐selective inversion pulse in the first three imaging blocks  fully inverted one of its adjacent slices (slices #2 or #4). Considering a normal native myocardial T1 at 1.5T (~1200 msec), recovery HBs were added to ensure a minimum delay of five times the native myocardial T1 time between the inversion pulses for two adjacent slices . As an example, with an HR of 60 bpm, two recovery HBs were used . In the physiological HR range (50–110 bpm), the corresponding nominal breathhold duration is 9–13 sec.To allow for large R1 map reconstruction was performed using an exhaustive search over a signal dictionary. Two models were developed and evaluated for the creation of the signal dictionary using Bloch equations simulation (BS) of the pulse sequence and an IR‐based model. The corresponding reconstructions are thereafter referred to as FAST1‐BS and FAST1‐IR, respectively. Each model was created using a T1 range of 1–4000 msec in steps of 1 msec.T1‐weighted image was simulated as the transversal magnetization at the k‐space center . An initial longitudinal magnetization of 1 was used. T1‐dependent slice profiles of the inversion pulse (phase‐modulated hyperbolic secant) and the excitation pulse (nonmodulated Hann‐filtered sinc) were integrated. T1‐dependent slice profiles were estimated using Bloch equations simulation of each pulse with a myocardial T2 = 45 msec and B0/B1 inhomogeneities / Hz in steps of 1%/10 Hz. T1‐dependent effective flip angles were approximated based on the average longitudinal magnetization over the slice profiles and all simulated T2/B0/B1 regimes.The signal dictionary was generated using Bloch equations simulation of FAST1. The signal of each T1/T2/B0/B1 regimes.The dictionary was created using a previously proposed normalized one‐parameter model1 = 100 msec) was selected as the reference phase image and was assumed to have "negative" polarity. Based on Bloch equations simulation, this assumption has been shown to be valid for any T1 time >172 msec (in the presence of any T2 time ≥30 msec and imaging flip angle ≤85°).meas was individually scaled to each dictionary entry Sdict as:Sdict¯ is the signal amplitude average of a dictionary entry over all TIs  and Smeas¯ is the signal amplitude average of the polarity‐restored measured signal over all TIs . Dictionary matching was finally performed by minimizing the L2‐norm between Smeasscaled and each dictionary entry. Graphic processing unit (GPU) implementation of both the dictionary creation and fitting process was developed using the compute unified device architecture (CUDA)  to enable fast T1 map reconstruction. For comparison, a standard central processing unit (CPU)‐based implementation was also developed.The same fitting process was used for both models. Prior to dictionary matching, the signal polarity of the measured signal was restored using a phase sensitive inversion recovery (PSIR) reconstruction approach.1‐dependence on HR.1 estimates obtained from this model were HR‐corrected as in previous workThe IR model led to substantial TN = 50,000 repetitions) was performed to investigate T1/T2‐dependent T1 accuracy and precision of FAST1‐BS, FAST1‐IR, and standard 5‐(3)‐3 MOLLI. The signal of FAST1 and MOLLI was generated using Bloch equations simulation with the following parameter ranges: T1 , and T2 . Random Gaussian noise was introduced to simulate a typical signal‐to‐noise ratio (SNR) of 50 in the longest TI image of the MOLLI sequence. T1 accuracy was calculated as the average over all repetitions of the difference between estimated and actual T1 times. T1 precision was measured as the standard deviation (SD) over all repetitions of the estimated T1 times.Monte Carlo simulation . FAST1‐BS and FAST1‐IR were compared with the standard MOLLI sequence (5‐(3)‐3 scheme) in phantom, in healthy volunteers as well as in patients. The in vivo studies were approved by a local Research Ethics Committee , with written informed consent obtained from all participants.1/T2 times representing typical ranges of native and postcontrast myocardial T1 times.2, acquisition matrix 256 × 144, acquired pixel size 1.4 × 2.1 mm2, reconstructed pixel size 1.4 × 1.4 mm2, slice thickness/gap 8/16mm, GRAPPA acceleration factor 2, partial Fourier factor 7/8, bandwidth 1085 Hz/px, TI1 100 msec. Five slices were acquired using FAST1, while a single slice  was acquired using MOLLI. Additionally, an IR spin echo (SE) experiment was performed on another day to obtain reference T1 times using the following parameters: TE/TR = 15/15000 msec, 15 TIs = , pixel size 1.4 × 1.4 mm2, slice thickness 5 mm, and bandwidth 130 Hz/px. Data analysis was performed based on vial‐wise region of interest (ROI) in the common slice unless stated otherwise.FAST1‐BS, FAST1‐IR, and MOLLI were initially compared in a phantom  with six vials of different TRD  and RTHK . A simulated HR of 60 bpm was used for this experiment. The maximum interslice T1 variation (max(|ΔSLICET1|)) was measured for each set of parameters to identify potential slice crosstalk effects. An empirically optimized pair of TRD (6 sec) and RTHK (4) was used for FAST1 in all the following experiments in phantom and in vivo.FAST1 was acquired multiple times using different values of T1 variation across HRs (with respect to T1 at 60 bpm) was compared for FAST1‐BS, FAST1‐IR, and MOLLI.FAST1 and MOLLI were repeated for different simulated HRs . Mean T1 accuracy, spatial variability, and repeatability were evaluated for FAST1‐BS, FAST1‐IR, and MOLLI. T1 accuracy was computed for each vial as the interrepetition average of difference between T1 mean in ROI and reference T1 obtained in IR SE experiments. T1 spatial variability was measured for each vial as the interrepetition average of T1 SD in ROI. T1 repeatability was evaluated for each vial as the interrepetition SD of T1 mean in ROI.FAST1 and MOLLI were each acquired five times using a simulated HR of 60 bpm. T1 mapping using FAST1‐BS, FAST1‐IR, and MOLLI was performed in nine healthy volunteers . Both FAST1 and MOLLI were acquired in the short‐axis orientation using the imaging parameters described in the phantom experiments with TRD of 6 sec and RTHK of 4. FAST1 was acquired three times to cover the entire LV. To this end, the second and third FAST1 acquisitions were positively and negatively shifted in the slice direction by the employed slice thickness, respectively. This thus resulted in the acquisition of 15 contiguous slices covering the entire LV in a total of three separated breathholds. For comparison, three slices were acquired using MOLLI in another three separated breathholds, matching the three central slices in the first FAST1 acquisition, mimicking a conventional clinical MOLLI protocol.In vivo characterization of native myocardial T1 mapping. Qualitative and quantitative comparisons between both techniques were undertaken in the three common slices .This entire protocol was performed twice within the same session without subject repositioning to assess the repeatability of in vivo native myocardial T1 times measured with FAST1 and MOLLI are very different (as FAST1 cannot estimate blood T1 due to the in‐flow effect caused by the slice‐selective inversion pulses), the assessment was restrained to the evaluation of map quality only within the myocardium for all techniques to ensure that the readers remain blinded to the acquisition techniques. To this end, endocardial and epicardial contours were manually delineated in the first T1‐weighted image of each slice and used to generate a binary mask of the myocardium. The myocardium from each T1 map was overlaid to the first T1‐weighted image to prevent any bias in the subjective analysis. Each resulting image was then rated using a 4‐point‐scale scoring system defined as: 1, nondiagnostic: artifacts in >50% of AHA (American Heart Association) myocardial segments1 occurring in areas assessed to be normal tissue.No data were discarded for the qualitative assessment. Subjective assessment of map quality for FAST1‐BS, FAST1‐IR, and MOLLI was performed independently by three experienced cardiac MRI readers (M.S.N./J.W./P.D.: >3/4/3 years of cardiac MRI experience) blinded to the techniques. Since blood T1‐weighted images. Slices with apparent severe artifacts in any of FAST1‐BS, FAST1‐IR, and MOLLI were discarded from the quantitative analysis of all techniques in that specific subject. Native T1 measures, spatial variability, and repeatability of the three techniques were calculated for each AHA myocardial segment.1 measures were calculated as the interrepetition average of the T1 mean in a given myocardial segment. Spatial variability was measured as the interrepetition average of the T1 SD in a given myocardial segment. Repeatability was evaluated as the interrepetition absolute difference of the T1 mean in a given myocardial segment. Subject‐wise T1 measures, spatial variability, and repeatability were then computed by averaging the segmental values over all nondiscarded segments for each subject. Segment‐wise T1 measures, spatial variability, and repeatability were also computed by averaging the nondiscarded segmental values over all subjects for each myocardial segment. Finally, intersegment variations of native T1 measures, spatial variability, and repeatability were calculated as the average over all subjects of the intersegment SD of native T1 measures, spatial variability, and repeatability, respectively.All data were visually inspected to detect the presence of severe artifacts or motion among the T1 mapping were performed in the short‐axis orientation using FAST1 (15 contiguous slices covering the entire LV in three separated breathholds) and MOLLI . Imaging parameters were as described as in the healthy volunteer experiments. Thirteen of these patients  received an injection of 0.1 mmol/kg of gadobutrol  in which postcontrast T1 mapping was also performed using FAST1 and MOLLI with the protocol described above.Seventeen consecutive patients  referred for cardiac MRI examination in our center were recruited. The clinical indication for the study included cardiomyopathy (twelve patients), assessment of volumes and function (two patients), assessment for aortopathy (two patients), and investigation of myocarditis (one patient). Native and postcontrast myocardial T1 maps as described above for the healthy volunteer study.Subjective assessment of map quality was performed for native T1 measures were assessed using FAST1‐BS, FAST1‐IR, and MOLLI, as described in the healthy volunteer study.Subject‐wise native and postcontrast TP < 0.05. When the Kruskal–Wallis test found statistical significance, Wilcoxon signed rank tests with Bonferroni correction were performed for each pair of techniques, with statistical significance threshold of P < 0.05/3 = 0.0167. Interreader variability was assessed using a two‐way mixed single‐measure intraclass correlation coefficient (ICC).Data are expressed as mean ± SD. the Kruskal–Wallis test was used to evaluate the null hypothesis that there is no difference in in vivo subjective map quality scores between FAST1‐BS, FAST‐IR, and MOLLI, with statistical significance defined at 1 times in healthy volunteers, with statistical significance defined at P < 0.05. When the ANOVA test found statistical significance, Student's t‐tests with Bonferroni correction were performed for each pair of techniques, with statistical significance threshold of P < 0.05/3 = 0.0167. The same methodology was used for analysis of myocardial T1 spatial variability and T1 repeatability in healthy subjects, as well as for analysis of native and postcontrast myocardial T1 times in patients.A one‐way analysis of variance (ANOVA) test was used to evaluate the null hypothesis that there is no difference between the three techniques in terms of myocardial T1 times. Bland–Altman 95% limits of agreement were calculated as the mean difference between methods ±1.96 × (SD of differences).Pearson correlation and Bland–Altman analyses were also performed between each of the two FAST1 techniques and MOLLI in terms of subject‐wise native/postcontrast myocardial T1 map with a matrix size of 256 × 256, T1 map reconstruction of FAST1‐BS/FAST1‐IR took 6.5 sec using CPU implementation and 0.2 sec using GPU implementation. The reconstruction time of an entire FAST1‐BS/FAST1‐IR dataset  was reduced from 31 sec using CPU implementation to 0.6 sec using GPU implementation. The reconstruction time of three FAST1‐BS/FAST1‐IR datasets for full LV coverage  was reduced from 94 sec using CPU implementation to 1.4 sec using GPU implementation.For a single T2 on the T1 accuracy and precision of FAST1‐BS, FAST1‐IR, and MOLLI. FAST1‐BS led to higher accuracy (mean error: 0.2%) than FAST1‐IR (mean error: 6%) and MOLLI (mean error: 4%). All techniques were T2‐dependent. Over the entire studied range of T1 and T2 times, FAST1‐BS and FAST‐IR led to reduced precision with respect to MOLLI by factors of 1.7 and 1.5, respectively.Fig. 1 variation (max(|ΔSLICET1|)) as a function of TRD and RTHK is shown in Fig. 1 variations of up to 62 msec were observed using a short TRD of 4 sec, while maximum interslice T1 variations were substantially reduced to less than 11 msec for TRD exceeding 6 sec. For both techniques, large maximum interslice variations of up to 204 msec were observed using a large RTHK of at least 7, while maximum interslice T1 variations were substantially reduced to less than 11 msec for RTHK not exceeding 4.Maximum interslice T1 variation across HRs obtained using FAST1‐BS, FAST1‐IR, and MOLLI are shown in the 1 variations across all HRs <13 msec for all vials and all techniques.Mean T1 accuracy, spatial variability, and repeatability of FAST1‐BS, FAST1‐IR, and MOLLI are shown in Fig. 1 error of –26 ± 5 msec vs. –73 ± 53 msec vs. –56 ± 36 msec (mean error: 4% vs. 9% vs. 7%), T1 spatial variability of 9 ± 6 msec vs. 8 ± 4 msec vs. 6 ± 4 msec  and T1 repeatability of 1.6 ± 0.8 msec vs. 1.4 ± 0.6 msec vs. 0.8 ± 0.3 msec, respectively.T1 maps obtained using FAST1‐BS, FAST1‐IR, and MOLLI in one healthy volunteer are shown in Fig. P = 0.48; reader #2: 3.4 ± 0.7 vs. 3.6 ± 0.5 vs. 3.6 ± 0.6, respectively, P = 0.49; reader #3: 3.6 ± 0.6 vs. 3.9 ± 0.4 vs. 3.7 ± 0.6, respectively, P = 0.23; ICC = 0.66).HR among all healthy volunteers was 66 ± 9 bpm . Breathhold length using FAST1 among all healthy volunteers was 12 ± 1 sec. Example T1,78 bpm)1 times, spatial variability, and repeatability. Each technique led to different native myocardial T1 times  and spatial variability . Spatial variability increases of FAST1‐BS and FAST1‐IR with respect to MOLLI were by factors of 1.4 and 1.2, respectively. There were no statistically significant differences between all techniques in terms of T1 repeatability .Among all healthy volunteers, no slices were excluded due to severe artifact level from the data analysis of FAST1‐BS, FAST1‐IR, and MOLLI. Fig. 1 measures , segmental variations of T1 spatial variability , and segmental variations of T1 repeatability .Myocardial segment‐based analysis is shown in Fig. 1 maps obtained using FAST1‐BS, FAST1‐IR, and MOLLI in a 31‐year‐old male patient admitted for suspected myocarditis. Over all patients, FAST1‐BS resulted in higher subjective map quality than MOLLI , although these differences only reached statistical significances for readers #1 and #2. FAST1‐IR resulted in higher subjective map quality than MOLLI . The interreader ICC was 0.58.HR among all patients was 68 ± 12 bpm . Breathhold length using FAST1 among all patients was 12 ± 2 sec. Figs. 2 bpm). B1 times using FAST1‐BS, FAST1‐IR, and MOLLI were 1057 ± 50 msec, 987 ± 42 msec, and 1036 ± 39 msec, respectively (P < 0.0001). On the other hand, there were no statistically significant differences between all techniques for postcontrast T1 times .No slices in FAST1‐BS and FAST1‐IR were found with a severe artifact level, while a total of eight slices in MOLLI were identified with severe respiratory motion artifacts (8.9% of 90 slices) and subsequently discarded for all techniques for the quantitative analysis. Native myocardial T1 times  between FAST1‐BS and MOLLI as well as between FAST‐IR and MOLLI are shown in Fig. 1 estimates (Pearson correlation coefficient = 0.93/0.93 with P < 0.001 for native and 0.98/0.98 with P < 0.001 for postcontrast). For native myocardial T1 estimates, FAST1‐BS and FAST1‐IR led to a bias of 24 ± 18 msec and –44 ± 15 msec with respect to MOLLI, respectively, with a narrow width of 95% limits of agreement . For postcontrast myocardial T1 estimates, FAST1‐BS and FAST1‐IR led to a bias of 15 ± 12 msec and 1 ± 11 msec with respect to MOLLI, respectively, with a narrow width of 95% limits of agreement .Pearson correlation and Bland–Altman analyses of subject‐wise native and postcontrast myocardial T1 mapping in one breathhold and full LV coverage in three breathholds. Two FAST1 reconstructions were developed, characterized, and compared with MOLLI in simulation, phantom, healthy volunteers, and patients. The resulting native and postcontrast myocardial T1 times obtained using FAST1‐BS/FAST1‐IR and MOLLI showed strong linear correlation. In comparison to MOLLI, FAST1‐BS/FAST1‐IR led to a 5‐fold increase of spatial coverage within the same time frame, limited precision penalty, and no statically significant difference of repeatability.FAST1 enables multislice myocardial TRD and RTHK were optimized to ensure the robustness of the sequence in the presence of potential slice crosstalk due to cardiac/respiratory motion and imperfect slice profile with side lobes. TRD was optimized based on normal native myocardial T1 times at 1.5T. The application of FAST1 at different field strengths or for different tissues of interest may require adjustment of this parameter. The optimized RTHK was directly related to the employed imaging slice thickness and slice gap. In this work, RTHK of 4, ie, an inversion slice thickness of 32 mm, was found suitable to account for elevated HR. A slice gap of twice the imaging slice thickness was used in this work to avoid gaps or overlaps between slice groups within different breathholds, as we aimed to achieve full LV coverage in three separated breathholds. This parameter should be carefully selected with respect to RTHK, the employed imaging slice thickness, and the slice profile of the slice‐selective inversion pulse in order to avoid slice crosstalk. The development of a slice‐selective inversion pulse with improved slice profile could, however, increase the flexibility of the sequence with respect to these parameters.The sequence parameters T1‐weighted images, and thus the precision of T1 estimates. However, the relative precision penalty of FAST1 with respect to MOLLI is expected to be SNR‐independent based on our previous work using a two‐heartbeat T1 mapping scheme  as proposed in this alternative strategy is expected to have minimal impact on slice crosstalk. Reducing the spatial resolution would reduce the SNR in the Tsee Ref. . Alterna1 time using MOLLI.FAST1‐BS was more accurate than FAST‐IR and MOLLI, which is likely due to its more accurate modeling of the imaging pulses. FAST1‐BS was found to be HR‐independent. FAST1‐IR required the use of a novel HR correction approach to reduce its original HR‐dependence.1 spatial variability is an important criterion for clinical applicability of any T1 mapping technique. FAST‐IR led to an increase of T1 spatial variability by a factor of 1.2 for in vivo native myocardial T1 times when compared with MOLLI. This result is in the same order as those reported for the widely used ShMOLLI technique compared with MOLLI for native myocardial T1 mapping at 1.5T.1‐weighted images only for native myocardial T1 setting, this suggests that long TI T1‐weighted images have reduced contributions to the precision of T1 estimates due to their reduced T1‐weighted contrast. FAST1‐BS leads to slightly higher increase of T1 spatial variability (by a factor of 1.4 when compared with MOLLI), but has higher accuracy, as discussed above.T1 mapping using two images only and a saturation recovery approach has been previously proposed using the arrhythmia insensitive rapid (AIR) T1 mapping technique, although this technique only enabled the acquisition of one T1 map per breathhold.1 mapping by a factor of 2.5 when compared with MOLLI.1 mapping by a factor of 1.4 (FAST1‐BS) and 1.2 (FAST1‐IR) when compared with MOLLI. Furthermore, the HR‐independence of FAST1‐BS and FAST1‐IR also suggests their insensitivity to arrhythmia, as only two images are acquired per slice. Although not directly demonstrated in this study, these findings suggest that an IR‐based FAST1 approach may have substantial advantages over a saturation recovery‐based FAST1 approach.Although FAST1 is based on inversion pulses, this sequence could be modified to use saturation pulses instead. Myocardial TIn this work, only the short‐axis orientation was investigated to minimize the sensitivity to the partial volume effect compared with the other orientations. However, the short‐axis orientation is suboptimal for imaging at the apical level, and the use of an additional long‐axis slice may be beneficial if mapping of the apex is intended.1 map is reconstructed from only two images in FAST1 and eight images in MOLLI, it is possible than FAST1 provide better native image registration, which could have potentially explained the slightly reduced T1 map quality of MOLLI with respect to FAST1 in patients. Existing image registration algorithms may provide different performance based on the number of T1‐weighted images and the presence of an in‐flow effect in the LV blood pool such as in FAST1. Therefore, to prevent any bias between the techniques induced by the choice of the image registration algorithm, this step was not applied in this work. Nevertheless, image registration algorithms were shown to improve myocardial T1 map quality.Motion correction was not performed for FAST1 and MOLLI. Since each T1 times due to the in‐flow effect caused by the slice‐selective inversion pulse. Therefore, FAST1 cannot be directly applied for extracellular volume (ECV) quantification. The combination of FAST1 with an additional mid‐ventricular T1 map acquired using nonselective inversion for blood T1 quantification could enable multislice ECV mapping with FAST1 and will be investigated in future work.FAST1 does not allow for quantification of blood T1 times at 3T, a longer TRD may be necessary to achieve nearly full recovery of the longitudinal magnetization. The combination of FAST1 with a gradient recalled echo (GRE) readout could also be beneficial to reduce off‐resonance artifacts at higher fields.This work was performed at 1.5T. Future work will investigate the feasibility of FAST1 at 3T with the potential benefit for scar assessment in patients with chronic myocardial infarction.1 mapping using FAST1 was not characterized in healthy volunteers. However, the phantom and patient experiments demonstrated the feasibility of postcontrast myocardial T1 mapping using FAST1. Third, no statistical analysis was performed for the phantom study, as only six vials with realistic myocardial T1 times were available, thus limiting the available power. However, the trend observed in the phantom experiments was confirmed in both numerical simulations and in vivo studies. Finally, the patient study was used for studying feasibility. Further studies in larger patient cohorts are now warranted.This work has several limitations. First, the approximation of the slice profile was approximated by one flip angle only. More advanced modeling could be considered in future work to better represent the nonlinear signal response to the flip angle.1 mapping with full LV coverage in three separated breathholds. In comparison with MOLLI, FAST1‐BS and FAST1‐IR yield a 5‐fold increase of spatial coverage, limited penalty of T1 precision/spatial variability, no significant difference of T1 repeatability, and highly correlated T1 times. FAST1‐IR provides improved T1 precision/spatial variability but reduced accuracy when compared with FAST1‐BS.In conclusion, FAST1 enables myocardial TAppendix S1: Supplementary MaterialsClick here for additional data file.


Combined anthracycline-trastuzumab chemotherapy has been associated with LV dysfunction. We aimed to assess early changes in left ventricular (LV) and right ventricular (RV) mechanics associated with combined anthracycline-trastuzumab treatment for breast cancer. As well as explore whether early changes in 2-dimensional (2D)–speckle tracking echocardiography (STE) could predict later chemotherapy-induced cardiotoxicity.Sixty-six patients with breast cancer who received anthracycline-trastuzumab treatment were included . Echocardiograms were available for analysis with 2D-STE at the following time points: pretreatment (T0), first cycle (T1), and second cycle (T2) of combined chemotherapy. All patients had a normal pretreatment LV ejection fraction (LVEF). Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography.P = .003). Compared with baseline (T0), left ventricular longitudinal strain, LV circumferential strain, circumferential peak systolic strain rate (SR), circumferential peak early diastolic SR, right ventricular longitudinal strain, and longitudinal peak systolic SR at T1 and T2 were reduced significantly in patients with cardiotoxicity (P < .05).Cardiotoxicity developed in 13 of the 66 patients (20%). The mean (±SD) LVEF at T0 was 66% (±6); at T1 60% (±7); and at T2, 54% (±6). For the 53 patients without cardiotoxicity, the LVEF was 65% (±4%) at T0, 63% (±5%) at T1, and 62% (±4) at T2. Global longitudinal strain (GLS) at T1 was the strongest indicator of subsequent cardiotoxicity (area under the curve, 0.85; cutoff value, − 14.06; sensitivity, 91%; specificity, 83%; Anthracycline-trastuzumab treatment leads to early deterioration of LV GLS, circumferential strain, and systolic SR. Right ventricular GLS and SR were also affected. Early changes in GLS are good predictors of subsequent development of anthracycline-trastuzumab–induced cardiotoxicity. HoweverMonitoring for early signs of cardiotoxicity during a patient’s treatment with chemotherapy can be done by using strain measurements . Two-dim2 and trastuzumab was administered for an average of 11 (±2.7) months in 3 week cycles and a mean dose of 5.4 (±2.7) gr. All patients had to have a normal pretreatment (T0) LV ejection fraction (LVEF), had to have been followed up for 1 year, as well as an echocardiogram at baseline. Patients who met the inclusion criteria and had images of adequate quality, as well as follow-up, were included (N = 66). Because of lack of consensus, we followed the definition of cardiotoxicity used in the clinical trials for combined chemotherapy in HER 2 positive patients, where it was defined as an absolute decrease in LVEF of 10 or more percentage points from baseline echocardiogram [For this retrospective study, we enrolled women newly diagnosed with breast cancer between December 1, 2004, and June 1, 2012, who were treated with an anthracycline (doxorubicin and epirubicin), or a HER 2 inhibitor (trastuzumab), or both. Though the majority of the study population  received adjuvant therapy, a substantial number 26/66; 39%); received neoadjuvant therapy. Of the total cohort, one woman was found to have stage IV disease at diagnosis. Twenty three (35%) had stage III disease and 6 of those had inflammatory breast cancer. None of the study population received concurrent anthracyclines and trastuzumab. The average age was 52 (±9), mean anthracycline dose of 252 (±45) mg/mrdiogram , 25. Tra/66; 39%;rdiogram . The stuTo be included, patients needed to have at least 3 standard echocardiographic examinations: at baseline (T0); from the start of chemotherapy to first echocardiogram (T1) and from the start of chemotherapy to the second echocardiogram (T2) following the cardio oncology clinic protocol . EchocarFor all patients, the region of interest analyzed was adjusted to cover at least 90% of the myocardial wall thickness for myocardial strain and SR. LV longitudinal parameters were measured from the apical 4-chamber, 2-chamber, and 3-chamber views, and the myocardium was divided into 6 segments per view. Care was taken to ensure that the long axis of the ventricle was perpendicular to the plane of the mitral annulus in the LV apical views. Circumferential and radial parameters were measured using the parasternal short-axis plane at the midventricular level. RV longitudinal parameters were measured from the apical 4-chamber view. Global and segmental myocardial deformation parameters, including strain (S), peak systolic strain rate (SRs), and peak early diastolic strain rate (SRe) were measured for each patient.To determine intraobserver variability, echocardiograms from 20 randomly assigned patients were reanalyzed by the same observer (X.H.) 2 months after the initial analysis. For interobserver variability, the same patients and the same cardiac cycles were analyzed by a second observer (Z.Y.).t tests. Differences among age subgroups were assessed using the Tukey-Kramer multiple comparisons test. The first(T1) and second time point(T2) were used to construct a receiver operating characteristic (ROC) curve, which was used to predict cardiotoxicity. The best cutoff value was defined as the point with the highest sum of sensitivity and specificity. Univariate and multivariate logistic regression analyses were used to determine predictors of a significant decrease in LVEF. Intraobserver variability, interobserver variability, and intraclass correlation coefficients (ICCs) with 95% CIs were calculated to evaluate test reliability [P value <.05 was considered statistically significant.Continuous data are presented as mean (SD) and categorical data as frequencies (percentages). Deformation parameters were compared among T0, T1, and T2 using 1-way ANOVA and paired iability , 31. AllSixty-six patients who completed anthracycline-trastuzumab treatment for breast cancer were included in the study . The patients’ clinical characteristics are summarized in Table Echocardiographic follow up was obtained in three time points: baseline (T0) at the time of diagnosis; (T1) from the start of chemotherapy to first echocardiogram ; and (T2) from the start of chemotherapy to the second echocardiogram (T2) .P < .01 for all). Also significantly reduced were RV GLS at T1, SRs at T1, RV GLS at T2, SRs at T2 and SRe at T1 . There was a significant decrease with increasing age in LV GLS both at T1 and T2, in LV longitudinal SRe at T2, and in RV longitudinal SRe at T1 . There was no significant decrease in any parameter measured with increasing age . LV GLS at T1  was also a strong indicator of subsequent cardiotoxicity. Combining LV GLS with longitudinal early diastolic strain rate (LSRe) at T1  and combining GLS with radial early diastolic strain rate (RSRe) at T1  were also strong predictors of subsequent cardiotoxicity  , 32. As 00 mg/m2 , 33. Ourreceptor , 24, 34.receptor .RV abnormalities may also occur in patients with cancer, although the frequency has not been determined. One study of 37 patients showed a decrease in RV systolic and diastolic indices on echocardiography relatively soon after chemotherapy with anthracyclines; however, most indices were within normal ranges . In our P<. 05 for all), in favor of improvement rather than further worsening of heart failure. These results suggest that patients with breast cancer can better tolerate the appropriate dose of anthracycline-trastuzumab treatment after early changes in myocardial mechanics occur.Fifty-four of our patients received anthracycline at T1 and anthracycline plus trastuzumab at T2. When compared with the changes from T0 to T1, the differences for T1 to T2 were significant  after less than 3 months of treatment with chemotherapy.


Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression.A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months.p < 0.01), maximal in leg muscles . Clinical and electrophysiological associations were evident. By 12 months, 16 patients had died or could not continue. In the remainder, relative T2-signal increased over 12 months by 14–29% in right tibialis anterior, right quadriceps, bilateral hamstrings and gastrocnemius/soleus (p < 0.01), independent of onset-site, and paralleled progressive weakness and electrophysiological loss of motor units. Highest clinical, electrophysiological and radiological SRMs were found for revised ALS-functional rating scale scores (1.22), tibialis anterior MUNIX (1.59), and relative T2-weighted leg muscle MR (right hamstrings: 0.98), respectively. Diffusion MR detected minimal changes.MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls  contains supplementary material, which is available to authorized users. A significant challenge in motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) research is the facility to track disease changes objectively over manageable time-scales, to reduce the duration and expense of clinical trials. Whilst survival remains a commonly applied outcome measure, slower progressing patients appear relatively over-represented in clinical trials , 2, and Clinical heterogeneity in anatomical site of onset, pattern of spread, and rate of deterioration are important barriers to quantifying progression at group-level, whether using clinical, electrophysiological or radiological measures. Most previous imaging studies have focused on the central nervous system (116 in a recent review ), and thThis was a prospective, longitudinal, observational cohort study. Patients were identified at first presentation to the tertiary referral neuromuscular clinic at the Royal Hallamshire Hospital, Sheffield, UK and were assessed at baseline, 4 and 12 months between October 2013 and May 2016. Inclusion criteria were age > 18 years, a clinical diagnosis of ALS fulfilling El Escorial criteria  or progrDemographic data, site of onset and duration of weakness were recorded. At each visit, the following data were collected: weight; revised ALSFRS-R ; MedicalCompound muscle action potentials (CMAPs), motor unit number index (MUNIX) and motor unit size (MUSIX)  were obt3, 5–6 stations, 50 coronal slices, reformatted to correspond to axial DWI acquisitions; DWI: TR = 9412 ms, TE = 66 ms, TI = 250 ms, b0, b1000 s/mm2, voxel size 2.3 × 2.3 × 5 mm3, eight stations, 50 axial slices. Total acquisition times including localizers and breath-holds were approximately 20 min and 40 min for the T2- and diffusion-weighted acquisitions, respectively.T2-weighted fast spin-echo and diffusion-weighted imaging (DWI) sequences were obtained at 3 T  with the following parameters: T2: TR = 1107 ms, TE = 80 ms, interpolated voxel size 0.78 × 0.78 × 5 mmMuscle regions-of-interest were contoured by two observers using standardized anatomical landmarks using a semi-automated spline function  on single slices for both T2- and diffusion-weighted images Fig. a–i. Priop values were corrected for multiple comparisons by applying the Benjamini–Hochberg method to each table of results at each time-point, . In patients, mean ALSFRS-R and median MRC summary score were 40/48 (SD 4.5) and 161/170 (SD 10.6), respectively. Fourteen patients presented with upper limb-onset, 11 patients lower limb-onset, and four patients bulbar-onset disease. Patients were assessed at a median of 66 weeks from symptom onset . Median follow-up was at 19 and 55 weeks for patients and 29 weeks for controls.Twenty-nine MND patients (26 ALS and 3 progressive muscular atrophy) and 22 healthy volunteers entered the study. Follow-up rates are reported in Fig. Radiological and clinical differences are reported in Table Associations between relative T2-weighted MR in each tested muscle with clinical power using hand-held dynamometry and MUNIX are reported in Table p = 0.012*).For ADC, the only finding was that greater weakness in left tibialis anterior was associated with higher ADC , Longitudinal clinical, electrophysiological and relative T2-signal changes in MND patients are reported in Tables p < 0.05). Median MRC summary score was 103/170 at baseline, 94/170 at 4 months (p < 0.05), and 97/170 at 12 months (p < 0.05 from baseline).Decreases in median MRC of up to one point were found in the following muscles at 4 months: left abductor pollicis brevis, right first dorsal interosseous, left wrist extensors, bilateral hamstrings, and right tibialis anterior; and in the following muscles at 12 months: left abductor pollicis brevis, bilateral first dorsal interossei, and left abductor digit minimi. Right tibialis anterior MRC decreased by 1.5 points at 12 months .ADC decreased only in patients’ right sternocleidomastoid at 12 months , There were no significant changes in healthy controls in any measure.Individualized plots of longitudinal relative T2-weighted changes summarized for all muscles, by region-of-onset, by muscle-of-onset and for a single leg muscle , are illustrated in Fig. r) = − 3.88 , p = 0.025), right gluteus maximus , p = 0.014), bilateral quadriceps , p = 0.044; left: r = − 1.11  right hamstrings , p = 0.045) and left gastrocnemius/soleus at four months , p < 0.001*); and right hamstrings , p = 0.025), right tibialis anterior , p = 0.008) and left gastrocnemius/soleus at 12 months , p = 0.001*).Associations between higher baseline relative T2 muscle signal and subsequent development of clinical weakness were found in right thenar eminence [regression coefficient , p = 0.002*), right hamstrings , p = 0.001*) and left gastrocnemius , p = 0.007*) at 4, but not 12 months.When only clinically normal muscles at baseline were included, higher baseline relative T2-signal was associated with development of weakness in right gluteal muscles , bilateral first dorsal interosseous and bilateral psoas. Of these muscles, ADM weakness is perhaps surprising, because generally considered relatively spared in MND, at least in terms of wasting (the basis of the split hand phenomenon), whilst involvement of first dorsal interosseous is typical . PatientThe difficulties of capturing change in MND with simple clinical measures, such as MRC scores, were illustrated in this study and highlight the challenges of phenotypical heterogeneity. Group-level longitudinal changes were detectable in first dorsal interosseous and tibialis anterior on dynamometry, muscles generally recognized as typically affected in MND , 32, butOn objective tests, progressive electrophysiological motor unit loss was evident, as in previous studies , especia2 [b = 1000 s/mm2 used in this study. We conclude that T2-weighted muscle imaging approaches appear more sensitive to MND change than diffusion-weighted MR, at least using the parameters applied.This was the first application of whole-body diffusion-weighted MR to assess muscle tissue integrity in MND. Very few changes were found, either because opposing effects of pathophysiological processes occurred or due to technical factors. It is possible that concurrent effects of myofibrillar cell membrane damage and increased intramuscular fluid increased diffusion, whilst consequent cellular debris and increased fat deposition caused a decrease, resulting in no detectable net ADC change. Alternatively, exponential signal intensity decay at high b values may have resulted in loss of signal. A previous study of muscle denervation in rats applied a lower b value of 600 s/mm2 , compareLeg muscles appear the best target for future fully quantitative T2 studies, although assessment in an independent cohort is necessary to determine whether this finding is generalizable. Whilst an increase in whole-body relative T2 was evident, this did not survive adjustment for multiple comparisons. Longitudinal changes were more readily detectable in the lumbar region, compared with cranial, cervical and thoracic body segments. This does not appear to be attributable to clinical factors; whilst lower limb-onset and progression were quite prevalent in our cohort, this was also the case for arm muscles. Technical factors may have contributed; leg muscles are larger, central within the acquisition field-of-view, with clearly defined anatomical boundaries, and these factors could influence the observed lower regression variance ratios. Measurement error might be reduced by developing fully automated analysis algorithms for whole-body MR in the future. Technical factors also prevented assessment of other muscles of interest, such as the diaphragm, which was not consistently identifiable using the slice thickness applied in this study. Thinner slices are possible but would necessitate longer scan-times.Despite cohort attrition, typical of longitudinal cohort studies in MND, resulting in lower statistical power, longitudinal relative T2 changes from baseline were more marked at 12 than 4 months. In our previous study, which assessed this cohort to four months using different methodology, longitudinal changes were identified in tibialis anterior  . In the A limitation of relative T2-weighted MR is the necessity to adjust measurements to reference tissue within each acquisition station to allow for differential coil-loading effects between participants, because the sequence is not fully quantitative. This could have biased between-muscle comparisons. We sought to minimize bias by reporting percentage T2-signal differences relative to healthy controls. Previous studies using similar sequences have applied qualitative grading scales and expert raters , 10. We In summary, this longitudinal study is the first to demonstrate clinically and electrophysiologically relevant progressive muscle denervation on MR across a wide range of muscle groups over 12 months. Although we hypothesized that whole-body muscle MR would capture generalized changes, our data suggest that leg muscles are sensitive to detect group-level longitudinal changes, irrespective of clinical onset-site, and could represent a biomarker target for future quantitative studies. Relative T2-weighted MR appeared more sensitive to detect denervation than diffusion-weighted MR.Supplementary file1 (DOCX 107 kb)Below is the link to the electronic supplementary material.