Takotsubo syndrome (TTS) was described in Japan 3 decades ago to affect predominately postmenopausal women after emotional stress. This history is the basis of commonly held beliefs which may contribute to the underdiagnosis and misperception of TTS.TTS affects not only women, but can be present in both sexes, and can appear in children as well as in the elderly. TTS is characterized by unique clinical characteristics with morphological variants, and incurs a substantial risk for recurrent events and adverse outcomes. Physical triggers are more common than emotional triggers and are major disease determinants. TTS seems not to be completely transient as patients report ongoing chest pain, dyspnea, or fatigue even after months of the acute event.Knowledge of the clinical features and outcomes of TTS patients has evolved substantially over the past decades. The heterogeneous appearance of TTS needs to be recognized in all medical disciplines to maximize therapy and improve outcomes. In 1991, Sato and colleagues from the Hiroshima City Hospital reported 5 cases of women who presented with an unusual left ventricular (LV) wall motion pattern after severe emotional stress . The uniTakotsubo syndrome is an acute heart failure syndrome characterized by LV systolic dysfunction –5. PatieOver the past years, more than 70 names have been introduced how to call this cardiac condition, further underpinning the diversity and heterogeneity of features , 13. TheTTS was originally designated as a primary acquired cardiomyopathy by the American Heart Association and as an unclassified cardiomyopathy by the European Society of Cardiology , 16. WitAn estimated 4% of patients who are admitted with signs and symptoms of an ACS are diagnosed as TTS –20. The TTS is characteristically triggered by emotional or physical inciting events. However, absence of triggering factors does not preclude the diagnosis of TTS. Negative emotional life events have unequivocally been acknowledged as the prototypical provocation for TTS. In earlier years, physical factors  were not known to trigger TTS. Similarly, it was inconceivable that TTS could also occur in the absence of stressful life events or in the presence of both emotional and physical stress. In the InterTAK Registry, only 28% of patients had emotional triggering factors . PhysicaPheochromocytoma is a catecholamine-releasing adrenal tumor . The incCardiac abnormalities are frequently observed after neurologic disorders such as stroke, subarachnoid hemorrhage, or epilepsy –42. The Diagnostic criteria for TTS were proposed from multiple centers in various countries , 51, 52.www.takotsubo-registry.com.Clinically, TTS is indistinguishable from AMI. The InterTAK Diagnostic Score is a validated model for differentiation of TTS and ACS with high specificity and sensitivity . Low IntTakotsubo syndrome is classified in 4 distinctive phenotypes, depending on the region of LV wall motion abnormalities . In the Anterior myocardial infarction with wrap-around left anterior descending (LAD) artery can resemble an apical TTS phenotype. The “apical nipple sign” can help to distinguish TTS from anterior ST-segment elevation myocardial infarction (STEMI) in such cases .One strongly held belief was that the diagnosis of TTS requires the absence of coronary artery disease (CAD). In the InterTAK Registry, 15.3% of patients had single-vessel and 7.8% of patients had multi-vessel disease, in whom the underlying CAD could not explain the wall motion abnormalities . If TTS The short- and long-term sequelae of TTS were initially underestimated, because it was assumed that TTS is a harmless and self-healing condition. Recent data have demonstrated that TTS is associated with substantial risk of morbidity and mortality, with rates comparable to AMI , 59. TheExtra-cardiac predictors for adverse outcomes are male sex, physical triggering factors, and acute neurologic disorders. Cardiac predictors for adverse outcomes are troponin levels over 10 times the upper limit of the normal range, high BNP values, left ventricular ejection fraction (LVEF) below 45%, moderate-to-severe mitral regurgitation, and right ventricular involvement , 65, 66.The recurrence rate is estimated at 2% per patient-year, occurring over a period of 30 days to 10 years after documented wall motion recovery of the index event. Initially, the previously affected area was thought to be protected from recurrence, analogous to regional ischemic preconditioning . HoweverTransience of wall motion abnormalities and recovery of LV function have historically been acknowledged as central concepts of TTS , 32. In However, ongoing chest discomfort, dyspnea, fatigue, and reduced exercise capability beyond the acute phase can persist for months after the TTS event despite normalization of myocardial function . StructuContemporary management of TTS is mainly empiric and relies on a combination of heart failure treatment and therapy of pre-existing medical conditions. Randomized controlled trials have not been performed yet, and data from observational studies or case series have partially shown conflicting results . In 2018QT prolongation can be found in a substantial number of cases and can predispose the risk for development of torsade de pointes tachycardia –79. QT-pCardiogenic shock in TTS can either develop from severe pump failure or left ventricular outflow tract obstruction (LVOTO) , 81. CatLV thrombus may develop in regions of akinetic segments , 88. In Observational studies and meta-analyses consistently reported that short- and long-term treatment with β-blockers is not beneficial for mortality reduction nor recurrence prevention , 90–92. New England Journal of Medicine extensively describing clinical features and outcomes of patients with TTS using data from 1750 patients derived from 26 sites in 9 countries [In the past decades, we have learned major lessons from several single center and multicenter registries, which have contributed to an advanced understanding of the condition. The International Takotsubo Registry (InterTAK Registry) was established at the University Hospital Zurich, Switzerland, in 2011 to represent a unique multicenter database to raise awareness, provide insights regarding clinical features and outcomes, develop risk stratification tools for diagnosis and prognosis, and guide management for patients with TTS , 96. In Three decades after the seminal description of TTS, the knowledge base on clinical features, risk factors, and outcomes has remarkably expanded, and many myths and misconceptions were uncovered. Future investigations are needed to gain a better understanding of the pathophysiological mechanisms and to provide tailored therapeutic approaches to improve outcomes and prevent recurrences.


A significant milestone in cardiac pacing occurred approximately two decades ago, when the primary operating mode was reimagined to more closely mimic normal top-down cardiac activation. When introduced, Managed Ventricular Pacing  was an unprecedented dual-chamber mode as it preferentially paced the right atrium in the AAI/R mode and simultaneously protected against transient heart block, albeit only in the instance of dropped ventricular beats. At the time, dual-chamber DDD/R with atrial-based timing and programmable atrioventricular delay was state of the art. MVP™ “unlocked” conventional dual-chamber pacing by not consistently requiring a 1:1 atrioventricular relationship during its primary operating mode . Ultimately, MVP™ emerged as a primitive means to promote His–Purkinje activation, and it is not a coincidence that its roots can be traced back to first-in-man permanent His-bundle pacing. Don’t let the noise of others’ opinions drown out your inner voice. And, most importantly, have the courage to follow your heart and intuition.”—Steve Jobs1 At the time, pacemakers were indicated in more than two-thirds of paced patients to correct symptoms resulting from abnormally slow origination of impulses in the sinoatrial node. Yet, as pacemakers were developed from the bottom up, starting with a VOO mode, they incrementally evolved to pace in a dual-chamber fashion such that every cardiac cycle ended with a ventricular sensed or paced event. Atrioventricular (AV) hysteresis, introduced in 1995, periodically extended AV delay for one beat and represented the first attempt to encourage intrinsic conduction. More sophisticated AV search hysteresis algorithms became available in 1999 and strived to discover intrinsic conduction over a series of beats. However, as aggressive as these algorithms were, they were limited by the programming confines of DDD/R pacing, including, most notably, the restrictions imposed to avoid 2:1 pacemaker block. MVP™ was revolutionary as it differed from all other dual-chamber modes and relaxed the requirement that all atrial events be followed by a ventricular event. In doing so, ventricular pacing was practically eliminated in all patients except those with persistent complete heart block.2Managed Ventricular Pacing  was conceived as a permanent pacing modality in 1999, nearly three decades after an atrial lead was added to permanent pacing and dual-chamber pacemakers were commercialized.3 and the Mode Selection Trial (MOST) and its substudy4 published between 2002 and 2003. In combination, these trials provided incontrovertible evidence that ventricular overpacing contributed to heart failure (HF) and atrial fibrillation (AF). Another important contemporaneous realization came from evidence that iatrogenic left bundle branch block created by RV pacing activation was equally harmful in patients with congestive HF without left bundle branch block.5 As such, results from early cardiac resynchronization therapy trials further contributed to the early adoption of MVP™.7The approval of MVP™ by the United States Food and Drug Administration in August 2004 did not require a large, prospective randomized trial. Instead, it was approved following two relatively small temporary software download trials involving a total of 211 patients . Both trials proved MVP™ to be safe and highly effective in reducing right ventricular (RV) pacing, with no clinical endpoints. The commercial release was bolstered by emerging and compelling evidence showing the harmful effects of RV overpacing. The most compelling trial findings came from the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial.8 Prior to pacemaker systems having a real-time, multichannel electrocardiogram (ECG) and event marker display, the assessment of atrial capture during attended follow-up was difficult and virtually impossible in patients with sinus tachycardia or frequent premature atrial contractions and complete heart block . An innovation known as “facilitated atrial pacing threshold testing” (FAPTT) emerged as a means to more easily perform the atrial threshold test by way of 2:1 AV pacing. Doing so thereby extends the isoelectric time and allowed visualization of atrial capture on alternating beats .8 Notably, the invention maintained atrial-only pacing in the event of intrinsic conduction and thereby allowed for atrial capture inference during sustained overdrive atrial pacing .The true origin of MVP™ can be traced back to 1995, when its predominant AAI+ operation was first described by David Casavant, a Boston-based field clinical engineer, as a means to safely facilitate atrial capture threshold determination The timeline and motivations for the development of MVP™, highlighting the controversies and uncertainties that surrounded the conception of a feature that continues to be considered standard of care, are described henceforth.In the case of MVP™, a common falsehood is that the development of MVP™ was a response to multicenter trials—most notably, the DAVID trial—which were designed to confirm the general understanding that excess ventricular pacing was harmful. When MVP™ was initially developed in 1999 and 2000, the idea of harm from ventricular pacing was a very small minority opinion. In fact, the original purpose of the DAVID trial was to establish the superiority of dual-chamber pacing, and the results of the DAVID trial (which was terminated early) represented only the beginning of a reevaluation of that idea.9 Although AAI-mode pacing was prescribed routinely in some European countries, atrial-only pacing never obtained a foothold in the United States, with few American device implanters willing to risk the possibility of frank syncope in a pacemaker patient. At the time that evidence of AAI pacing’s superiority in sick sinus syndrome patients began to mount, insertion of an RV pacing lead had already become an established practice. In a country having a robust health care system and a degree of litigiousness, single-lead ventricular pacing simply evolved directly to dual-lead AV pacing systems and, in the United States, little consideration was given to atrial-only pacing. In fact, AAI pacing was declared extinct in 2001.10 The best option for sick sinus syndrome patients at the time was programming DDD/R or DDI/R with a long AV  delay, but static, long AV delays introduced the potential for retrograde conduction and resultant arrhythmias, including pacemaker-mediated tachycardia and repetitive non-reentrant ventriculoatrial synchrony.MVP™ has been recognized as a disruptive innovation that was introduced well before its time and continues to be prescribed as a mainline treatment for patients with sinus node dysfunction and/or paroxysmal heart block. At the time of its conception in 1999, the most significant clinical evidence that AAI was superior to DDD was from a small , randomized, prospective (DANPACE I) trial performed in Denmark, which showed a significantly lower incidence of AF in patients paced with the AAI mode.11 and before the MOST substudy results were published.4 Interestingly, the MOST and DAVID trials hypothesized that dual-chamber DDD pacing, then considered the universal pacing mode, was likely to prove superior. Ultimately, the MOST trial showed that DDD pacing was equivocal to VVIR with respect to the combined endpoint of death or nonfatal stroke and confirmed that the degree of ventricular pacing in both the DDD and VVIR modes contributed to increased HF hospitalizations and AF, while the DAVID trial showed that DDD pacing increased the combined endpoint of death or HF hospitalization relative to backup VVVI pacing in patients with implantable cardioverter-defibrillators (ICDs) having compromised left ventricular function. It was ultimately the combined results from DANPACE I, the MOST substudy, and DAVID, together with the coincidental realization of the harmful effects of dyssynchronous ventricular activation gained from early cardiac resynchronization therapy trials,16 that cinched the destiny of MVP™.MVP™ was fully described before the plan for the DAVID trial was publicly announced17 As the collaborator and coauthor of the landmark publication describing first-in-man permanent His-bundle pacing, Casavant learned the paramount importance of preserving normal activation in pacemaker-indicated patients with failing hearts.18 Published studies suggesting adverse consequences from the use of conventional DDD/R pacemakers already existed but were largely ignored.23 Most notably, a publication in 1993 from a large single-center study involving 557 patients hospitalized for HF showed that the risk of non–sudden cardiac death at one year was 48% higher in patients with pacemakers.24 Belk had done his PhD work in developing a finite element model of ventricular arrhythmias and had concluded that abnormal ventricular activation increased ventricular tachyarrhythmia susceptibility in ICD-indicated patients. Under the guidance of Dr. Mark E. Josephson, he designed a simple protocol in patients being evaluated for ICDs and showed that ventricular tachycardia (VT) was more readily induced when premature ventricular stimuli  were delivered in the wake of a ventricular paced (S1) drive train than when premature ventricular stimuli were delivered at the same coupling intervals following a narrow QRS drive train produced by atrial pacing.25Although dual-chamber pacing had become widely accepted as the “physiologic” or “universal” pacing modality in the mid- to late 1990s, the existence of excessive ventricular pacing was troubling to Casavant and Paul Belk, a Medtronic field scientist stationed at Boston’s Beth Israel Hospital. Casavant had worked extensively with Dr. Pramod Deshmukh, widely recognized as the electrophysiologist who pioneered permanent His-bundle pacing. In the early 1990s, Dr. Deshmukh had realized that pacemaker implantation in patients with compromised left ventricular function often seemed to exacerbate their HF and accelerate mortality. More importantly, though, he understood why. In 1968, researchers had shown that those ventricles that were activated normally via temporary His bundle pacing functioned better.28 they had not yet been implemented or even tested on a dual-chamber ICD platform. In fact, initial DDD ICDs introduced in the United States in 1998 , 1999 , and 2000 , respectively, did not incorporate AV search algorithms.MVP™ was conceived in a clinical environment in Boston without substantial input from the vast array of Medtronic in-house engineers, scientists, marketing, and product planners. The widespread realization that ventricular pacing was possibly not benign began following a presentation of the MOST results as a late-breaking clinical trial at the North American Pacing and Electrophysiology Society Meeting in 2001. Thereafter, it became a higher priority for pacemaker practitioners to avoid ventricular pacing. Programming long AV delays within the constraints of DDD/R pacing, mainly to avoid pacemaker 2:1 block at elevated sinus rates, however, was often a difficult task. Although pacemakers with AV search hysteresis DDD/R-mode algorithms did prove to be quite effective in reducing ventricular pacing in pacemaker recipients,. At the time, most electrophysiologists and industry experts maintained that the primary function of ICDs was to protect patients from malignant ventricular tachyarrhythmias and accepted that some degree of ventricular overpacing was acceptable.The most important influence on the “AV delay-less” design of MVP™ was that it provided a means to overcome a mandate imposed by Medtronic’s dual-chamber ICD designers that the VP–AP interval “fit” within the VT detection zone at all times so as to not interfere with VT detection due to same-chamber and cross-chamber post-pace blanking periods. Such a scenario could easily be demonstrated on a simulator Figure 1 demonstrates basic MVP™ operation.To fully define MVP™ as a permanent pacing modality, the following enhancements were added to the FAPTT algorithm: (1) an AV delay of 80 ms following a nonconducted atrial event, which was chosen for being the shortest AV delay known to be asymptomatic during the clinical evaluation of Medtronic’s noncompetitive atrial pacing feature in the Thera™ DR pacemaker (Medtronic); (2) a postatrial refractory period of 600 ms for rates below 75 bpm and 75% of the ventricular interval for rates above 75 bpm, both of which were somewhat arbitrarily chosen to delineate premature atrial contractions from “physiologic” atrial sensed events originating from the sinus node; (3) a reverse mode switching AA/IR+ to DDD/R in the event of 2:1 block or rhythms having a ratio of A:V events below 4:3; (4) a mode switching to DDI/R from either AAI/R+ or DDD/R, in the event of AF; (5) periodic attempts to restore AAI/R+ operation following DDD/R reversion by withholding singular ventricular paced events at geometrically increasing intervals ; and (6) a premature ventricular contraction (PVC) response during AAI/R+ operation that suspends atrial pacing to eliminate potential VT detection interference from postatrial and ventricular cross-blanking following PVCs and PVC runs. 29 Casavant and Belk were the primary architects, while Tom Mullen, PhD, contributed solutions to several of the pace timing issues necessary to make the final MVP™ design reliable in the general pacing population and was also instrumental in the design, data analysis, and publication of the MVP Gem III DR download study.30 The fourth inventor, John Stroebel, a veteran Medtronic system engineer, contributed to the final design of MVP™ and conceived a sophisticated “under-the-hood” method to implement MVP™ as a download algorithm in the Gem III ICD. His contribution expedited the clinical evaluation of the algorithm and hastened commercial approval for MVP™. The timeline for MVP™ conception to market approval is depicted in Figure 4.In the end, four engineers can be credited as the inventors of MVP™.31 The commercial release occurred in 2004 with the launch of the Medtronic Intrinsic™ ICD.32 The MVP™ story would not be complete without also crediting Dr. Sweeney for coincidentally coming to the nearly simultaneous realization that RV overpacing was harmful. Dr. Sweeney’s first recognition of the deleterious impact of RV pacing came during analyses of the results from the landmark MOST study, which failed to show a significant benefit of DDD over VVIR pacing,33 and his extensive subanalyses showed that ventricular overpacing, either in the DDD or VVIR mode, contributed to incidence rates of HF hospitalization and AF in pacemaker patients.4 After joining Medtronic as a consultant on the MVP™ technology, his relentless advocacy and teachings solidified his position as a primary advisor and investigator of MVP™. Dr. Sweeney oversaw the first-in-man applications of MVP™ at BWH in late 2002 and his established authority as a key opinion leader greatly influenced expedited testing and commercial approval of MVP™. Dr. Sweeney is primarily responsible for ultimately convincing the worldwide pacing community that MVP™ was a solution to DDD/R pacing and that the maintenance of cardiac harmonious activation via its innate “infinite virtual electrode” is highly preferable over optimal AV timing.Of course, the complete list of MVP™ contributors is vast and includes all those who participated in the planning, design, development, and regulatory approval. MVP™ received regulatory approval based on one-week data obtained from 30 patients of Dr. Michael O. Sweeney, an electrophysiologist from Boston’s Brigham and Women’s Hospital (BWH), and on multicenter data from 206 patients having the MVP™ algorithm temporarily downloaded as “RAMware” into the Marquis DR ICD.® and AAISafeR 2 , released internationally in 2003 and 2005, respectively, were the only other pacing modes having AAI/R↔DDD/R functionality similar to MVP™ at the time.  Strategies used by other manufacturers included Auto-intrinsic Conduction Search® (AICS) in 2006 , Ventricular Intrinsic Preference® (VIP) in 2007 , AV Search Hysteresis® (AVSH) in 2007 (Guidant), Vp Suppression® and Intrinsic Rhythm Search® (IRSplus) in 2010 , and Rhythm IQ® in 2012 .Near the time of MVP™’s approval or soon thereafter, all other cardiac rhythm device companies secured approval for commercial release of more assertive ventricular pace minimization algorithms. AAISafeR35The second generation of MVP™ was implemented in cardiac rhythm devices released beginning in 2017 with slight modifications, including an optional programmable limit for the longest allowed A–R interval and an enhancement to lessen the duration of long V–V intervals and the severity of short–long–short (S–L–S). This second version of MVP™ employs a dynamic, adjusting A–A interval and a programmable maximum AV interval limit such that switching to DDD/R occurs if two of four Ap–Vs or As–Vs intervals exceed this limit.Many agree that the rapid acceptance of MVP™ was largely due to its simplicity in that it more closely mimicked normal activation of the heart and allowed for the management of non–pacemaker-indicated rhythms—including first-degree and second-degree Mobitz I, type I “Wenckebach” heart block. This simplicity was enhanced by its lack of programmable parameters. MVP™ was introduced as an ON/OFF feature, a characteristic the inventors vehemently defended, thereby avoiding the “feature creep” that often results from the desire to appease all. The naming of this mode is owed to Dr. Sweeney.In some ways, MVP™ can be viewed as a precursor to future permanent His-bundle pacemaker modalities  given that both favor normal ventricular activation. In fact, it is being employed on occasion for patients with intermittent heart block receiving A–H pacing systems by programming short AV delays consistent with normal A–H intervals.31 The Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVe PACe) pacemaker trial showed that, in patients paced using a minimal ventricular pacing strategy, the risk of progression to persistent AF was reduced by 40%.36 An ensuing multicenter 1,166-patient pacemaker trial known as Minimize Right Ventricular Pacing to Prevent AF and HF (MINERVA) demonstrated that the combined efficacy of MVP™ when prescribed alone—and particularly when combined with atrial antitachycardia pacing—achieved a significant overall reduction in the progression to permanent or persistent AF as compared with among DDDR-paced patients.37MVP™ has seen very high levels of clinical success in prospective, randomized clinical trials. The MVP™ versus VVI 40 pacing trial, performed in an ICD population, similar to the DAVID trial, was stopped for futility as the combined endpoint of worsening HF or all-cause death was equally low in both arms.38 some criticisms of the mode for allowing occasional pauses that were excessively long have arisen. Sweeney et al. somewhat debunked the notion that pauses were more significant than in other modalities such as backup VVI pacing and showed that, although (nonpaced) S–L–S sequences were permitted more frequently by MVP™, S–L–S sequences terminating with a paced beat were not.39Although the MVP™ mode significantly reduced ventricular pacing in the majority of patients, including those having a heart block indication,43 However, some patients have reported vague symptoms from pseudo-pacemaker syndrome due to sustained periods of first-degree block with very long P–R intervals. Some patients have not tolerated MVP™ due to symptoms attributed to extended pauses following nonconducted atrial events. Still, experience to date has revealed that only a small minority of MVP™-paced patients have been reprogrammed to conventional DDD/R pacing. Overall, MVP™ 2.0 has addressed concerns.MVP™ has not experienced unconditional patient acceptance. MVP™ has been implicated in VTs in prone patients.Despite its shortcomings, MVP™ has been a huge clinical success that resulted from hard work, research, and serendipity. MVP™ represents a product of collaboration amongst engineers and physicians, an attribute that is shared by so many important innovations in medicine.44 In HF patients, physician sentiment continues to favor AAI/R  and other modes that limit RV pacing.47 Ultimately, permanent His-bundle and direct conduction-system pacing will provide better solutions.Importantly, MVP™ is not the optimal solution: clinical equipoise is imposed by the competing goals of optimizing AV synchrony while maintaining normal ventricular activation, particularly in patients having long P–R and narrow QRS intervals. In pacemaker-indicated patients, optimizing the AV interval using DDD pacing is only indicated in the event of symptoms due to severe AV decoupling .


Preterm birth increases risk of cardiovascular disease and early death. A body of evidence suggests left ventricle (LV) echocardiographic alterations in children and adults born preterm. We aimed to determine if neonatal characteristics were associated with alterations in LV structure and function in preterm adults. We evaluated a cohort of 86 young adults born preterm below 30 weeks of gestation, and 85 full-term controls. We determined LV dimensions and function using tissue Doppler imaging, conventional and speckle tracking echocardiography (STE). Adults born preterm had smaller LV dimensions, but these differences did not remain after adjustment for body surface area (BSA), which was smaller in the preterm group. Stroke volume and cardiac output were reduced even after adjustment for BSA. We found a smaller e’ wave in the preterm group, but other markers of systolic and diastolic function did not differ. Use of antenatal steroids may be associated with a further reduced cardiac output in those born preterm. Adults born preterm show alterations in markers of LV dimensions and function. Identification of these markers may represent opportunities for early prevention of cardiovascular events in this at-risk population. Every year, 1% of all neonates are born below 30 weeks of gestational age (GA) . HoweverStudies analyzing echocardiography images have shown abnormalities in the cardiac structure and function of infants and children born preterm, from early post-natal life  throughoData were obtained from the HAPI study, which has been previously described ,27. We oHeight and weight were measured in duplicates, on study day. BSA was calculated using the Mosteller formula (square root of the height (cm) multiplied by the weight (kg) divided by 3600) . Office Neonatal information was collected from medical files (preterm group) and immunization booklets (term group). Birth weight for gestational age percentile was calculated according to Hadlock et al.  (preterm2 × Pi. The cardiac output (CO) was then estimated by multiplying the resultant stroke volume by the heart rate [Echocardiographic views were obtained at rest in the left lateral decubitus position on a General Electric (GE) Vivid E9 ultrasound machine with standard transducers, and standard echocardiographic measurements were extracted and analyzed using EchoPac PC software . Offline measurements were done on Tomtec Arena platform . Measurements were performed according to the American Society of Echocardiography guidelines ,33. Cardart rate .Inter-rater variability was assessed in a subset of 50 participants (25 born full-term and 25 born preterm) by two echocardiography experts  blinded to the previously obtained values and to the exposure group for selected parameters. We determined consistency intraclass correlation coefficients (ICC) using a two-way mixed model. Inter-rater agreement was considered poor (ICC below 0.40), fair (ICC between 0.40 and 0.59), good (ICC between 0.60 and 0.74) or excellent (ICC above 0.75), according to Cicchetti .Based on previous literature, we investigated the association of neonatal characteristics that were reported to be associated with LV changes  [Descriptive statistics were calculated as mean with standard deviation (SD) for continuous variables and counts with proportions for categorical variables. All between-group comparisons of cardiac volumes and dimensions were performed with and without adjustment for BSA, because of a significant difference in BSA between term and preterm groups and the well-known physiological association between BSA and cardiac dimensions. Univariate and bivariate linear regressions were performed to assess mean and adjusted mean differences, except for baseline characteristics . NormaliAustria) .In this study, 85 participants born full-term (GA at birth ≥ 37 weeks) and 86 participants born preterm below 30 weeks GA were included. Among those born preterm, 28 (33%) had a history of moderate to severe BPD. Detailed neonatal and adult clinical characteristics of study participants are shown in Conventional markers of LV systolic function , were preserved and similar in participants born at term and preterm . IndividHeart rate was higher in the preterm group. Stroke volume and cardiac output were lower in the preterm group, even after adjustment for BSA . Mitral LV STE measurements could be performed in 87% of the study participants. Poor image quality did not allow for accurate measurements in the remaining participants. We found no significant difference among the analyzed strain and strain rate parameters in systole or diastole .In the preterm group, we did not find a significant association of maternal preeclampsia, birth weight percentile and bronchopulmonary dysplasia on LV mass, LVEF, LVCO, LV E/A, LV e’, and peak longitudinal strain. Use of antenatal steroids was associated with a lower LVCO in the preterm group .We performed analyses of LV echocardiography markers stratified by sex and found that the differences observed between term and preterm adults were similar among males and females .All measurements had good or excellent reproducibility. Specifically, ICC was of 0.81 for S’, 0.86 for e’, 0.90 for EDV and 0.89 for LV mass.Using echocardiography-derived markers of dimension and function, we report characterization of the LV in a large cohort of young adults born preterm < 30 weeks, compared to term counterparts. Overall, LV estimates of volumes as measured by echocardiography were decreased in the preterm population but did not remain after adjustment for BSA. LV mass, when adjusted for BSA, was similar between groups. While most markers of cardiac function were preserved in those born preterm, we observed a lower stroke volume, a smaller LV e’ wave and a smaller s’ wave in the preterm group, in line with previous reports. LV length was also shorter in the preterm group. Use of antenatal steroids may be associated with a further decreased cardiac output.As shown by previous studies and a recent meta-analysis, children and adults born extremely preterm who survive the neonatal period display mild but significant echocardiographic alterations of systolic and diastolic function . Most ofTwo recent studies were not included in the meta-analysis. Similar to our finding, Harris et al.  found a While our study, in line with other recent studies, suggests mild but long-term alterations of cardiac structure and function in adults born preterm, little is known on the association of these alterations with the adverse conditions associated with preterm birth. In an experimental study conducted in an experimental model that replicates some of the adverse conditions of preterm birth, we previously reported changes in LV structure and function, including increased susceptibility to heart failure in 12-week old rats that had been exposed to high (80%) oxygen levels from day 3 to 10 of life, compared to controls not exposed . FurtherTwo studies from the 1990s performed around the period of birth of our study population, found alterations in LV filling and increased wall thickness in preterm neonates receiving postnatal administrations of steroids ,22. In cAlthough a history of preeclampsia during pregnancy has been associated with alterations in LV strain in adult offspring born preterm , we did Intrauterine growth restriction has been associated with different cardiac shape, subclinical systolic and diastolic changes in children, with decreased myocardial peak velocities, increased E/e’ ratio and E deceleration time, higher blood pressure, and increased intima-media thickness . While wWe found a smaller LV length in the preterm group. A shorter LV length was previously reported to be associated with an altered exercise systolic response in adults born preterm . Thus, aOur study has limitations. First, although the number of very preterm individuals included in our study is relatively high and similar to previously reported cohorts, our study may not have the power to identify smaller associations of antenatal and perinatal factors with adult cardiac characteristics. Second, it is possible that changes observed between groups are the result of regional differences in neonatal care, including rates of antenatal steroids as suggested by current results, habitus, and/or genetic backgrounds. Our findings were obtained from mainly white individuals born in Quebec, which could limit generalizability. In addition, there is a strong inherited component to the risk of cardiac diseases, which the current study, as well as previous studies on the matter, did not have the power to take into account. In women, having delivered preterm (independently of hypertensive disorders of pregnancy) is a recognized risk factor for cardiovascular diseases . Hence, Beyond these limitations, the current results add to the increasing evidence that individuals born preterm display altered LV structure and function, with a possible association with prematurity-associated conditions such as antenatal steroids.Stroke volume, cardiac output, and e’ wave are decreased in young adults born preterm included in this study, and cardiac output may be further reduced in case of antenatal steroid use. The differences observed between groups were relatively small and overall measures of LV function were within normal ranges—fortunately so at such a young adult age. Whether the observed alterations translate into a higher risk of heart failure later in life and could be used to refine risk stratification remains to be determined.


Galectin-3 as a cardiac biomarker has proven to be a significant prognostic tool in adults. However, it has not yet been established in the pediatric population as a biomarker in daily clinical practice. The aim of the study was to summarize the current knowledge on galectin-3 as a biomarker in children with cardiac conditions by reviewing the literature. Bibliographic databases such as PubMed, Web of Science and Embase were searched, and consequently twelve articles met the inclusion criteria. Supplemental handsearching of references delivered one additional source. These prospective studies concerning galectin-3 as a cardiac biomarker present analyses performed in cohorts composed of healthy children and children with cardiovascular diseases. The results, despite being based on small cohort studies, inform that galectin-3 could serve as a potential biomarker in cardiovascular risk stratification in children with heart failure, arrhythmia, Kawasaki disease or in patients undergoing cardiac surgery. The evidence for the usefulness of galectin-3 in the assessment of such pathologies as idiopathic dilated cardiomyopathy, coarctation of the aorta, functionally univentricular heart or tetralogy of Fallot were not completely confirmed. Galectin-3 seems to be a promising biomarker; however, there is a need for further research to establish its use in daily clinical practice. Galectin-3 protein is a novel biomarker, known mostly as an indicator of inflammation and fibrosis. It is a member of the betagalactosidase-binding galectin protein family and contains a carbohydrate-recognition domain (CRD). Galectin-3 is a chimera-type galectin with a single CRD connected to an N-terminal domain . In the The understanding of the mechanisms of galectin-3 activity gave rise to many studies concerning the protein as a biomarker in clinical practice in adults as well as children. In the pediatric population, apart from the cardiovascular diseases discussed below, galectin-3 was studied in a variety of illnesses; one example of which was children with hepatitis B, proving that serum galectin-3 levels may be a beneficial indicator of chronicity of hepatitis B infection in children . Borges Although other biomarkers such as troponin or NT-proBNP are commonly used in pediatric cardiology, their value is limited by some disadvantages. Among these limitations, the alternating, age-dependent and broad normal range, as well as their relatively difficult interpretation, are the major ones ,16. As aThe aim of the study was to review the literature on galectin-3 as a cardiac biomarker in pediatric populations.The authors performed a comprehensive search according to the Preferred Reporting Items for Systematic Reviews and Meta—Analyses Extension for Scoping Reviews (PRISMA-ScR)—Studies assessing galectin-3 as a cardiac biomarker in children with cardiovascular diseases included in this review are listed in I and AI velocity—were found. Concurrently, significant negative correlations of galectin-3 plasma concentrations in relation to contractile function parameters such as ejection fraction and shortening fraction were presented.In the studies conducted in pediatric patients with congenital heart diseases, galectin-3 plasma concentration was significantly higher in children presenting with heart failure signs and symptoms than in those without ,20,21,22In a trial by Woulfe et al. , the expIn children in the pre-treatment phase of Kawasaki disease, the plasma concentration of the galectin-3 was found to be significantly higher than in the control group . HoweverGalectin-3 is a strong predictor of poor prognosis in the early follow up after surgery in children treated for such congenital heart diseases as a ventricular septal defect, atrioventricular septal defect or pulmonary valve regurgitation after tetralogy of Fallot repair . PreoperIn the study of Pietrzak et al. , galectiManagement of patients with cardiovascular diseases usually requires risk stratification for complications and further clinical course of the disease. Therefore, reliable prognostic biomarkers that help to improve the accuracy of the diagnosis and the way of the treatment are still desirable. The understanding of the mechanisms of galectin-3 activity gave rise to the consideration of this biomarker as a valuable tool in clinical practice, either in the initial phase of the disease or during follow up in various circulatory system pathologies, including those seen in children. For these reasons, we reviewed the literature on galectin-3 as a cardiac biomarker in the pediatric population.The published studies in children revealed that galectin-3 is elevated in diseases which are connected with volume overload and is thus related to the clinical signs. The results clearly presented the differences of the concentrations of this biomarker in children presenting varying degrees of heart failure symptoms—from the asymptomatic to patients presenting symptoms at rest—as correlated by the Ross Heart Failure Classes ,21. MoreIn summation, galectin-3 could be a valuable prognostic biomarker in the assessment of heart failure in children; however, the data are still sparse and further trials are necessary to evaluate the value of the biomarker and its relationship to hemodynamical dysfunction. The role of galectin-3 is widely investigated in adults with heart failure. The trials show galectin-3 as a biomarker of prognostic importance, being a significant predictor of mortality and rehospitalization in the population with acute, as well as chronic, heart failure ,34. As sGalectin-3 may also be a valuable tool to establish the extent of tissue destruction in chronic inflammation. In Kawasaki disease, galectin-3 plasma concentration is higher in children in whom chronic inflammation drives aneurysmal changes in the coronary arteries, as compared to those patients in whom the disease takes the form of the progressive condition. To some extent, this hypothesis is confirmed by the data showing that the results of surgical treatment of congenital heart disease are worse in patients with increased levels of galectin-3 than in those with normal plasma concentrations of the protein . These rThe prognostic nature of galectin-3 was also a point of research for Greenber et al. and Parsons et al. ,27. In rContrarily, Zegelbone et al. , in his Although Karatolios et al.  reportedThe results presented in the study of Frank et al.  were notBoth children and adults with functionally univentricular hearts with Fontan circulation were assessed by researchers in order to determine the potential of galectin-3 as a prognostic biomarker in this cohort. A large group of 133 young patients at a median age of 13.2 years was studied, and no evidence for distinguishing high-risk patients  was found . The autGalectin-3 was also broadly studied in grown-ups with congenital heart diseases, and the results could serve as a direction for future research in younger cohorts. In the study by Frogoudaki et al.  of galecConsidering the results in adults with congenital heart disease, there is an optimistic view for galectin-3 to serve as a valuable marker, especially for the prediction of life-threatening arrhythmias, and hopefully for ventricular function assessment and risk stratification in specific groups of patients. Expert consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension emphasize the fact that galectin-3 is a promising biomarker in adult pulmonary arterial hypertension, setting the direction for further research [In the literature, many trials exist in the adult population with clinical problems such as pulmonary hypertension, hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy, showing that galectin-3 plasma concentrations are higher in those patients when compared to healthy individuals. Galectin-3 levels reflect heart remodeling. This was proven by the relationship of the biomarker level and echocardiographic measurements. In the study performed by Fenster et al.  in patieresearch . The direction of research in children leads, as it does in adults, to the field of arrhythmias, where galectin-3 is researched for its ability to detect patients with a worse course of the disease and assumingly with poorer prognosis. The main area of focus is atrial fibrillation. Galectin-3 plasma concentrations predict arrhythmia recurrence following a single ablation procedure, whilst the data considering the value of galectin-3 in the anticipation of the effectiveness of the ablation are conflicting. Furthermore, galectin-3 was independently associated with atrial remodeling in patients with chronic atrial fibrillation ,50,51. GLast but not least, it is worth mentioning the report of Dencker et al.  of a heaAs the first studies of galectin-3 in children with cardiovascular diseases are very optimistic, there is need for further research. We can assume that galectin-3 in pediatric cardiology appears to be a potential biomarker; however, there is still insufficient data to be able to introduce galectin-3 in clinical practice guidelines. Further investigations should doubtlessly focus on multicenter studies consisting of larger cohorts. A potential and promising direction for research is galectin-3 concentrations in children with congenital heart diseases, heart failure symptoms, arrhythmias or myocarditis .The limitations of the study include the lack of statistical meta-analysis, as well as heterogeneous data and small sample sizes .


Cardiomegalia pela radiografia de tórax (RXT) é preditor independente de morte em indivíduos com cardiomiopatia crônica da doença de Chagas (CCDC). Contudo, a correlação entre o aumento do índice cardiotorácico (ICT) na RXT e do diâmetro telediastólico do ventrículo esquerdo (DDVE) pela ecocardiografia (ECO) nessa população não está bem definida. Analisar a relação entre cardiomegalia pela RXT e DDVE pela ECO em pacientes com doença de Chagas (DC) e sua aplicabilidade ao escore de Rassi. Estudo retrospectivo incluiu 63 pacientes ambulatoriais com DC avaliados por RXT e ECO. Cardiomegalia na RXT foi definida como ICT > 0,5. DDVE foi avaliado como variável contínua. Curva ROC foi utilizada para avaliar o potencial do DDVE para identificação de cardiomegalia pela RXT, com ponto de corte definido pela maior somatória de sensibilidade e especificidade. Idade mediana = 61 anos [intervalo interquartil: 48-68], 56% mulheres. CCDC foi identificada em 58 pacientes; 5 tinham a forma indeterminada da DC. Cardiomegalia foi detectada em 28 indivíduos. A área sob a curva ROC do DDVE para identificação de cardiomegalia foi de 0,806 . O ponto de corte ótimo para DDVE foi de 60 mm . O uso do DDVE pela ECO em substituição ao ICT pela RXT alterou o escore de Rassi em 14 pacientes, e em 10 deles houve redução do risco presumido. DDVE pela ECO é parâmetro adequado e com alta especificidade para distinguir entre presença e ausência de cardiomegalia na RXT na DC. :68-74) Trypanosoma cruzi (T. cruzi), cujo principal vetor de transmissão ao ser humano são insetos da subfamíliaTriatominae, embora isso possa ocorrer por outros mecanismos, tais como transfusão sanguínea, transplante de medula óssea ou de órgãos sólidos a partir de doadores contaminados, transmissão vertical entre mãe e filho e ingestão de alimentos contaminados.1 Estimativas da Organização Mundial da Saúde (OMS) reportam que aproximadamente 7 milhões de indivíduos estão infectados mundialmente, proporcionando elevada morbimortalidade e impacto social.2A doença de Chagas (DC) resulta de infecção pelo protozoário4 O escore de Rassi é estratificador do risco de morte validado em pacientes com cardiomiopatia crônica da DC (CCDC). Dentre os fatores de risco que compõem esse escore, destaca-se a cardiomegalia na radiografia de tórax (RXT), que se associa a significativo risco de morte total e cardiovascular em pacientes com a CCDC.5A cardiomiopatia é a mais séria e frequente forma clínica da DC crônica, que ocorre em 20% a 30% dos indivíduos cronicamente infectados.5 tenha utilizado a ecocardiografia (ECO) para determinar o diâmetro telediastólico do ventrículo esquerdo (DDVE), esse parâmetro não se mostrou marcador independente de mortalidade na CCDC. Entretanto, deve-se ressaltar que, naquele estudo, o DDVE foi avaliado de maneira categórica, com pontos de corte convencionais que podem não ser os mais adequados para pacientes com CCDC, devido ao típico envolvimento miocárdico segmentar nessa doença. De outra parte, o cálculo do índice cardiotorácico (ICT) pela RXT pode englobar, em muitos casos, a dilatação de átrios e ventrículos, que se expressam linearmente na RXT. Embora o estudo radiológico do coração seja bastante disponível, implica radiação, enquanto a ECO tornou-se atualmente um método amplamente utilizado para avaliação cardiovascular. Dessa maneira, haveria indiscutível interesse em, com um único exame, avaliar função sistólica e dimensão do ventrículo esquerdo (VE), a fim de estimar o risco de morte com variáveis correlatas às aplicadas no escore de Rassi original.Embora o estudo de Rassi Jr et al.O presente estudo teve por objetivo analisar a relação entre cardiomegalia definida pelo ICT na RXT e o DDVE avaliado com ECO em pacientes com DC.T. cruzi, embasados em técnicas distintas, que se encontravam em seguimento ambulatorial no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo em Ribeirão Preto (HCFMRP-USP), hospital terciário e centro de referência em pesquisa de DC.Neste estudo transversal retrospectivo, foram incluídos pacientes de ambos os gêneros, adultos (> 18 anos de idade), com diagnóstico de DC, caracterizados por positividade em dois exames sorológicos para detecção de anticorpos contra o6 Foram incluídos neste estudo os pacientes que tivessem RXT e avaliação completa dos preditores independentes do escore de Rassi, mediante os exames essenciais de eletrocardiograma de 12 derivações, em repouso, ECO, RXT e exame de monitoramento de 24 horas do ritmo cardíaco, além de anamnese focada na gradação de dispneia conforme a New York Heart Association (NYHA). Para inclusão no estudo, o limite máximo de tempo entre a realização da RXT, considerada como método comparativo de referência, e a ECO foi de 1 ano, desde que ostatusclínico do paciente tivesse se mantido estável nesse período. Foram excluídos da análise os pacientes que apresentaram mudança no quadro clínico no decorrer do período entre a realização desses dois exames.A coleta de dados foi realizada por meio de revisão sistematizada de prontuários clínicos, a partir de um grupo de 158 pacientes com DC que participaram de estudo clínico prévio, cujos critérios de inclusão e exclusão foram anteriormente reportados em detalhes por outra publicação.A cardiomegalia na RXT foi sempre avaliada na incidência posteroanterior e definida como a presença de ICT > 0,5. Foi envidado esforço adicional para eventual caracterização de aumento ventricular direito, por comparação com a telerradiografia em perfil, nos casos em que essa incidência radiológica estava disponível.7 Outros parâmetros ecocardiográficos também relacionados ao remodelamento do VE foram analisados, tais como o índice de massa e a fração de ejeção (FE) do VE e o volume indexado do átrio esquerdo.Foram utilizados os dados de ECO transtorácica em repouso, realizada na data mais próxima à da RXT, desde que respeitado o período máximo de 1 ano. O DDVE foi mensurado pelo método bidimensional, seguindo diretrizes ecocardiográficas recentes.Receiver Operating Characteristic) foi realizada para verificar a capacidade de o DDVE, avaliado pela ECO, distinguir entre presença e ausência de cardiomegalia pela RXT. Por fim, foi avaliado o impacto na reclassificação dos pacientes com a forma cardíaca da DC pelo escore de Rassi, utilizando-se a ECO para a definição de cardiomegalia, em substituição ao tradicional ICT. Os indivíduos com a forma indeterminada da DC não foram classificados pelo escore de Rassi neste estudo, pois pacientes com essa forma da doença não foram contemplados na investigação original desse escoreVariáveis contínuas foram apresentadas como média e desvio padrão quando distribuídas normalmente, e representadas como mediana e intervalo interquartil quando apresentavam distribuição não normal. Análise de curva ROC  e conduzido sob os princípios éticos da declaração de Helsinque e em conformidade com a resolução do Conselho Nacional de Saúde nEste estudo transversal retrospectivo incluiu 63 pacientes com DC que preencheram os critérios de inclusão, correspondendo a 40% do total de 158 pacientes avaliados. As características demográficas e clínicas dos participantes estão descritas naCardiomegalia foi detectada pela RXT em 28 (44%) indivíduos. O tempo médio entre a realização da RXT e da ECO foi de 5 ± 174 dias. O DDVE dos indivíduos no grupo com cardiomegalia (61 IIQ [53-70]) pela RXT mostrou-se maior do que no grupo sem cardiomegalia (49 IIQ [46-55]), p < 0,001. A área sob a curva ROC do DDVE para identificação de cardiomegalia detectada pela RXT foi de 0,806  . Na amoOs indivíduos com resultados discordantes para cardiomegalia definida pelos dois métodos de imagem não mostraram diferenças estatisticamente significativas quanto a idade, gênero, índice de massa ventricular esquerda e volume indexado do átrio esquerdo em comparação aos indivíduos com resultados concordantes.Na presente amostra populacional, a proporção de indivíduos considerados de risco baixo, moderado e alto de morte pelo escore de Rassi, utilizando a RXT para identificação de cardiomegalia, foi de 36% (n = 21), 33% (n = 19) e 31% (n = 18), respectivamente. Ao utilizar-se a ECO para identificação de cardiomegalia, com o ponto de corte de maior acurácia, a proporção de pacientes com risco baixo, moderado e alto foi de 40% (n = 23), 28% (n = 16) e 32% (n = 19), respectivamente . Em 44 Este estudo demonstrou existir relação bastante nítida e significativa entre a detecção de cardiomegalia pela RXT e a verificação de dilatação ventricular esquerda, pela ECO, em amostra não selecionada de pacientes ambulatoriais com diagnóstico de CCDC. Esses resultados abrem a perspectiva para que o DDVE avaliado na ECO transtorácica em repouso possa substituir a aferição do ICT na RXT, no sentido de se determinar o risco de morte em pacientes com a CCDC com o escore de Rassi, assim eventualmente modificado. Isso permitiria dispensar o exame radiológico que requer irradiação do paciente, embora de pequena monta, e determinar com apenas um exame  tanto a função sistólica ventricular esquerda quanto a dimensão dessa câmara. Essa perspectiva torna-se atraente, uma vez que o DDVE, pela ECO, constituiu parâmetro adequado, com alta especificidade, para distinguir entre presença e ausência de cardiomegalia em pacientes com DC crônica.8 com amostra bem menor, composta por 22 pacientes, que também focalizou resultados da RXT e da ECO e concluiu por boa correlação entre os valores de ICT e de função ventricular esquerda.8 Em contraposição, outro estudo, por Perez et al. em 2003, relatou sobre análise comparativa entre os resultados da RXT em incidência posteroanterior e os da ECO em repouso.9 Diversamente dos resultados de nosso estudo, aqueles pesquisadores descreveram baixa correlação de valores de ICT pela RXT, tanto com o DDVE quanto com a FE do VE. Além disso, o ICT naquela pesquisa não demonstrou ter elevados índices de sensibilidade ou valor preditivo positivo para detectar disfunção ventricular esquerda. Dessa maneira, concluiu-se que o ICT anormal  apesar de elevada especificidade para detectar a disfunção sistólica do VE, não seria exame útil na avaliação dessa anormalidade na DC, em vista de sua baixa sensibilidade para detectar tanto a dilatação ventricular avaliada pela ECO transtorácica em repouso quanto a disfunção sistólica da câmara, medida pela FE do VE com o mesmo método.Os resultados da presente investigação corroboram os de pesquisa anterior relatada em 1983 por Pereira-Barreto et al.,9 Ambos os estudos são embasados em amostras populacionais de pacientes com CCDC que eram ambulatoriais, orbitando em ambientes de hospitais universitários, mas há também alguns aspectos diferenciais entre as amostras estudadas. Assim, não houve praticamente critérios de exclusão em nosso estudo, salvo os de conveniência logística, decorrentes da disponibilidade dos dois exames comparativos em intervalo de tempo prefixado de 1 ano. Em contraste, os critérios de exclusão na pesquisa de Perez et al.9 foram bastante amplos e abrangentes, embora aplicados a pacientes sucessivos, e possivelmente resultaram em amostra relativamente selecionada e menos representativa da população de pacientes com DC. Assim, naquele estudo, apenas 28% e 29% dos pacientes apresentavam, respectivamente, aumento do ICT e disfunção ventricular esquerda. Em contraste, em nosso estudo, 44% dos pacientes exibiam aumento do ICT. Ademais, no estudo de Perez et al.,9 o valor médio de FE do VE foi de 61%; enquanto, na presente investigação, esse parâmetro foi em média bem menor, de 51%. Em conjunto, tais aspectos configuram maior gravidade da CCDC em nossa amostra populacional estudada, incluindo o fato de apenas 8% de indivíduos estarem com a forma indeterminada da DC.Não são claros os possíveis motivos para a discrepância entre os resultados do presente estudo e aqueles relatados por Perez et al.9 é também plausível inferir que a discrepância de conclusões quanto ao valor da RXT seja mais aparente do que real. De fato, quando aqueles autores dividiram sua amostra em dois grupos, com ICT normal e anormal , seus resultados evidenciaram que o aumento de ICT associou-se significativamente  com queda da FE do VE, e com aumento da dimensão diastólica ventricular, bem como com a disfunção segmentar do VE, como avaliada por índice de mobilidade parietal ventricular esquerda.Ainda comparando os resultados da presente pesquisa com a relatada por Perez et al.,11 uma proposta de substituição desse critério por ecocardiograma em repouso dentro da normalidade já foi publicada em 2002.12É relevante ressaltar que os resultados da presente pesquisa indicam que a ausência da cardiomegalia ao RXT não descarta comprometimento cardíaco quando pacientes são avaliados por métodos capazes de prover mais detalhes anatômicos e funcionais como a ECO transtorácica em repouso. Portanto, embora específica, a RXT apresenta baixa sensibilidade para detectar acometimento cardíaco em pacientes com DC, e pode ser questionado seu uso como exame de rastreio e como critério para diagnóstico de forma indeterminada da DC. Nesse contexto, deve-se observar que, embora a forma indeterminada da DC continue a ser definida em consensos recentes com base no conceito de uma RXT evidenciando ICT normal,versusnão aumento, pode não ser apropriado à avaliação de pacientes com a CCDC devido ao típico envolvimento miocárdico segmentar nessa doença.1O escore de Rassi é universalmente entendido nos dias atuais como a ferramenta mais valiosa no estabelecimento do prognóstico vital de pacientes com a CCDC. Trata-se de escore robusto, desenvolvido por análise multivariada de vários fatores simples de risco de morte na CCDC e validado externamente em outras coortes independentes. Entretanto, deve-se observar que o estudo em questão abordou variáveis de maneira dicotomizada e não contínua, o que abre margem para complementações. Dentre as variáveis abordadas de maneira não contínua está o DDVE, mensurado padronizadamente com a ECO. Entretanto, o DDVE, quando avaliado em categorias dicotomizadas de aumento10 Além de possibilitar a confirmação (ou não) de cardiomegalia por RXT duvidosas, a ECO torna-se previsivelmente essencial para análise de uma cardiomiopatia em que alterações regionais da contratilidade ventricular são distúrbios precoces e proeminentes na história natural da doença de base.13 Ademais, a detecção dessas anormalidades regionais, em fases precoces da evolução da CCDC, passa a ter implicação prognóstica e terapêutica eventual, face aos resultados recentes de pesquisas evidenciando que um escore de mobilidade segmentar mesmo minimamente alterado – e ainda que a função ventricular sistólica global fosse preservada – é determinante para desfechos graves, incluindo mortalidade.13Os resultados do presente estudo estão alinhados com a ênfase na ECO como instrumento fundamental para o seguimento clínico do paciente com DC crônica, mormente quando já se configura o aparecimento da CCDC.5 coorte incluída para análise multivariada e elaboração do escore foi constituída de 424 indivíduos, com a maioria deles de baixo risco (61%), enquanto aqueles com risco moderado e alto representaram 19% e 20% da amostra, respectivamente. Já no presente estudo, obteve-se distribuição mais equilibrada entre os grupos de risco, com a proporção de indivíduos de risco baixo, intermediário e alto igual a 36%, 33% e 31%, respectivamente. De forma análoga, quando se substituiu o ICT pelo DDVE para composição do escore, registrou-se pequeno aumento da proporção de baixo risco (40%) às custas de discreta redução na de risco intermediário (28%). Dessa forma, torna-se imperativo conduzir estudos futuros (de seguimento clínico) para eventual validação de um escore de Rassi modificado pela substituição do ICT como parâmetro radiológico de dilatação cardíaca pelo mais específico parâmetro ecocardiográfico de dilatação do VE, para se determinar. o impacto prognóstico dessa modificação.No estudo seminal de Rassi et al.,O presente estudo tem algumas limitações. Os exames utilizados de maneira comparativa (RXT e ECO) não foram realizados no mesmo dia. Os outros exames e avaliações pertencentes ao escore de Rassi também diferem em data. De toda maneira, objetivou-se diminuir ao máximo fatores de confusão ou associados a alterações clínicas, de forma a destacar-se que, no período entre os exames, não houve alteração no quadro clínico dos pacientes ou medicamentosa nos tratamentos dos mesmos. Não houve mensuração das dimensões do átrio direito pela ECO, limitando assim a avaliação da dilatação dessa câmara cardíaca como fator de discordância entre a ECO e a RXT para definição de cardiomegalia. Os pacientes não foram avaliados de maneira longitudinal para análise prognóstica do DDVE pela ECO, mas estão em seguimento ambulatorial e, em ocasião propícia futura, serão reavaliados quanto a isso.O DDVE pela ECO é parâmetro adequado para distinguir entre presença e ausência de cardiomegalia na RXT, com alta especificidade em pacientes com DC crônica. A substituição do ICT radiológico pela DDVE ecocardiográfica na composição do escore de Rassi revelou-se possível e não alterou substancialmente os valores do escore assim obtidos. Dessa maneira, abre-se relevante perspectiva de evitar um teste que implique radiação e, com um único exame – ECO – obter mensuração de dois constituintes do escore de Rassi (dimensão cardíaca e função sistólica ventricular). O potencial papel prognóstico do escore assim modificado passa a ser alvo preferencial de estudos futuros. Trypanosoma cruzi(T.cruzi), which is mainly transmitted to humans by insects in the subfamily Triatominae. Other modes of transmission include blood transfusion, bone marrow or solid organ transplantation from infected donors, vertical transmission from mother to fetus and oral ingestion of contaminated food.1The World Health Organization estimates that CD affects approximately 7 million individuals in the world, causing high morbidity and mortality, and significant social impact.2Chagas disease (CD) is caused by infection with the protozoan parasite4The Rassi score is a validated score for mortality risk stratification of patients with chronic Chagas cardiomyopathy (CCC). Among the risk factors assessed by the score, cardiomegaly on chest X-ray stands out for its strong association with overall and cardiovascular mortality risk in patients with CCC.5Chagas cardiomyopathy is the most common and serious clinical form of CD, affecting 20-30% of chronically infected individuals.5although echocardiography was used to assess left ventricular end-diastolic diameter (LVEDD), this parameter was not shown to be an independent marker of mortality in CCC. However, in their study, LVEDD was analyzed in a categorical manner, using conventional cut-off points, which may not be the most appropriate for CCC patients, due to the segmental myocardial dysfunction, characteristic of this condition. Besides, calculation of the cardiothoracic ratio (CTR) by chest X-ray, in many cases, may encompass both atrial and ventricular dilatation, that are expressed linearly in this method. Despite widely available, the radiological study of the heart involves radiation, and echocardiography has become the most used method for cardiovascular evaluation. Therefore, there is a genuine interest in assessing left ventricular size and systolic function to estimate the risk of death using a single imaging test and the variables used in the original Rassi score.In the study by Rassi Jr. et al.,The present study aimed to evaluate the relationship between cardiomegaly defined by the CTR on chest X-ray and the LVEDD determined by echocardiography in patients with CD.T. cruzi, using different techniques.In this retrospective cross-sectional study, we studied patients of both sexes, adults (>18 years old), with diagnosis of CD, attending the outpatient clinic of the General Hospital of the University of Sao Paulo Medical School in Ribeirao Preto (HCRP-FMRP-USO), a tertiary referral hospital for CD. The diagnosis of CD was confirmed by two positive serological tests for detection of antibodies against6which describes in detail the inclusion and exclusion criteria applied. Patients with CTR and complete evaluation of the independent predictors of the Rassi score by resting 12-lead electrocardiogram, echocardiography, CTR and 24-hour heart rhythm monitoring, and of the degree of dyspnea according to the New York Heart Association (NYHA) criteria were included. The maximum interval between the CTR (considered the reference method for comparison) and the echocardiography was of one year, and patients were clinically stable in this period. Patients who had changes in the clinical status in this period between the two tests were excluded from the study.Data were obtained by a systematic review of medical records of 158 patients who had participated in a previous clinical study,Cardiomegaly on chest X-ray was always evaluated in an anteroposterior view and defined as a CTR > 0.5. Eventual enlargement of the right ventricle was also evaluated by comparison with profile teleradiography, when this technique was available.7Other echocardiographic parameters related to left ventricular remodeling were assessed, including the left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and the left atrial volume index (LAVI).Data of resting transthoracic echocardiography (the last before the chest X-ray) were used for analysis, considering the maximum interval of one year between the tests. The LVEDD was measured by the two-dimensional test, following recent echocardiography guidelines.Continuous variables with normal distribution were expressed as mean and standard deviation, and those without normal distribution were expressed as median and interquartile range (IQR). Analysis of the ROC (Receiver Operating Characteristic) was conducted to verify the ability of LVEDD, determined by echocardiography, to differ between presence and absence of cardiomegaly by the CTR. Finally, the impact of using cardiomegaly assessed by echocardiography, rather than the traditional CTR, on reclassification of patients with the cardiac form of CD by the Rassi score was evaluated. Individuals with the indeterminate form of CD were not classified by the Rassi score in the study, since patients with this form of the disease were not included in the original investigation of this instrument.The present study was approved by the research ethics committee  and conducted according to the Helsinki declaration and the Brazilian National Health Council resolution number 466/2012.Of the 158 patients with CD evaluated, 63 (40%) patients met the inclusion criteria and were included in this retrospective cross-sectional study. Demographic and clinical characteristics of participants are described inCardiomegaly, assessed using the CTR, was detected in 28 (44%) patient. The mean interval between chest X-ray and echocardiography was 5 ± 174 days. LVEDD on chest X-ray was larger in the group of patients with cardiomegaly (61 IQR [53-70]) than in patients without cardiomegaly (49 IQR [46-55]), p < 0.001. The area under the ROC curve for LVEDD for detection of cardiomegaly on chest X-ray was 0.806  . A LVEDPatients with discordant test results regarding the detection of cardiomegaly did not show statistically significant differences in age, sex, LVMI, and LAVI compared with those patients with concordant test results.In our study, the proportion of individuals at low, moderate and high risk by the Rassi score, using the CTR for detection of cardiomegaly was 36% (n = 21), 33% (n = 19) and 31% (n = 18), respectively. These proportions were 40% (n = 23), 28% (n = 16) and 32% (n = 19), respectively when cardiomegaly was detected by echocardiography using the most accurate cut-off point . In 44 The present study demonstrated that there is a clear and significative relationship between detection of cardiomegaly by CTR and detection of left ventricular dilatation by echocardiography in a non-selected group of outpatients with diagnosis of CCC. These results open new perspectives to the use of LVEDD determined by resting transthoracic echocardiography in substitution for the estimation of CTR by chest X-ray, to determine the risk of death in patients with CCC using the Rassi score, whose results were eventually modified. This would prevent the use of radiological test, which requires radiation, despite low, and allow determining both left ventricular size and left ventricular systolic function by a single, non-invasive test that does not involve radiation. This perspective seems attractive, since the LVEDD determined by echocardiography was shown to be a highly specific parameter to distinguish between the presence and absence of cardiomegaly in patients with chronic CD.8in 1983, of chest X-ray and echocardiographic results of a smaller sample (n=22), showing a good correlation between CTR values and left ventricular function.8On the other hand, in a study published in 2003, Perez et al.,9conducted a comparative analysis between posteroanterior chest X-ray and resting echocardiographic results, and showed a poor correlation between the tests for LVEDD and LVEF results. Also, in this study,9CTR did not show high sensitivity or positive predictive value in detecting left ventricular dysfunction. Therefore, despite its high specificity in detecting left ventricular systolic dysfunction, a CTR > 0.5 would not be useful in assessing this condition in CD, due to its low sensitivity in detecting, on resting transthoracic echocardiography, left ventricular dilatation or left ventricular systolic dysfunction by altered LVEF.Our findings corroborate previous observations reported by Pereira-Barreto et al.9and in our study, although the population sample consisted of outpatients with CCC attending university hospital, there were differences between them. In our study, there were almost no exclusion criteria, except for those related to the availability of CTR and echocardiographic results within a one-year period. In contrast, the broad exclusion criteria used in consecutive patients in the study by Perez et al.9may have resulted in a highly selected sample that may not be representative of CD patients. Thus, in their study,9only 28% and 29% of patients had increased CTR and left ventricular dysfunction, respectively, and the mean LVEF was 61% (vs. 51% in our study). These aspects indicate that our population with CCC were more severely ill, especially considering that only 8% of them had the indeterminate form of CD. In addition, it is plausible that differences in the chest X-ray results regarding CTR values between the two studies are more apparent than real. In fact, in the study by Perez et al.,9patients were divided into two groups by CTR values , and results showed a significant association (p<0.05) of LVEF reduction with increase in ventricular diastolic dimension and left ventricular segmental dysfunction, as evidenced by the left ventricular wall motion index.The reasons of the discrepancies between these studies are not clear. In the study by Perez et al.11substitution of this criterion with normal resting echocardiogram was already proposed in 2002.12It is worth pointing out that the results of the present study indicate that the absence of cardiomegaly on chest X-ray does not discard cardiac involvement when patients are assessed by methods able to provide better anatomic and functional details, comparable with resting transthoracic echocardiography. Thus, despite specific, chest X-ray has low sensitivity in detecting cardiac involvement in CD patients, and its use as screening method or diagnostic criterion for the indeterminate form of CD may be questionable. In this context, although the indeterminate form of CD is still defined in current guidelines based on a normal CTR on chest X-ray,9variables were analyzed in a dichotomous rather than continuous manner, which gives room for complementation. Among the variables analyzed in a non-continuous manner, there was the LVEDD, conventionally measured by echocardiography. However, when LVEDD was assessed in dichotomized categories,i.e., presence or absence of increase, may be not appropriate for the evaluation of patients with CCC due to the typical segmental myocardial abnormality of the disease.1The Rassi score is universally regarded as the most valuable instrument for the establishment of the vital prognosis of patients with CCC. This is a robust score, developed by a multivariate analysis of many risk factors of death in CCC, externally validated in other independent cohorts. However, in the study by Perez et al.,10Echocardiography allows not only confirmation (or not) of cardiomegaly in case of questionable findings on chest X-ray, but also analysis of cardiomyopathy marked by regional changes of ventricular contractility that result from early and prominent disturbances in the natural course of the underlying disease.13Also, detection of these regional abnormalities at early stages of CCC has prognostic and therapeutic implications, in light of recent reports showing that even minimal changes in the left ventricular segmental wall motion index when left ventricular systolic function is preserved are determinant of severe outcomes including mortality.13Results of the present study are in line with the importance of echocardiography as an essential instrument for the follow-up of patients with chronic CD, especially of those with early myocardial deficits of CCC.5the cohort included in the multivariate analysis and development of the score consisted of 424 patients, most of them at low risk (61%), while 19% and 20% of the patients were at moderate and high risk, respectively. In the present study, we found a more balanced distribution of patients into the risk groups – 36%, 33% and 31% at low, intermediate, and high risk, respectively. Similarly, when LVEDD is substituted for CTR in the score, there was a small increase in the proportion of patients at low risk (40%) at the expense of a slight reduction in the percentage of patients at intermediate risk (28%). Therefore, further studies with clinical follow-up are warranted for validation of the Rassi score modified by substitution of the CTR as the radiological parameter of cardiac dilatation with the more specific echocardiographic parameter of left ventricular dilatation, and determination of the prognosis impact of such modification.In the seminal study by Rassi Jr. et al.,The present study has some limitations. The tests compared (chest X-ray and echocardiography) were not conducted on the same day, similar to the other tests included in the Rassi score, which were performed on different days. In any case, efforts were made to minimize confounding factors and factors associated with clinical changes, to assure that no change in clinical status or in drug therapy of patients occurred in the interval between the tests. Right atrial dimensions were not measured, thereby limiting the assessment of dilation of this chamber as a discordant factor between echocardiography and chest X-ray. Finally, although patients were not followed longitudinally for the prognostic assessment of LEVDD by echocardiography, they have been followed-up at an outpatient clinic and will be reassessed for this parameter in the future.LVEDD measured by echocardiography is an appropriate parameter to distinguish between the presence and absence of cardiomegaly on chest X-ray, with high specificity in patients with chronic CD. Substitution of echocardiographic LVEDD for the radiological CTR in the Rassi score was shown to be feasible and did not cause substantial change in the scores obtained. These results open new perspectives to avoid the use of a test that involves radiation and, rather, use a single test (echocardiography) to measure two components of the Rassi score – cardiac dimension and ventricular systolic function. The potential prognostic role of this modified Rassi score is a worthy subject for future studies.


In patients with mechanical aortic and mitral valves and left ventricular (LV) tachycardia (VT), catheter ablation is technically challenging due to the limited access to the LV. Promising new alternatives to radiofrequency ablation include pulsed-field electroporation, percutaneous or surgical sympathetic neuromodulation, and noninvasive stereotactic radioablation therapy (SBRT). We herein describe the effect of SBRT as a bailout therapy on the management of a challenging VT case in the presence of double left-sided mechanical valves. Several operators have reported on the application of non-conventional techniques for VT ablation, including transventricular septal puncture, transmechanical valve, transcoronary venous, and transapical approaches.. Due to his previous double valve surgery, we planned and performed an epicardial VT ablation via a lateral thoracotomy . Electroanatomic mappings  showed scar regions containing local abnormal ventricular activities (LAVAs) in the inferolateral wall of the LV . Despite epicardial LAVA ablation, after five months, recurrent VT episodes with similar exit sites from previously delineated scar regions recurred under amiodarone, mexiletine, and sotalol therapies. We also transiently switched off the CRT device to exclude the possible lead-related VT, as there are some controversial data concerning the proarrhythmic or antiarrhythmic potential of CRT therapy.10 As all available cardiologic therapeutic strategies failed to free the patient from VT recurrence, we decided to implement SBRT as a therapy of last resort after discussions in our group and with the patient and his relatives. In the next step, positron-emission tomography-computed tomography (PET-CT) showed hypometabolic scar areas in the inferolateral walls corresponding with previous electroanatomic maps . A four-dimensional (4D) CT scan  with 10 respiratory phases was performed for radiotherapy planning using an alpha cradle and a chest board for immobilization after an eight-hour fast. After transferring the CT images to the radiotherapy planning system , an average-phase CT (avgCT) was created to evaluate cardiac and respiratory movements. After the fusion of PET-CT and avgCT images using the RT planning software  , an inferolateral hypometabolic scar region with the guidance of electroanatomic mapping was created as the internal gross target volume (IGTV). To overcome any uncertainties during positioning, motion, and therapy, a 5-mm safety margin was added to the IGTV for obtaining the final planned target volume (PTV) . Before treatment delivery, re-imaging with cone-beam CT was performed for comparison and alignment of images with simulation images. All treatment procedures were handled by a team of electrophysiologists, radiation oncologists, nuclear medicine specialists, and radiation physicists. Radiotherapy was given using a linear accelerator device . A total dose of 25 Gy was delivered in a single fraction to the PTV in 7.5 minutes to be targeted by at least 95% of the given dose. Despite rare hemodynamically stable slow VT episodes responding to antitachycardia pacing, a significant reduction in VT episodes was observed within the first eight months after radioablation therapy . No abnormal device parameters nor acute or chronic adverse effects were detected at 10 months. At present, the patient is being followed up with at the outpatient clinic.A 58-year-old man with two mechanical valves in mitral and aortic positions was referred after multiple appropriate implantable cardioverter-defibrillator shocks despite oral amiodarone and mexiletine therapies. He had nonischemic, valvular, dilated cardiomyopathy with an LV ejection fraction of 15% and had undergone implantation of a cardiac resynchronization therapy (CRT) device 10 years prior. His documented monomorphic VT suggested a lateral mid-LV exit 13 potentially keeping ventricular arrhythmias quiescent while awaiting heart transplantation,14 as was done in the current case. Because of its high precision and target conformity, it can deliver a high dose of radiation to a specific area in tissue without significantly affecting the nearby tissues.18 Indeed, the radiobiology of this treatment when applied to noncancer myocytes is limited, but endothelial vacuolization is a well-described effect of radiation.19 There have been studies that have investigated single-fraction whole-heart irradiation in animal models, and these demonstrated dose-dependent myocardial degeneration and fibrosis progressing from the epicardial tissue to full transmurality in the months after irradiation at doses of 20 Gy and higher.21 Histopathologic findings in the human myocardium after SBRT for recalcitrant VT have also provided radiobiological mechanisms of acute cellular injury during SBRT for VT, which may have an antiarrhythmic effect before the onset of fibrosis.22 These data suggest that SBRT can also be used as a relatively acute antiarrhythmic palliation in patients with electrical storm.21 Nonetheless, the optimal dose regimen has yet to be elucidated, and the long-term efficacy and toxicity of SBRT remain unsettled. Before more data on efficacy and safety are obtained, it could be offered as a “bailout” procedure after failed endo- and/or epicardial catheter ablation.23 The current case suggested that the noninvasive SBRT was applicable as a potential salvage treatment option for patients with double mechanical valves with dosage at 25 Gy providing the safest short-term profile. A recent systematic literature review summarized that VT was targeted with reduction in the number of episodes beyond 85% during follow-up, with an encouraging short-term safety profile.24 Nevertheless, the same analysis revealed significant heterogeneity in the available study designs, limiting the clinical evidence on the efficacy and safety of SBRT.24 Moving forward, randomized clinical trials will be essential to establish the safety, efficacy, and comparative effectiveness of this new and promising modality.23The growing burden of ventricular arrhythmias and their significant morbidity and mortality rates demand new effective therapeutic approaches based on a given patient’s triggers, comorbidities, and underlying pathology. Mechanical prosthetic aortic and mitral valves impede either a retrograde aortic or transseptal approach to the LV endocardium. SBRT, delivered in a single dose of 25 Gy, may serve as an alternative or palliative therapy for otherwise untreatable patients with refractory VT and electrical storm who are otherwise ineligible for catheter ablation,